(12) STANDARD PATENT (11) Application No. AU 2013206218 B2 (19) AUSTRALIAN PATENT OFFICE

Home , Alminoprofen, Fenbufen, Pranoprofen, Zaltoprofen

(54) Title Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin penetration rate

(51) International Patent Classification(s) C07D 209/12 (2006.01) C07D 263/57 (2006.01) C07D 209/82 (2006.01) C07D 491/04 (2006.01)

(21) Application No: 2013206218 (22) Date of Filing: 2013.06.07

(43) Publication Date: 2013.06.27 (43) Publication Journal Date: 2013.06.27 (44) Accepted Journal Date: 2016.06.30

(62) Divisional of: 2006347391

(71) Applicant(s) Chongxi Yu;Techfields Biochem Co. Ltd

(72) Inventor(s) Xu, Lina;Yu, Chongxi

(74) Agent / Attorney Spruson & Ferguson, L 35 St Martins Tower 31 Market St, Sydney, NSW, 2000

(56) Related Art WO 2003/029187 SONG, N. et al, Journal of Ocean University of Qingdao, 2002, Vol. 32, No. 6, pages 911-913 EP 0289262 FR 2410641 POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLPROPIONIC ACIDS WITH VERY FAST SKIN PENETRATION RATE

Abstract

A0W

Striuture 1 Sntradar 2 The novel positively charged pro-drugs of aryl- and heteroarylpropionic acids in the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2 methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, (for example acid halides or mixed anhydrides), by reaction with suitable alcohols, thiols, or amines. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin -100-130 times faster than do their parent drugs. It takes 2-4 hours for naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the drug in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrugs enable naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5 methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, almino, profen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. Another great benefit of trans dermal administration of these pro-drugs is that administering medication, especially to children, will be much easier. Description POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF ARYL- AND HETEROARYLPROPIONIC ACIDS WITH VERY FAST SKIN PENETRATION RATE Technical Field [1] The present invention relates to the preparations of positively charged and water soluble pro-drugs of aryl- and heteroarylpropionic acids and related compounds and their medicinal use in treating any nonsteroidal anti-inflammatory drugs (NSAIAs)-treatable conditions in humans or animals. More specifically, the present invention is to overcome the side effects that are associated with the use of NSAIAs. These pro-drugs can be administered orally or transdermally. Background Art [2] There are 2-aryl- and heteroarylpropionic acids, 3-aryl- and heteroarylpropionic acids and cyclized aryl- and heteroarylpropionic acids. 2-(6-methoxy-2-naphthyl) propionic acid (naproxen), a-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen), a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen), 6-chloro-a-methyl-9H-carbazole-2-acetic acid (carprofen), a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetic acid (pranoprofen), 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetic acid (benoxaprofen), a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetic acid (alminoprofen), 5-benzoyl-a-methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methylbenzeneacetic acid (pirprofen), 2-(10, 11 -dihydro- 10-oxodibenzo(b,f)thiepin-2-yl)propionic acid (zaltoprofen), 2-(8-methyl- 10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionic acid (bermoprofen), 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionic acid (loxoprofen), 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetic acid (indoprofen), a,3-dichloro-4-cyclohexylbenzeneacetic acid (fenclorac), and related compounds are members of 2-aryl and heteroarylpropionic acid group of nonsteroidal anti inflammatory drugs. 4,5-Diphenyl-2-oxazole propionic acid (oxaprozin), 3-(4-biphenylylcarbonyl)propionic acid (fenbufen), 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionic acid (orpanoxin), and related compounds are members of 3-aryl and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs. 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac), 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylic acid (clidanac), and related compounds are members of cyclized aryl- and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs. They are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis and for the treatment of dysmenorrhea. They are also used for the treatment of acute gouty arthritis and ankylosing spondylitis. The may be used for the treatment of dementia (McGeer; Patrick L. et al. U.S. Pat. No. 5,192,753). [3] Unfortunately, a number of side effects are associated with the use of naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, most notably GI dis turbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) indicated that an additional problem associated with oral medications, is that the concentration levels which must be achieved in the bloodstream must be significant in order to effectively treat distal areas of pain or inflammation. These levels are often much higher than would be necessary if it were possible to accurately target the particular site of pain or injury. Fishman and many others (Van Engelen et al. U.S. Pat. No. 6,416,772; Macrides et al. U.S. Pat. No. 6,346,278; Kirby et al. U.S. Pat. No. 6,444,234, Roentsch, et al., U.S. Pat. No. 5,654,337, Park, et al., U.S. Pat. No. 6,190,690, Pearson et al. U.S. Pat. No. 6,528,040 and Botknecht et al. U.S. Pat. No. 5,885,597) have tried to develop a delivery system for transdermal application by formulation. It is very difficult, however, to deliver therapeutically effective plasma levels of these kind drugs into the host by formulation, due to the slow skin penetration rate. Susan Milosovich, et al. designed and prepared testosteronyl-4-dimethylaminobutyrate.HC1 (TSBH), which has a lipophilic portion and a tertiary amine groups that exists in the protonated form at physiological pH. They found that the prodrug (TSBH) diffuses through human skin -60 times faster than does the drug (TS) itself [Susan Milosovich, et al., J. Pharm. Sci., 82, 227(1993). Disclosure of Invention Technical Problem [4] Naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, have been used medicinally for many years. They are used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, for the treatment of dysmenorrhea. [5] Unfortunately, a number of side effects are associated with the use of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ul cerations, and gastritis. They are not soluble in aqueous solution and gastric juice. They stay in the GI tract for a long time and thus, may cause gastric mucosal cell damage. Technical Solution [6] This invention relates to the preparation of novel positively charged pro-drugs of aryl- and heteroarylpropionic acids and related compounds and their use medicinally. 2-(6-methoxy-2-naphthyl)propionic acid (naproxen), a methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen), a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen), 6-chloro-a-methyl-9H-carbazole-2-acetic acid (carprofen), a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetic acid (pranoprofen), 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetic acid (benoxaprofen), a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetic acid (alminoprofen), 5-benzoyl-a-methyl-2-thiopheneacetic acid (tiaprofenic acid), 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetic acid (pirprofen), 2-(10, 11 -dihydro- 10-oxodibenzo(b,f)thiepin-2-yl)propionic acid (zaltoprofen), 2-(8-methyl- 10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionic acid (bermoprofen), 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionic acid (loxoprofen), 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetic acid (indoprofen), a,3-dichloro-4-cyclohexylbenzeneacetic acid (fenclorac), and related compounds are member s of 2-aryl and heteroarylpropionic acid group of nonsteroidal anti inflammatory drugs. The pro-drugs of 2-aryl- and heteroarylpropionic acids have the general formula (1) "Structure 1",

R A R1

Aryl C H2 n \R3 0

Structure 1 In structure 1, R represents CH , OH, C1, F, or Br; R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R2 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R3 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents 0, S, NH, OCH2COO, OCH2COS, or OCH2CONH; K represents C1, Br-, F, I, AcO , citrate, or any negative ions; and n=O,1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ...... ; Aryl represents:

In which, X represents CH 30, Cl, F, CH 3S, CHF20

In which, Y represents CH30, F, CH3CO, In which, X represents F, Cl, H (CH 3)2N, CH 3, or CH 2=CH-CH 2; X represents Cl, F, CF 3, CH 3 SO,or CH 3S; R represents CH 3, C2H5 , C3H 7 H N

) 0" xj -""N x

In which, X represents Cl, Br, F, CH3 5

fwc X otpresents C'' BrAF C .:

\ \ N

In wh ch X eenis F, Dg

Swh)ch Xnreprechn CO Of sx

N- R

lawihXrpreCsents 0 1r S wYrepre sen~ts f~ ilA d C'O a Z represen\g CO ad C i :R re resnu C c a All R groups may include C, 1H, 0, &, or N atoms and may have single, double, and trebie bond%, Any CH, gqoups may be replaced with 0, S. cr NIR

[6a] In an embodiment of the present invention, there is provided a compound of Structure 1

R A R A I, / X ; R ArylC H2 n R3

Structure 1 5a wherein R is CH3, OH, Cl, F, or Br;

R1 is H, C- 12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R2 is H, C- 12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R3 is H; X is 0; A- is a negative ion; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Aryl is

wherein X, is CH30, Cl, F, CH3S, or CHF 20

I X3

X2 wherein wherein X3 is F, Cl, or H

Y is CH30, F, CH3CO, (CH 3)2N, CH3, or CH2=CH-CH2; X2 is Cl, F, CF 3, CH3SO, or CH3S; and R is 4 CH3, C2H5 , or C3H7

wi r N O

wherein X4 is Cl, Br, F, or CH3 5b

N5 CH2

\ H3C C __*_ H2

wherein X 5 is Cl, Br, F, or CH3

wherein X6 is Cl, F, or Br

x7 x8

_____ S / _

wherein X 7 is CO or O wherein X8 is Cl, Br, F, or CH 30 5c

wherein

X9 is 0 or S; Y, is CH 2 or CO; Z is CO or CH2; and R 5 is H, CH3 , or C2H5

544hapey-ealyrxaunrpni aid (mpmox in and eae compounds are members of 3-aryl and heteroarylpropionic acid group of nonsteroidal anti-inflammatory drugs. The pro-drugs of 3-aryl- and heteroarylpropionic acids have the general formula (2) 'Structure 2'. Y E A R1 z -xE/ N- R2

2H n R3 W 0

Structure 2 In structure 2, W represents H, OH, Cl, F, or Br; R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R2 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R3 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents 0, S, NH,

OCH2COO, OCH2COS, or OCH2CONH; A represents Cr, Br-, F, I, AcO , citrate, or any negative ions; and 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 ; and Z represents:

__0 0

In which, X represents Cl, F, or Br

All R, R1, R2, R3, and R groups may include C, H, 0, S, N atoms and may have single, double, and treble bonds. Any CH2 groups may be replaced with 0, S, or NH. [8] In the general formula (2) 'Structure 2', when W represents H, Y and Z together represent: 7

In which, X represents Cl, F, or Br

[8a] In another embodiment of the present invention, there is provided a compound of

Structure 2

A R1 Z X_ N-R2 n R3 W O

Structure 2 wherein W is H, OH, Cl, F, or Br;

R1 is H, Ci-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R 2 is H, Ci-12 alkyl, C2 -12 alkenyl, or C2-12 alkynyl; R3 is H; X is 0; A- is a negative ion; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Y is H and Z is

0X1 0

wherein Xi is Cl, F, or Br 7a

I >| |

-N

or W is H and Y and Z taken together are:

(Y) (Y)

N_ (Z)

wherein X 2 is Cl, F, or Br

The cyclid aryl- aind heteroaryiprpionc acid are fTuT.e They re 5-hbcntoyl-2,3-ihydro- Hpyrlinne I -carboylic acid (ketwrilac) 6-chiao-cyclhxy2,3-dihyd-1H-indenet4catbxylic acid (clidaac) and Lted compound. Drug absorption, whether from, the gasrointastinal tract or other sites, aquires the pasage of the drug in a molkcular forM acroSs the tAier nmbrane. The dg must first dissolve, and if the drug possesses the desirable biophanaceutical properties, it wil Pass from a mgion of high caeoemirafion wa vTqgion of low concentration acrms the membmne into the blood or iIge circulation. All biokgca membrmes contain Ipids as major constitments. The mblncules that play the dominant. rats in tmmbtant formation al havc phosphate-conainig highly poia head groups, and, in most caes, two highly hydriphobic hydroemban taih. Membra are bilayers wh the hy drophilke head groups facing outward into the aqueaus regions on eiter side. Very by drophilk drgs cannot pass the hydrophic tayer of mmbrane and very hydrophobic drugs will stay in tW hydrophrbic layer as pat of the menmrane due tn their $ini ilarities and ennot cter the cytosol on the inside efficiently. 7b

The goal of this invention is to avoid the ade effects of naproxen, suprofen, ar methy[(p-hhobenzoy-5-nmethoxy-2-methylindolc 3-acetic acid, flurbipofem cmpofen, pranoprofen benoxaprofen, afminoprofen, riaprofenic acid, pirprofen, atoprofen, bermoprofen, TopOfen, indoprofen. fenderac, Oxapronn, fenbufen, urpanoxin, ketorolac, Cfidanac, and related compounds by increasing the their soluhity in gastric juice and their penetration rate through the membrane and skin barrier which will make it administrable transdcmafly (topical application) These novel pro-dmgs have two structund features in common: they have a lipophilic portion and a primary, secondary, or tertiary amine group that exists in the prorated fornm (hydrophilic part) at physiological piT Such a hydrmphilic-ipophilic balance is required for efficient passage through the membrane barrier [Susan 'Miksovich, e0 a. I Pharm, Ski, 82. 227(1993)1.The positively charged amino groups largely increase the solubility of the drugs. The solubility of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH, naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac in water are >450 mg, >400 mg, >450 mg, > 450 mg, >350 mg, >450 mg, >400 mg, >450 mg, >400 mg, >450 mg, >350 mg, >400 mg, >350 mg, >400 mg, >350 mg, >400 mg, >400 mg, >350 mg, >450 mg, >350 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, <0.1 mg, and <0.1 mg/ml, In many instances, the lowest or rate-limiting step in the sequence is the dissolution of the drug. Naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds have a very low solubility in gastric juice. They stay in the GI tract for a long time and thus, may cause gastric mucosal cell damage. When these new pro-drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in the gastric juice immediately. The positive charge on the amino groups of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration of the outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low con centration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drug into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in GI tract, the pro-drugs will not cause gastric mucosal cell damage. The pH of the stomach is 1-3, so the negative charge on the phosphate head group of membrane is bonded with proton (W). The positive charges of prodrugs cannot bond to the negative charge on the phosphate head group of the gastric mucosa. These prodrugs will be free both of primary insult (direct acid damage) and secondary insult (prostaglandin inhibition) to the stomach. [11] The penetration rates of aryl- and heteroarylpropionic acids and their positively charged prodrugs and related compounds through human skin were measured in vitro by using modified Franz cells, which were isolated from human skin tissue (360-400 pm thick) of the anterior and posterior thigh areas. The receiving fluid consisted of 10 ml of 2% bovine serum albumin in normal saline and was stirred at 600 rpm. The cumulative amounts of these prodrugs and their parent drugs penetrating the skin versus time were determined by a specific high-performance liquid chromatography method. The results using a donor consisting of either a 30% solution of these prodrugs or a 30% suspension of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac in 2mL of pH 7.4 phosphate buffer (0.2M) are shown in Figure 1, Figure 2, Figure 3, or Figure 4. Apparent flux values of 3.5 mg, 3.0 mg, 4.0 mg, 3.5 mg, 4.0 mg, 3.8 mg, 4.0 mg, 3.5 mg, 4.2 mg, 3.5 mg, 3.7 mg, 4.1 mg, 3.4 mg, 4.2 mg, 3.8 mg, 4.0 mg, 3.6 mg, 4.1 mg, 3.8 mg, 4.0 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.04 mg, 0.03 mg, 0.03 mg, and 0.04 mg/cm2/h were calculated for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, di ethylaminoethyl a-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethy laminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a- methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH, naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, and clidanac diffuses through human skin. The results suggest that the pro-drug, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, or diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH diffuses through human skin -100-130 times faster than does naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac . The results suggest that the positive charge on the dialkyaminoethyl group has a very important role in the passage of the drug across the membrane and skin barrier. Other prodrugs of the general 'Structure 1' or general 'St ructure 2' have very high penetration rates and are very close to that of diethy laminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH. [12] The in vivo rates of penetration of aryl- and heteroarylpropionic acids and their positively charged prodrugs and related compounds through the skin of intact hairless mice were compared. The donor consisted of a 20% solution of these compounds in 1 mL of isopropanol applied to a 10 cm2 on the backs of the hairless mice. Plasma levels of naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac were determined by a specific high-performance liquid chromatography method. The results (Figure 5, Figure 6, Figure 7, Figure 8) show that the peak levels of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a-methyl-4-(2-thien ylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, diethylaminoethyl 6-ch loro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH were reached -50 minutes after application of the donor systems. It takes 2-4 hours for naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac to reach their peak plasma level when they are taken orally. The peak plasma levels were -0.01 mg/ml for naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac and -2 mg/ml for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, or diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (approximately 200 times difference). -2 mg/ml of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac in plasma is more than 20-100 times higher than plasma level for effective analgesia and effective anti-inflammatory activity. This is a very exciting result. It will be very easy and fast to deliver therapeutically effective plasma level of naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac into the host by admin istration of these prodrugs transdermally. These results suggest that the pro-drugs can be administered not only orally, but also transdermally for any kind of medical treatments. The in vivo rates of penetration of other Pro-drugs of the general 'Structure 1' or general 'Structure 2' are close to that of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH. [13] To check the gastroduodenal bleeding caused by these prodrugs, rats were orally administered with 50 mg/kg of diethylaminoethyl 2-(6-methoxy-2-naphthyl )propionate.AcOH, diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH, naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac per day for 21 days. We found an average of 1-4 mg of fecal blood per gram of feces in the naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac groups and none in diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylamninoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylamninoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylamninoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylamninoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylamninoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylamninoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylamninoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylamninoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylamninoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH groups. [14] The acute toxicity of the prodrugs was investigated. The LD orally in mice are: 2.2 g/kg, 0.8 g/kg, 0.7g/kg , 0.75 g/kg, 1.3 g/kg, 3.5 g/kg, 1.1 g/kg, 0.6 g/kg, 0.2 g/kg for diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH. The results show that the prodrugs are less toxic than their parent drugs, naproxen (LD =1.234 g/kg), suprofen (LD=0.59 g/kg), carprofen (400 mg/kg), pranoprofen (447 mg/kg), benoxaprofen (LD =0.8 g/kg), alminoprofen (LD =2400 mg/kg), indoprofen (LD =0.7 mg/kg), fenclorac (LD =0.43 g/kg), clidanac (LD,=0.035 g/kg). [15] Naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac have demonstrated anti-inflammatory, analgesic, antipyretic, and antirheumatic activity. A good prodrug should go back to the parent drug in plasma. Diethylaminoethyl ester group of these prodrugs can be rapidly cleaved by the enzymes in human plasma in vitro and more than 90% of the pro-drugs are changed back to their parent drugs. Due to the pro-drugs having a much better absorption rate, the prodrugs will have more strength than their parent drugs at the same dosage. The analgetic, antipyretic, and anti-inflammatory activities of these prodrugs were tested using naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac as a comparison. [16] Analgetic activity: The prolongation time of the pain threshold of a mouse tail was determined in accordance with the D'Amour-Smith Method (J. Pharmacol. Exp. Ther., 72, 74(1941)). After 50mg/kg of these prodrugs were administered transdermally, the tails of mice were exposed to heat and the prolongation time of pain threshold was determined. The results obtained are shown in Figure 9, Figure 10, Figure 11, and Figure 12. Diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethy laminoethyl a-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH have shown analgesic activity nicely. [17] The number of writhings that occurred when mice were administered an acetic acid solution intraperitoneally were counted, and the rate of inhibition based on the control group was calculated. diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), di ethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), di ethylaminoethyl a-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethy laminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benze neacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethy laminoethyl 2-(8-methyl-10, 11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethy laminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH (100 mg/kg, 0), diethylaminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), di ethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethy laminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally the mice 30 minutes before the acetic acid solution was administered. The A group is the control group. The results are shown in Table 1. Table 1. The rate of writhings inhibition by prodrugs of aryl- and het eroarylpropionic acids [18]

Group Dose (mg/kg) No. of Writhings % 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 0 100 13.2 62 P 100 15.2 57

Q 100 15.7 55 R 100 14.2 59 S 100 15.6 55 T 100 16.1 54 U 100 15.2 57

The results show that the prodrugs demonstrate exceptional analgetic activity. Other compounds of the general 'Structure 1' or general 'Structure 2' show similar analgetic activity. [19] Antipyretic activity: Rats received a sterilized E. coli suspension as a pyrogen. The control group is group A. 2 hours later, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl a- methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), di ethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), di ethylaminoethyl a-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethy laminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benze neacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethy laminoethyl 2-(8-methyl-10, 11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethy laminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH (100 mg/kg, 0), diethylaminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), di ethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethy laminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. The body temperature of rats was taken at 90 min. intervals before and after the administration of the test compounds. The results are shown in Table 2. Table 2. Antipyretic Activity of prodrugs of aryl- and heteroarylpropionic acids. [20]

Compound t=0 min. t=90 min. t=180 min. t=270 min. A (Control 37.34±0.05 37.36±0.07 37.37±0.05 37.44±0.08 group) E (100mg/kg) 37.33±0.07 36.80±0.06 36.72±0.05 36.50±0.08 F (100mg/kg) 37.28±0.06 36.65±0.06 36.58±0.08 36.45±0.07 B (100mg/kg) 37.35±0.06 36.71±0.05 36.60±0.08 36.59±0.07 M (100mg/kg) 37.29±0.07 36.82±0.06 36.70±0.05 36.67±0.08 C (100mg/kg) 37.28±0.06 36.68±0.05 36.62±0.08 36.58±0.07 D (100mg/kg) 37.27±0.06 36.76±0.05 36.65±0.08 36.49±0.07 E (100mg/kg) 37.25±0.07 36.82±0.06 36.70±0.05 36.50±0.08 F (100mg/kg) 37.23±0.06 36.69±0.06 36.52±0.08 36.40±0.07 J (100mg/kg) 37.26±0.06 36.65±0.06 36.58±0.08 36.36±0.07 G (100mg/kg) 37.27±0.06 36.68±0.05 36.62±0.08 36.58±0.07 H (100mg/kg) 37.25±0.06 36.71±0.05 36.65±0.08 36.64±0.07 I (100mg/kg) 37.26±0.07 36.80±0.06 36.70±0.05 36.57±0.08 H (100mg/kg) 37.25±0.06 36.71±0.05 36.65±0.08 36.64±0.07 J (100mg/kg) 37.28±0.06 36.65±0.06 36.58±0.08 36.56±0.07 K (100mg/kg) 37.25±0.06 36.75±0.05 36.62±0.08 36.58±0.07 M (100mg/kg) 37.24±0.07 36.82±0.06 36.70±0.05 36.67±0.08 L (100mg/kg) 37.23±0.06 36.81±0.05 36.65±0.08 36.61±0.07 M (100mg/kg) 37.29±0.07 36.82±0.06 36.60±0.05 36.67±0.08 J (100mg/kg) 37.22±0.06 36.65±0.06 36.58±0.08 36.51±0.07

The results shown that the prodrugs demonstrated strong antipyretic activity at 100 mg/kg dose. Other compounds of the general 'Structure 1' and general 'Structure 2' show similar antipyretic activity. [21] Anti-inflammatory activity: diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), di ethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F), di ethylaminoethyl a-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethy laminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benze neacetate.AcOH (100 mg/kg, K), diethylaminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethy laminoethyl 2-(8-methyl-10, 11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethy laminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH (100 mg/kg, 0), diethylaminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P), diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), di ethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethy laminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. Group A is the controlled group. 60 minutes later, a carrageenin solution was administered subcutaneously to the foot pads of the rats. The volume of the hind paw was measured at every hour after the administration of the carrageenin, and the rate of increase in the volume of the paw was calculated and designated as the rate of swelling (%). The results obtained are shown in Figure 13, Figure 14, Figure 15, and Figure 16. The results show that these prodrugs by transdermal administration demonstrated good anti-inflammatory activity. Other compounds of the general 'Structure 1' or general 'Structure 2' show similar anti inflammatory activity. [22] It is also known that a high oral dose of some of NSAIAs shows an anti reactive-antiasthmatic activity by inhibition of the cyclooxygenase activity. Due to their very high membrane penetration rate, these prodrugs can be used in treating asthma by spraying into the mouth or nose of the host. [23] These prodrugs can also be used to treat psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties and very high skin penetration rate. [24] The present invention relates to pharmaceutical preparations comprising of prodrugs of the general 'Structure 1' or general 'Structure 2' in addition to customary auxiliaries and excipients, e.g. in the form of tablets, capsules or solutions for admin istration orally and in the form of solutions, lotion, ointment, emulsion or gel for transdermal administration. The new active compounds of the general 'Structure 1' or general 'Structure 2'can be combined with vitamins such as A, B, C or E or beta carotene, or other pharmaceuticals, such as folic acid, etc., for treating any NSAIAs treatable conditions in humans or animals. [25] Transdermal therapeutic application systems of compounds of the general' Structure 1' or general 'Structure 2' or a composition comprising of at least one compound of the general 'Structure 1' or general 'Structure 2' as an active ingredient, can be used for treating any NSAIAs-treatable conditions in humans or animals. These systems can be a bandage or a patch comprising of one active substance-containing matrix layer and an impermeable backing layer. The most preferable system is an active substance reservoir, which has a permeable bottom facing the skin. By controlling the rate of release, this system enables NSAIAs to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of NSAIAs. These systems can be worn on the wrist, ankle, arm, leg, or any part of body. [26] The compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from functional derivatives of aryl- and heteroarylpropionic acids, for example, acid halides or mixed anhydrides of the general formula (3) 'Structure 3' and general formula (4) 'Structure 4'. R y

Aryl

0 w o

Structure 4 Structure 3 In structure 3 & 4, X represents halogen, alkoxycarbonyl or substituted aryloxy carbonyloxy, Aryl, R, Y, Z, or W represent same groups as that are listed in 'structure 1' or 'structure 2', by reaction with compounds of the general formula (5) 'Structure 5',

R3 H-X

H2 n R4

Structure 5 In structure 5, R3 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X represents 0, S or NH; and n=O, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10...... [27] The compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, by reaction with compounds of the general formula (5) 'Structure 5' by using coupling reagents, such as N,N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, 0 (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 0 (Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol 1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. [28] When X represents 0, the compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from metal salts or organic base salts of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds, by reaction with compounds of the general formula (6) 'Structure 6'.

A R2

N--R 3 H 2Hn \R4

Structure 6 In structure 6, R2 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R3 represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl, or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; Z represents halogen, or p-toluenesulphonyl, A represents Cr, Br-, F, F, AcO, citrate, or any negative ions; and n=O,1,2,3,4,5..... [29] When X represents 0, the compounds of the general formula (1) 'Structure 1' or general formula (2) 'Structure 2' indicated above can be prepared from immobilized base salts of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds of the general formula (7) 'Structure 7', R

0 HB ' P Aryl

Structure 7

In structure 7, P represents cross-linked resin; Aryl represents aryl- and heteroaryl groups that are listed in 'structure 1' and 'structure 2', B represents any base groups, such as pyridine, piperidine, triethylamine, or other base groups, by reaction with compounds of the general formula (6) 'Structure 6'. Advantageous Effects [30] These pro-drugs of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds have a lipophilic portion and a hydrophilic portion (the amine groups that exist in the protonated form at physiological pH). The positively charged amino groups of these pro-drugs have two major advantages. First, it largely increases the solubility of the drugs; when these new pro drugs are administered orally in a dosage form such as a tablet, capsule, solution, or suspension, they will dissolve in gastric juice immediately. Second, the positive charge on the amino group of these pro-drugs will bond to the negative charge on the phosphate head group of membrane. Thus, the local concentration outside of the membrane will be very high and will facilitate the passage of these pro-drugs from a region of high concentration to a region of low concentration. When these pro-drugs enter the membrane, the hydrophilic part will push the pro-drugs into the cytosol, a semi-liquid concentrated aqueous solution or suspension. Due to the short stay in the GI tract, the pro-drugs will not cause gastric mucosal cell damage. Experiment results show that more than 90% of the pro-drugs were changed back to the drugs itself. The pro-drugs have a much better absorption rate, and thus the pro-drugs will have better strength than naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds at the same dosage. The experiment results suggest that the pro-drugs, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH, diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH, diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH, diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH, diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH, diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH, diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH, diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH, diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH, diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH, diethy laminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH, di ethylaminoethyl 2-(8-methyl-10, 11 -dihydro- 11 -oxodibenz(b,f)oxepin-2-yl)propionate.AcOH, diethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH, diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH, diethy laminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH, diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH, diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH, diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH, or diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH diffuses through human skin -100-130 times faster than does naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac, and related compounds. It takes 2-4 hours for naproxen, suprofen, a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about 40-50 minutes to reach the peak plasma level. The most exciting result is that the pro drugs can be administered not only orally, but also transdermally for any type of medical treatment and should avoid most of the side effects of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac, and related compounds, most notably GI dis turbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, and renal toxicity. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier. Description of Drawings [31] Figure 1: Cumulative amounts of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (A, 30% solution), diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B, 30% solution), diethy laminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (C, 30% solution), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D, 30% solution), diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (E, 30% solution), naproxen (F, 30% suspension), suprofen (G, 30% suspension), a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (H, 30% suspension), flurbiprofen (I, 30% suspension), or carprofen (J, 30% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M). [32] Figure 2: Cumulative amounts of diethylaminoethyl a-methyl-5H-[1] benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A, 30% solution), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (B, 30% solution), diethy laminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (C, 30% solution), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (D, 30% solution), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benze neacetate.AcOH (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) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M). [33] Figure 3: Cumulative amounts of diethylaminoethyl 2-(10, 1 1-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A, 30% solution), di ethylaminoethyl 2-(8-methyl-10, 1 1-dihydro-1 1-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B, 30% solution), diethy laminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (C, 30% solution), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH (D, 30% solution), diethylaminoethyla,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (E, 30% solution), zaltoprofen (F, 30% suspension), bermoprofen (G, 30% suspension), loxoprofen (H, 30% suspension), indoprofen (I, 30% suspension), or fenclorac (J, 30% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M). [34] Figure 4: Cumulative amounts of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (A, 30% solution), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (B, 30% solution), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (C, 30% solution), diethy laminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (D, 30% solution), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (E, 30% solution), oxaprozin (F, 30% suspension), fenbufen (G, 30% suspension), orpanoxin (H, 30% suspension), ketorolac (I, 30% suspension), or clidanac (J, 30% suspension) crossing isolated human skin tissue in Franz cells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2 M). [35] Figure 5: Total plasma levels of naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen after topical application of 1 ml of a 20% solution of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (A), diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (B), diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (C), diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (D), diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (E), naproxen (F) , suprofen (G), a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid (H), flurbiprofen (I), or carprofen (J) in isopropanol to the backs of hairless mice (n=5). [36] Figure 6: Total plasma levels of pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, or pirprofen after topical application of diethylaminoethyl a methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (A), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (B), diethylaminoethyl a methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (C), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (D), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH (E), pranoprofen (F), benoxaprofen (G), alminoprofen (H), tiaprofenic acid (I), or pirprofen (J) 1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5). [37] Figure 7: Total plasma levels of zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac after topical application of diethylaminoethyl 2-(10, 11 -dihydro- 10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (A), diethylaminoethyl 2-(8-methyl-10, 11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (B), di ethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (C), diethy laminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH (D), diethylaminoethyla,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (E), zaltoprofen (F), bermoprofen (G), loxoprofen (H), indoprofen (I), fenclorac (J) 1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5). [38] Figure 8: Total plasma levels of oxaprozin, fenbufen, orpanoxin, ketorolac, and clidanac after topical application of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (A), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (B), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (C), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (D), di ethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (E), oxaprozin (F), fenbufen (G), orpanoxin (H), ketorolac (I), or clidanac (J)1 ml of a 20% solution of in isopropanol to the backs of hairless mice (n=5). [39] Figure 9: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (B), diethylaminoethyl a-methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (C), diethylaminoethyl a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (D), diethy laminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (E), diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (F) were administered transdermally. Group A is the control group. [40] Figure 10: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl a-methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate.AcOH (G), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (H), diethylaminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (I), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (J), diethy laminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benzeneacetate.AcOH (K) were administered transdermally. Group A is the control group. [41] Figure 11: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 2-(10, 11 -dihydro- 10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (L), diethylaminoethyl 2-(8-methyl-10, 11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (M), di ethylaminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (N), diethy laminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenzeneacetate.AcOH (0), diethylaminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (P), were ad ministered transdermally. Group A is the control group. [42] Figure 12: The prolongation time of the pain threshold of mice tails after 50mg/kg of diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (S), diethylaminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (U) were ad ministered transdermally. Group A is the control group. [43] Figure 13. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH (100 mg/kg, B), diethylaminoethyl a methyl-4-(2-thienylcarbonyl)benzeneacetate.AcOH (100 mg/kg, C), diethylaminoethyl a-methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetate.AcOH (100 mg/kg, D), diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH (100 mg/kg, E), di ethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH (100 mg/kg, F) were administered transdermally. A group is the control group. [44] Figure 14. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl a-methyl-5H-[1]benzopyrano[2,3-b] pyridine 7-acetate.AcOH (100 mg/kg, G), diethylaminoethyl 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetate.AcOH (100 mg/kg, H), diethy laminoethyl a-methyl-4-[(2-methyl-2-propenyl)amino]benzeneacetate.AcOH (100 mg/ kg, I), diethylaminoethyl 5-benzoyl-a-methyl-2-thiopheneacetate.AcOH (100 mg/kg, J), diethylaminoethyl 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-a-methyl benze neacetate.AcOH (100 mg/kg, K) were administered transdermally. Group A is the control group. [45] Figure 15. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 2-(10, 11-dihydro-10-oxodibenzo(b,f)thiepin-2-yl)propionate.AcOH (100 mg/kg, L), diethy laminoethyl 2-(8-methyl-10, 11-dihydro-11-oxodibenz(b,f)oxepin-2-yl)propionate.AcOH (100 mg/kg, M), diethy laminoethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.AcOH (100 mg/kg, N), diethylaminoethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-a-methylbenz eneacetate.AcOH (100 mg/kg, 0), diethylaminoethyl a,3-dichloro-4-cyclohexylbenzeneacetate.AcOH (100 mg/kg, P) were administered transdermally. Group A is the control group. [46] Figure 16. The rate of swelling (%) after a carrageenin injection. 1 Hour before the carrageenin injection, diethylaminoethyl 4,5-Diphenyl-2-oxazole propionate.AcOH (100 mg/kg, Q), diethylaminoethyl 3-(4-biphenylylcarbonyl)propionate.AcOH (100 mg/kg, R), diethylaminoethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.AcOH (100 mg/kg, S), diethy laminoethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.AcOH (100 mg/kg, T), diethylaminoethyl 6-chloro-5-cyclohexyl-2,3-dihydro-1H-indene-1-carboxylate.AcOH (100 mg/kg, U) were administered transdermally. Group A is the control group.

[47] Figure 17. In structure 1, R represents CH3, OH, Cl, F, or Br; R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R2 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X

represents 0, S, NH, OCH2COO, OCH2COS, or OCH2CONH; A represents Cl, Br-, F , I, AcO , citrate, or any negative ions; and n=0,1,2,3,4,5,6,7,8,9,10 ...... ; Aryl represents aryl- and heteroaryl groups [48] Figure 18. In structure 2, W represents H, OH, C1, F, or Br; R represents H, one of any alkyl, alkyloxyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R2 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; R3 represents H, one of any alkyl, alkyloxy, alkenyl or alkynyl residues having 1 to 12 carbon atoms, or aryl residues; X

represents 0, S, NH, OCH2COO, OCH2COS, or OCH2CONH; A represents Cl, Br-, F , 1, AcO , citrate, or any negative ions; and n=0,1,2,3,4,5,6,7,8,9,10 ...... ; Y or Y and Z together represent aryl- and heteroaryl groups. Best Mode Preparation of diethylaminoethyl 2-(6-methoxy-2-naphthyl)propionate.AcOH [49] 11.7 g (0.1 mol) of diethylaminoethanol was dissolved in 10% sodium bicarbonate (200 ml) and acetone (100 ml). 24.9 g (0.1 mol) of 2-(6-methoxy-2-naphthyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (89.9 %). Hygroscopic product; Solubility in water: 350 mg/ml; Elementary

analysis: C H 31NO ; MW: 389.49. Calculated % C: 67.84; H: 8.02; N: 3.60; 0: 20.54; Found % C: 67.82; H: 8.04; N: 3.58; 0: 20.56. 1H-NMR (400 MHz, D2O): 8: 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). Mode for Invention Preparation of diethylaminoethyl a-methyl-4-(2-thienylcarbonyl) benze neacetate.AcOH. [50] 28.1 g (0.1 mol) of a-methyl-4-(2-thienylcarbonyl) benzeneacetyl chloride was dissolved in 100 ml of chloroform. The mixture was cooled to 00 C. 15 ml of triethylamine and 11.7 g (0.1 mol) of diethylaminoethanol were added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is dissolved in methanol (300ml), 5% sodium bicarbonate (200 ml) is added into the reaction mixture. The mixture is stirred for 3 hr. The mixture is evaporated to dryness. Methanol (300 ml) is added into the residue with stirring. Solid is removed by filtration and washed with methanol. The solution is evaporated to dryness and the residue is dissolved in chloroform (200 ml). 6 g of acetic acid is added into the reaction mixture with stirring. Some solid is removed by filtration. Another 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (83.2%). Hygroscopic product;

Solubility in water: 400 mg/ml; Elementary analysis: C H 31NO 5S; MW: 419.53. Calculated % C: 62.68; H: 7.41; N: 3.32; 0: 18.98; S: 7.61; Found % C: 62.63; H: 7.45; N: 3.31; 0: 19.01; S: 7.60. 'H-NMR (400 MHz, D2O): 8: 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). Preparation of S-diethylaminoethyl 2-(2-fluoro-4-biphenylyl)propionate.AcOH [51] 13.2 g (0.1 mol) of diethylaminoethyl mercaptan was dissolved in 10% sodium bi carbonate (200 ml) and acetone (100 ml). 26.3 g (0.1 mol) of 2-(2-fluoro-4-biphenylyl) propionyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 36 g of the desired product (85.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary

analysis: C23H 30FNO 3S; MW: 419.55. Calculated % C: 65.84; H: 7.21; F: 4.53; N: 3.34; 0: 11.44; S: 7.64. Found % C: 65.80; H: 7.23; F: 4.55; N: 3.32, 0: 11.47; S: 7.63. 1H-NMR (400 MHz, D2O): 8: 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). Preparation of N-diethylaminoethyl 5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylamide.AcOH. [52] 11.6 g (0.1 mol) of diethylaminoethylamine was dissolved in 10% sodium bi carbonate (200 ml) and acetone (100 ml). 27.4 g (0.1 mol) of 5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylyl chloride was added into the reaction mixture. The mixture is stirred for 3 hours at RT. The solvents are evaporated off. The residue is suspended in ethyl acetate (500ml). 5% sodium bicarbonate (200 ml) is added into the reaction mixture with stirring. Ethyl acetate layer is collected and washed with water (3 x 500 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate. Sodium sulfate is removed by filtration. 6 g of acetic acid is added into the reaction mixture with stirring. The organic solution was evaporated off. After drying, it yielded 35 g of the desired product (84.8 %). Hygroscopic product; Solubility in water: 400 mg/ml;

Elementary analysis: C23H 31N 30 ; MW: 412.50. Calculated % C: 66.81; H: 7.56; N: 10.16; 0: 15.48; Found % C: 66.90; H: 7.38; N: 10.18; 0: 15.54. 1H-NMR (400 MHz,

D 20): 8: 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). Preparation of N-dimethylaminoethyl 4, 5-Diphenyl-2-oxazole pro pionamide.AcOH amide.AcOH [53] 29.3 g (0.1 mol) of 4, 5-Diphenyl-2-oxazole propionic acid was dissolved in 100 ml of acetonitrile. 32.1 g of 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetraflu oroborate and 30 ml of triethylamine were added into the reaction mixture. 11.6 g of diethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 40 g of the desired product (88.6%). Hygroscopic product;

Solubility in water: 400 mg/ml; Elementary analysis: C H 33N30 ; MW: 451.56. Calculated % C: 69.16; H: 7.37; N: 9.31; 0: 14.17; Found % C: 69.11; H: 7.40; N: 9.30; 0: 14.19. 'H-NMR (400 MHz, D2O): 8: 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). Preparation of diethylaminoethyl 6-chloro-a-methyl-9H-carbazole-2-acetate.AcOH. [54] 60 g of Polymer-bound triethylamine (3 mol/g, 100-200 mesh) was suspended in 180 ml of chloroform. 27.4 g (0.1 mol) of 6-chloro-a-methyl-9H-carbazole-2-acetic acid, was added into the mixture with stirring. 43 g (0.15mol) of diethylaminoethyl bromide.HBr was added into the mixture and the mixture was stirred for 5 hours at RT. The polymer was removed by filtration and washed with tetrahydrofuran (3 x 50 ml). 8.2 g (0.1 mol) of sodium acetate was added into the reaction mixture with stirring. The mixture was stirred for 2 h. The solid was removed by filtration and washed with chloroform (3 x 50 ml). The solution was concentrated in vacuo to 100 ml. Then 300 ml of hexane was added into the solution. The solid product was collected by filtration and washed with hexane (3 x 100 ml). After drying, it yielded 38 g of the desired product (87.8%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H ClN 0 ; MW: 432.94. Calculated % C: 63.81; H: 6.75; Cl: 8.19, N: 23 29 2 4 6.47; 0: 14.78; Found % C: 63.85; H: 6.78; Cl: 8.17; N: 6.44; 0: 14.76. 1H-NMR (400 MHz, D2O): 8: 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 [55] The pro-drugs of the general formula (1) 'Structure 1' and general formula (2) 'Structure 2' are superior to naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, or clidanac, and related compounds. They may be used medicinally in treating any naproxen, suprofen, a methyl-(p-chlorobenzoyl)-5-methoxy-2-methylindole 3-acetic acid, flurbiprofen, carprofen, pranoprofen, benoxaprofen, alminoprofen, tiaprofenic acid, pirprofen, zaltoprofen, bermoprofen, loxoprofen, indoprofen, fenclorac, oxaprozin, fenbufen, orpanoxin, ketorolac, clidanac, and related compounds-treatable conditions in humans or animals. They may be used for the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis, the reduction of fever, and the treatment of dysmenorrhea. They may be also prescribed for diabetic neuropathy and acute migraine headache. Due to their very high membrane penetration rate, these pro-drugs can be used in treating asthma by inhalation to a host. They can be used to treat psoriasis, acne, sunburn or other skin disorders due to their anti-inflammatory properties. Sequence List Text [56] 33 CLAIMS

1. A compound of Structure 1 R A A R2

Aryl ( N ly H2n R3 0

Structure 1 wherein

R is CH 3, OH, Cl, F, or Br;

R1 is H, C- 12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R2 is H, C- 12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R3 is H; X is 0; A- is a negative ion; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Aryl is

wherein Xi is CH30, Cl, F, CH3S, or CHF 20 34

X2 wherein wherein X3 is F, Cl, or H Y CH is 30, F, CH3CO, (CH 3)2N, CH3 , or CH2=CH-CH2; X2 is Cl, F, CF3, CH 3SO, or CH 3S; and R 4 is CH3, C2Hs, or C3H7

wherein X4 is Cl, Br, F, or CH3

wherein X is Cl, Br, F, or CH3

wi, OH 3C__ 35 0

wherein X 6 is Cl, F, or Br

x7 X8

wherein X 7 is CO or O wherein X8 is Cl, Br, F, or CH 30

wherein

X9 is 0 or S; Y, is CH 2 or CO; Z is CO or CH2; and R 5 is H, CH3 , or C2H5

2. The compound of claim 1, wherein n is 1, 2, 3, or 4.

3. The compound of claim I or 2, wherein at least one of R2 or R3 is CH 2CH 3.

4. The compound of any one of claims I to 3 selected from: 36

H3CO OH 3

2-(diethylamino)ethyl 2-(6-methoxy-2-naphthyl)propionate.HA;

s y OH 3

2-(diethylamino)ethyl a-methyl-4-(2-thienylcarbonyl)benzeneacetate.HA;

CHHA

N CH3OH 3

2-(diethylamuno)ethyl a-methy1-(p-chlorobenzoy1)-5 -methoxy-2-methylindole 3-acetate.HA;

OH3 37 2-(diethylamino)ethyl 2-(2-fluoro-4-biphenylyl)propionate. HA;

COH 3

H4A

NH O"" "' OH3

COH 3

2-(diethylamino)ethyl 2-(-chlorophn)--methyl- bnazole- acetate .HA;

CHHA

H 2 HA

H * O H3

OH3 CH

2-(diethylamino)ethyl a-methyl-- [I]-methoyl--ro[23en~yladin~en-7nacetate .HA; 38

OH3

2-(diethylamino)ethyl 5 -benzoyl-ax-methv 1-2-thiopheneacetate.HA;

CHHA

H3 c N

2-(diethy lamino)ethyl 3-chloro-4-(2,5 -dihv dro- 1H-pv rrol-1I-yl)-ax-methyl benzeneacetate.HA;

s OH 3

2-(diethylamino)ethyl 2-( 10, 11-dihydro-1I -oxodibenzo(b,f)thiepin-2-yl)propionate.HA;

H3C OHr

2-(diethylamino)ethyl 2-( 8-meth 1-10, Ii -dihv dro-I Ii-oxodibenzb,f~oxepin-2-y1)propionate.HA; 39

CH3 HA

0" N"' CH3

CH3

2-(diethylamino)ethyl 2-[4-(2-oxocyclopentyl-methyl)phenyl]propionate.HA;

CH3 HA

O NCH3

N CH3

2-(diethylamino)ethyl 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-ax-methylbenzeneacetate.HA; and

HA CI

CH3

2-(diethylamino)ethyl a,3-dichloro-4-cyclohexylbenzeneacetate.HA.

5. The compound of any one of claims I to 4, wherein A- is Cl-, Br-, F, F, AcO-, or citrate-.

6. A compound of Structure 2 40

A R1

N-R2

H R3 WO

Structure 2 wherein W is H, OH, Cl, F, or Br;

R1 is H, C- 12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R2 is H, C- 12 alkyl, C2-12 alkenyl, or C2-12 alkynyl;

R3 is H; X is 0; A- is a negative ion; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and Y is H and Z is

0_ 0

wherein X, is Cl, F, or Br

or W is H and Y and Z taken together are: 41

(Y)

N _(Z)

wherein X 2 is Cl, F, or Br

7. The compound of claim 6, wherein n is 1, 2, 3, or 4.

8. The compound of claim 6 or 7, wherein at least one of R2 or R3 is CH 2CH 3.

9. The compound of any one of claims 6 to 8 selected from:

CH 3

HA N CH3 CI0

2-(diethylamino)ethyl 5-(4-chlorophenyl)-beta-hydroxy-2-furanpropionate.HA;

CH 3

HA N C H3 0dit va i o eO

2-(diethylamino)ethyl 4,5-Diphenyl-2-oxazole propionate.HA; 42

CH3

HA| N CH 3

2-(diethylamino)ethyl 3-(4-biphenylylcarbonyl)propionate.HA;

COH3

HA CH3 0,,,,,, N ,, I N

2-(diethylamino)ethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.HA; and

CI CH3

HA | CH 3 ~N I

2-(diethylamino)ethyl 6-chloro-5-cyclohexyl-2,3-dihydro-iH-indene-1-carboxylate.HA.

10. The compound of any one of claims 6 to 9, wherein A- is C-, Br, F, F, AcO-, or citrate-.

11. A method of treating a NSAIAs-treatable condition in a human or animal comprising administering a compound of any one of claims I to 10 or a composition comprising a compound of any one of claims I to 10, wherein the compound or composition is administered orally or transdermally.

12 The method of claim 11, wherein the NSAIAs-treatable condition is pain from a toothache, a headache, arthritis and other inflammatory pain, fever, cancer, dysmenorrhea, radiation-induced vomiting, diabetic neuropathy, acute migraine headache, hemophilic arthropathy, bone loss, or sunburn. 43 13. The method of claim 11 or 12, wherein the compound or composition is administered transdermally to any part of body in the form of a solution, spray, lotion, ointment, emulsion or gel to achieve therapeutically effective plasma levels of the compound or composition.

14. Use of a compound of any one of claims I to 10 for the manufacture of a medicament for use in the treatment of a NSAIAs-treatable condition in a human or animal, wherein the medicament is administered orally or transdermally.

15. A method of treating pain in a human or animal in need thereof comprising administering a compound of any one of claims I to 10 or a composition comprising a compound of any one of claims 1 to 10, wherein the compound or composition is administered topically.

16. The method of claim 14, wherein the pain is headache, toothache, muscle pain, arthritis, and other inflammatory pain.

17. Use of a compound of any one of claims I to 10 for the manufacture of a medicament for the treatment of pain in a human or animal, wherein the medicament is administered topically.

18. A method of treating an eye inflammatory disease, ocular pain after comeal surgery, glaucoma, or ear inflammatory disease and/or painful conditions in a human or animal comprising administering a compound of any one of claims I to 10 or a composition comprising a compound of any one of claims 1 to 10.

19. Use of a compound of any one of claims I to 10 for the manufacture of a medicament for the treatment of an eye inflammatory disease, ocular pain after corneal surgery, glaucoma, or ear inflammatory disease and/or painful conditions in a human or animal.

20. A transdermal therapeutic application system comprising a compound of any one of claims I to 10 or a composition comprising a compound of any one of claims I to 10 for the treatment of a NSAIAs treatable condition in a human or animal.

21. The transdermal therapeutic application system of claim 20, wherein the system is in the form of a bandage or a patch comprising an active substance-containing matrix layer and an impermeable backing layer.

22. The transdermal therapeutic application system of claim 21, wherein the system has an active substance reservoir, which has a permeable bottom facing the skin. 44

Techfields Biochem Co. Ltd Chongxi Yu Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON 2013206218 07 Jun 2013 2013206218 07 Jun 2013 2013206218 07 Jun 2013 2013206218 07 Jun 2013 2013206218 07 Jun 2013 2013206218 07 Jun 2013 2013206218 07 Jun 2013 2013206218 07 Jun 2013