HK1137411B - Positively charged water-soluble prodrugs of prostaglandins and related compounds with very high skin penetration rates - Google Patents

Description

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

Technical Field

The present invention relates to positively charged water-soluble prodrugs of prostaglandins, prostacyclins, and related compounds and their use in treating any condition in which prostaglandins, prostacyclins, and related compounds may be treated in a human or animal. In particular, the present invention is directed to providing rapid skin penetration of prostaglandins, prostacyclins, and related compounds.

Background

Both natural prostaglandins and prostacyclins are eicosanoids, which are self-active substances derived from biological membrane phospholipids. They are present in almost any part of the body. The basic structure of prostaglandins is shown in formula 1.

Structural formula 1

All natural prostaglandins have a 15 α -hydroxy group and a C-13 trans double bond (William O. Foye, et al. principles of Medicinal Chemistry, four edition, Williams)&Wilkins, 1995, pg 538). The chain containing carboxyl groups is called the alpha-chain and the chain containing hydroxyl groups is called the omega-chain. Prostaglandins (PG) may be classified in capital letters as A, B, C, D, E, F, G, H, and I, depending on the nature of the oxygen substituents at the 9-and 11-positions and their steric configuration. The roles played by different prostaglandins vary. PGE₂When administered vaginally, it stimulates contractions in the endometrium of the pregnant uterus in a manner similar to the contractions observed during labor. Thus, PGE for treatment₂Such as dinoprostone (prostin E)₂Upjohn) can be used as an induced abortion drug. PGE₂Is also a highly effective gastrointestinal smooth muscle stimulant, can raise body temperature, and has highly effective vasodilatory properties in most ductal tissues, and also has the activity of a contractile agent in certain locations. PGF_2αHas many of the characteristics of prostaglandin E, and can also be used as artificial abortion medicine (Prostin F2 alpha, Upjohn). Artificially synthesized PGF_2αThe 15-methyl derivative, carboprost, is also used therapeutically as an induced abortion drug (Prostin 15/M, Upjohn). PGD₂Can cause the blood vessels to expand and contract. Although prostaglandin E relaxes bronchial and tracheal smooth muscle, prostaglandin F and prostaglandin D₂But may cause shrinkage. PGE₁For example, alprostadil can help newborns maintain the strength of arterial lines prior to surgery for repair of congenital heart defects. PGE₁And analogs thereof can be used to treat male erectile dysfunction (Yeager, James L. U.S. Pat. No. 6,693,135) and to increase female sexual arousal (Scott, Nathan Earl, U.S. Pat. No. 5,number 6,291,528). Analogs of prostaglandins are a very important class of glaucoma therapeutic drugs, which have proven safe and effective in controlling intraocular pressure. These prostaglandin analogs include bimatoprost { (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3S) -3-hydroxy-5-phenyl-1-pentenyl]Cyclopentyl group]-5-N-ethylheptenamide }, latanoprost (13, 14-dihydro-17-phenyl-18, 19, 20-trinuclear-PGF)_2αIsopropyl ester), travoprost { (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3R) -3 hydroxy-4- [ (α, α, α -trifluoro-m-tolyl) oxy]-1-butenyl radical]Cyclopentyl group]-5-heptrespectively acidic acid } and unoprostone (13, 14-dihydro-15-one-20-ethyl PGF_2α)。

However, prostaglandins, prostacyclins, and related compounds are metabolized very rapidly and can be inactivated via a variety of oxidative and reductive pathways. When prostaglandins are taken orally, first-pass metabolism, i.e., chemical degradation of the compound in the liver and gastrointestinal tract, causes them to be destroyed and inactivated within seconds. Prostaglandin administration is painful when injected and in many cases requires frequent and expensive visits to a physician for the treatment of chronic disease states, and most prostaglandins, prostacyclins and related compounds are destroyed and inactivated in the blood and liver before reaching the intended site of action.

An alternative method of administration is topical administration. Topical administration has several advantages. The method can avoid drug inactivation caused by first pass metabolism of liver and gastrointestinal tract. The method allows for local delivery of the drug to the site of action of interest and to achieve appropriate local concentrations without systemic drug exposure. Fishman (Fishman; Robert, U.S. Pat. No. 7,052,715) states that another problem associated with oral administration is that the concentration of the drug in the blood circulation must be high in order to effectively treat pain or inflammation at the distal site. These concentrations are often much higher than is actually necessary given the direct targeting of the drug to the site of pain or injury. Yeager et al have attempted to deliver PGE using penetration enhancers₁For the treatment of male erectile dysfunction (Yeager, James L. U.S. Pat. No. 6,693,135). SThe asan Milosovich et al designed and synthesized testosterone 4-dimethylaminobutyrate hydrochloride (TSBH) having a lipid soluble portion and a tertiary amine structure that exists in protonated form at physiological pH. They found that the pro-drug (TSBH) permeated human skin approximately 60 times faster than the parent drug per se (TS) [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993)]。

Disclosure of Invention

Technical problem

The effects of different Prostaglandins (PGs) are not the same. Prostaglandins (PGs) have a variety of medical uses. PGE₂And PGF_2αCan be used as medicine. Artificially synthesized PGF_2αThe 15-methyl derivative of (2), carboprost, can be used as artificial abortion medicine (Prostin 15/M, Upjohn). PGE₁Alprostadil can help infants maintain the strength of arterial ducts before congenital heart defect repair surgery is performed. PGE₁And analogs thereof can be used to treat male erectile dysfunction (Yeager, James l. U.S. patent No. 6,693,135) and to increase female sexual arousal (Scott, Nathan Earl, U.S. patent No. 6,291,528). Analogs of prostaglandins are a very important class of glaucoma therapeutic drugs, which have proven safe and effective in controlling intraocular pressure. These prostaglandins include bimatoprost { (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3S) -3-hydroxy-5-phenyl 1-pentenyl]Cyclopentyl group]-5-N-ethylheptenamide }, latanoprost (13, 14-dihydro-17-phenyl-18, 19, 20-trinuclear PGF_2αIsopropyl ester), travoprost { (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3R) -3 hydroxy-4- [ (α, α, α -trifluoro-m-tolyl) oxy]-1-butenyl radical]Cyclopentyl group]-5-heptrespectively acidic acid } and unoprostone (13, 14-dihydro-15-keto-20-ethyl prostaglandin F_2α)。

However, prostaglandins, prostacyclins, and related compounds are rapidly metabolized and can be inactivated via a variety of oxidative and reductive pathways. When prostaglandins are administered orally, the first pass metabolic effects, i.e. the chemical degradation of the drug by passage through the liver and gastrointestinal tract, can cause them to be destroyed and inactivated within a few seconds. Prostaglandin administration is painful when injected and in many cases requires frequent and expensive visits to a physician for the treatment of chronic disease states, and most prostaglandins, prostacyclins and related compounds are destroyed and inactivated in the blood and liver before reaching the intended site of action. Topical administration of prostaglandins directly to the eye for the treatment of glaucoma and ocular hypertension can cause blurred vision, inflammation or infection of the eye or eyelids, burning, stinging or discomfort due to their slow rate of penetration through the eye's membrane.

Solution scheme

The present invention relates to the synthesis of novel positively charged prodrugs of prostaglandins, prostacyclins, and related compounds and their pharmaceutical use. These prodrugs of prostaglandins, prostacyclins, and related compounds have the general formula (2) 'Structure 2'.

Structural formula 2

Wherein R is₁Represents H, alkyl of any one of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; r₂Represents H, alkyl of any one of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; r₃Represents H, alkyl of any one of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; x represents O, S or NH; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or any other negative ion; r represents a linear or branched chain, - (CH)₂)_n-，Wherein n is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …, aryl or heteroaryl and Z represents- (CH)₂)₆-，-(CH₂)_n-，-(CH₂)_m-O-CH₂-，-(CH₂)_m-S-CH₂-，-CH₂C≡C-(CH₂)_n-，-CH₂C≡C-(CH₂)_n-O-CH₂-，-CH₂C≡C-(CH₂)_n-S-CH₂-，-CH₂-CO-(CH₂)_n-，-CH₂-CH＝C＝CH-(CH₂)_n-，-CH₂-CH＝C＝CH-O-(CH₂)_n-，-CH₂-CH＝C＝CH-S-(CH₂)_n-，

Wherein, X₃And X₄Represents H, OH, Cl, F, OCH₃，S-CH₃，CH₃，C₂H₅，CH＝CH₂，CH₂CH＝CH₂And CF₃(ii) a m and n may be integers between 0 and 8, including 0 and 8; Cx-Cy is-CH₂-CH₂-，-S-CH₂-，-O-CH₂-, -C ≡ C-, or-CH ═ CH-; r₄Represents:

wherein R is₅RepresentsH, OH, acetyl, propionyl, isobutyryl, butyryl, pivaloyl, valeryl and isovaleryl; x₃，X₄And X₅Represents H, OH, Cl, F, OCH₃，S-CH₃，CH₃，C₂H₅，CH＝CH₂，CH₂CH＝CH₂And CF₃；Y₃And Y₄When separated, each represents different, and each represents H, OH, OR₅，OOH，OCOCH₃，OCOC₂H₅，OCOC₃H₇，OCOC₄H₉，OCOC₅H₁₁，OCOC₆H₁₃，CH₃，CH₂OH，CH₂OCOCH₃，CH₂OCOC₂H₅，CH₂OCOC₃H₇，CH₂OCOC₄H₉Cl, F, Br, I, or both taken together represent one O or two H; y is₅Represents CH₂NH, S or O; m and n may be integers between 0 and 6, including 0 and 6.

Represents:

wherein R is₅Represents H, OH, acetyl, propionyl, isobutyryl, butyryl, pivaloyl, valeryl and isovaleryl; x₁And Y₁When separated, each represents different, and each represents H, OH, OR₅，OOH，OCOCH₃，OCOC₂H₅，OCOC₃H₇，OCOC₄H₉，OCOC₅H₁₁，OCOC₆H₁₃，CH₂-OH, Cl, F, Br, I, or both taken together represent one O or two H; x₂And Y₂When separated, each represents different, mayRespectively represent H, OH, OOH, OCOCH₃，OCOC₂H₅，OCOC₃H₇，OCOC₄H₉，OCOC₅H₁₁，OCOC₆H₁₃，CH₂-OH, Cl, F, Br, I, none (when the dotted bond is a double bond) or both taken together represent one O or two H; z₁And Z₂Represents H, OH, OR₅，OOH，OCOCH₃，OCOC₂H₅，OCOC₃H₇，OCOC₄H₉，OCOC₅H₁₁，OCOC₆H₁₃，CH₂-OH or Cl. W represents H, CH₃Cl, F, Br, I or OH; the dotted bond represents a single or double bond; all R, - (CH)₂)_n-or- (CH)₂)_mThe group may be branched or linear, may contain C, H, O, S or N atoms, and may have single, double and triple bonds; any CH₂The groups may be substituted with O, S or NH.

Drug absorption, whether through the gastrointestinal tract or other routes, requires passage through a barrier membrane as a single molecule. The drug must first dissolve and, if the drug has the desired biopharmaceutical properties, it will pass from a region of high concentration to a region of low concentration, across the cell membrane into the blood or systemic circulatory system. All biofilms contain lipids as a major component. The molecules that play a major role in the structure of the biofilm all have a highly polar head structure containing phosphate and, in most cases, two highly hydrophobic hydrocarbon tails. The biofilm has a bilayer structure with a hydrophilic head structure facing the aqueous phase regions on both sides. Very hydrophilic drugs cannot cross the lipid layer of the biological membrane, while very hydrophobic drugs stay in the membrane as part of the membrane for similar compatibility reasons and thus cannot effectively enter the inner cytoplasm.

The object of the present invention is to make prostaglandins, prostacyclins and related compounds transdermally administrable (topical administration) by increasing their solubility in the moisture of the skin surface and increasing their speed of penetration through biological membranes and skin barriers.These novel prodrugs of prostaglandins, prostacyclins, and related compounds share two common structural features: they all have a lipophilic moiety (oil soluble moiety) and a primary, secondary, or tertiary amine group (water soluble moiety) that exists in protonated form at physiological pH. Such a water-oil balance is necessary for the drug to be able to effectively cross the biological membrane [ Susan Milosovich, et al, J.Pharm.Sci., 82, 227(1993)]. The positively charged amino groups greatly increase the solubility of the drug in water. The solubility of these pro-drugs of prostaglandins, prostacyclins, and related compounds in water is > 100mg/ml, whereas the solubility of prostaglandins, prostacyclins, and related compounds in water is < 0.01 mg/ml. In most cases, dissolution of the drug is the slowest or rate-limiting step in the series. Prostaglandins, prostacyclins, and related compounds have very low solubility in moisture at the skin surface and cannot cross the skin barrier in the form of a single molecule. They stay outside the eye membrane or skin for a long time, thereby causing pain, itching or swelling of the eyes or skin. When these novel prodrugs are administered transdermally in a dosage form such as a solution, spray, lotion, ointment, emulsion, or gel, they dissolve rapidly in the moisture on the eye or skin surface. The positive charge on the amino group of the prodrug molecule will bond to the negative charge on the phosphate head group of the cell membrane. Thus, the local concentration of the drug outside the membrane is high, thereby facilitating passage of the prodrug molecule from a region of high concentration to a region of low concentration. When these pro-drugs enter the cell membrane, the hydrophilic part of the pro-drug molecule pushes the pro-drug into the cytoplasm, a semi-liquid aqueous solution or suspension. Because the prodrugs are retained on the outside of the eye or skin for a short period of time, they do not cause burning, pain, itching or swelling of the eye or skin. The penetration rate of these prodrugs in human skin was measured in vitro by modified Franz cells. Wherein the human skin is separated from human skin tissue (360-400 μm thick) anterior or posterior to the thigh region. The receiving solution consisted of 2ml of 2% bovine serum albumin in physiological saline and was stirred at 600 rpm. Cumulative total amount of these pro-drugs and their parent drugs that cross the skin versus timeSpecific high performance liquid chromatography. As donor solutions, 0.2ml of a solution containing 10% of some of the prodrugs dissolved in a phosphate buffered solution (0.2M) at pH 7.4, or 0.2ml of a suspension containing 10% of some of prostaglandins, prostacyclins and related compounds dissolved in a phosphate buffered solution (0.2M) at pH 7.4, are used, and the results are shown in FIG. 1, FIG. 2 and FIG. 3. Calculating to obtain 11, 15-dihydroxy-9-ketone-13-prostanoic acid N, N-diethylaminoethyl acetate, 11, 15-dihydroxy-9-ketone-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate, 9, 11, 15-trihydroxy-13-prostanoic acid N, N-diethylaminoethyl acetate, 9, 11, 15-trihydroxy-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate, 9, 11, 15-trihydroxy-15-methyl-4, 5, 13-prostatrienoic acid N, n-diethylaminoethyl acetate, 9, 11-dihydroxy-15-keto-20-ethyl-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate (9, 11-dihydroxy-15-keto-20-ethylprostaglandin F)_2αN, N-diethylaminoethyl ester), 11, 16-dihydroxy-9-one-16-methyl-13-prostenoic acid N, N-diethylaminoethyl ester acetate, (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3R) -3-hydroxy-4- [ (α, α, α -trifluoro-m-tolyl) oxy) ethyl ester]-1-butenyl radical]Cyclopentyl group]-5-heptenoic acid N, N-diethylaminoethyl ester acetate, (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (3R) -3-hydroxy-5-phenylpentyl ester]Cyclopentyl group]-5-heptenoic acid N, N-diethylaminoethyl ester acetate, (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3S) -3-hydroxy-5-phenyl-1-pentenyl]Cyclopentyl group]-heptenoic acid N, N-diethylaminoethyl acetate, 11, 15-dihydroxy-16, 16-dimethyl-9-one-2, 13-prostadienoic acid N, N-diethylaminoethyl acetate, 7- [ 3-hydroxy-2- (3-hydroxy-4-phenoxy-1-butenyl) -5-oxocyclopentyl-ethyl acetate]-5-heptenoic acid N, N-diethylaminoethyl ester acetate, 6, 9-epoxy-11, 15-dihydroxy-5, 13-prostadienoic acid N, N-diethylaminoethyl ester acetate, 7- [3, 5-dihydroxy-2- (3-hydroxy-4- (3-trifluoromethylphenoxy) -1-butenyl) cyclopentyl ] acetate]-5-heptenoic acid N, N-diethylaminoethyl ester acetate, 7- [2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl]-3，5-dihydroxycyclopentyl-5-heptenoic acid N, N-diethylaminoethyl ester acetate, 7- [3, 5-dihydroxy-2- (3-hydroxy-4-phenoxy-1-butenyl) cyclopentyl]-4, 5-heptadienoic acid N, N-diethylaminoethyl ester acetate, prostaglandin E₁Prostaglandin E₂Prostaglandin F_1αProstaglandin F_2αThe apparent penetration values of carboprost, prostacyclin, unoprostone, misoprostol, travoprost, latanoprost, bimatoprost, gemeprost, sulprostone, prostaglandin I2, fluprostol, cloprostol and fenoprost through human skin are respectively: 1.01mg/cm²/h，1.10mg/cm²/h，0.85mg/cm²/h，0.94mg/cm²/h，0.80mg/cm²/h，0.90mg/cm²/h，1.05mg/cm²/h，1.09mg/cm²/h，0.91mg/cm²/h，0.95mg/cm²/h，0.85mg/cm²/h，0.88mg/cm²/h，1.01mg/cm²/h，1.11mg/cm²/h，0.86mg/cm²/h，0.92mg/cm²/h，0.81mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²/h，0.001mg/cm²H and 0.001mg/cm²H is used as the reference value. The results of the experiments indicate that the pro-drugs diffuse nearly 1000 times faster in human skin than prostaglandins, prostacyclins, and related compounds. The results demonstrate that the positive charge on the dialkylaminoethyl group is important for the drug to cross biological membranes and skin barriers. Other prodrugs of general formula (2) 'Structure 2' have very fast penetration rates, approaching the transdermal rate of 11, 15-dihydroxy-9-one-13-prostanoic acid N, N-diethylaminoethyl acetate.

Prostaglandins are very effective drugs for the treatment of ocular hypertension and are ideal drugs for the long-term treatment of glaucoma (Woodward, d.f. et al.U.S. patent No. 5,688,819). Prostaglandins such as PGA, PGB, PGD, PGF have been reported_2α，PGF_1α，PGE₂，PGE₁And their alkyl esters have ocular hypotensive activity but are generally responsible for inflammation and skin stinging characterized by conjunctival congestion and edema. European patent application 0364417 discloses that certain phenyl and phenoxy substituted mono-, tri-and tetranorprostaglandins and their esters are useful for the treatment of glaucoma or ocular hypertension. Buchman et al (buchmann et al, U.S. patent No. 5,756,818) teach that certain cyclopentyl heptanoic acid, 2-cycloalkyl or arylalkyl compounds reduce intraocular pressure. Woodward et al (Woodward, d.f. et al, U.S. patent No. 5,688,819) teach that cyclopentylheptanoic acid, 2-cycloalkyl or arylalkyl compounds can be used to treat glaucoma and ocular hypertension. Recently, unoprostone, travoprost, latanoprost and bimatoprost have become the main drugs for the treatment of glaucoma. These drugs have side effects due to the slow rate of penetration. These side effects include blurred vision, redness of the eye, foreign body sensation in the eye, discoloration of the iris, itching, burning, stinging, dryness of the eye, tearing, ocular pain, and other ocular discomfort.

Laser trabeculoplasty in cats induced ocular hypertension, and the intraocular pressure lowering effect of certain compounds of the present invention was evaluated in cats with these ocular hypertension. After a mild corneal anesthesia with the diluted prohibitin, intraocular pressure was measured with an air pressure tonometer. The basal intraocular pressure (in mmHg) was determined prior to using an aqueous solution of the test compound. Six doses (one dose every 12 hours) were administered each over a three day experimental period. Intraocular pressure was measured 24 hours after the initial dose and then measured every 12 hours. The therapeutically effective concentration of the drug, typically 0.001% to 0.01%, is dissolved in a phosphate buffered solution (0.1M) at pH 7.2. One drop of the composition (approximately 30 microliters) was used per treatment. 11, 15-dihydroxy-9-ketone-13-prostanoic acid N, N-diethylaminoethyl acetate (A), 11, 15-dihydroxy-9-ketone-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate (B), 9, 11, 15-trihydroxy-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate (B)Salt (C), 9, 11-dihydroxy-15-ketone-20-ethyl-5, 13-prostadienoic acid N, N-diethylaminoethyl ester acetate (9, 11-dihydroxy-15-ketone-20-ethyl prostaglandin F)_2αN, N-diethylaminoethyl acetate) (D), (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3R) -3-hydroxy-4- [ (alpha, alpha-trifluoro-m-tolyl) oxy]-1-butenyl radical]Cyclopentyl group]-5-heptenoic acid N, N-diethylaminoethyl ester acetate (E), (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (3R) -3-hydroxy-5-phenylpentyl ester]Cyclopentyl group]-5-heptenoic acid N, N-diethylaminoethyl ester acetate (F), and (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3S) -3-hydroxy-5-phenyl-1-pentenyl]Cyclopentyl group]The results of measurement of heptenoic acid N, N-diethylaminoethyl acetate (G) are shown in Table 1.

TABLE 1 Effect of prodrugs of natural prostaglandins and their modified analogs in lowering intraocular pressure in cats.

After topical administration of naturally occurring and modified prostaglandins and novel prodrugs thereof, the corresponding test drugs were evaluated for ocular irritation or ocular discomfort in cats during the first few hours. Ocular discomfort was assessed on a standard scale from 0 to 4, with 0 indicating complete absence of any signs of discomfort and 4 indicating that maximal irritation apparently resulted in complete closure of the eyelids. The results are shown in Table 2.

TABLE 2 stimulation of drugs tested correspondingly in the first two hours after topical administration of naturally occurring and modified prostaglandins and their novel prodrugs

Compound (I)	Dosage%	Degree of irritation
			PGE1	0.001	4
A	0.001	1
			PGE2	0.001	3.5
B	0.001	1
			PGF2α	0.001	3.5
C	0.001	1
			Unoprostone	0.01	2.5
D	0.01	1
			Travoprost	0.001	2.5
E	0.001	1
			Latanoprost	0.001	2.5
F	0.001	1
			Bimatoprost	0.001	2.5
G	0.001	1

After topical administration of naturally occurring and modified prostaglandins and their novel prodrugs, conjunctival hyperemia of the corresponding test drugs on rabbit eyes was evaluated in the first 2 hours. The degree of conjunctival congestion was assessed on a standard scale from 0 to 4, with 0 indicating complete absence of any signs of congestion and 4 indicating significant congestion with conjunctival edema. The results are shown in Table 3.

TABLE 3 Conjunctional hyperemia of rabbit eyes following topical administration of naturally occurring and modified prostaglandins and novel prodrugs thereof over the first two hours

Compound (I)	Dosage%	Degree of irritation
			PGE1	0.001	4
A	0.001	1
			PGE2	0.001	4
B	0.001	1
			PGF2α	0.001	4
C	0.001	1
			Unoprostone	0.01	2.5
D	0.01	1
			Travoprost	0.001	2.5
E	0.001	1
			Latanoprost	0.001	2.5
F	0.001	1
			Bimatoprost	0.001	2.5
G	0.001	1

The experimental results show that the effect of these prodrugs on treating ocular hypertension and glaucoma is superior to that of their parent drugs. They are highly effective in reducing intraocular pressure and cause no or minimal side effects. Prostaglandins and related compounds are very lipid soluble substances. When prostaglandins are administered topically to the eye, they are insoluble in the aqueous humor of the eye. They stay on the outside of the eye membrane for a long time and thus may cause pain, itching or swelling of the eyes. After prostaglandins enter the ocular membrane, they become part of a hydrophobic membrane that resides in the membrane for similar compatibility reasons and thus do not enter the cytoplasm efficiently. Prodrugs of prostaglandins dissolve rapidly in the aqueous humor of the eye when applied topically to the eye. The positive charge on the amino group of these pro-drugs can bond to the negative charge on the phosphate head group of the eye membrane. The local concentration of the drug outside the membrane is therefore high, facilitating passage of these pro-drugs from a region of high concentration to a region of low concentration. After the prodrug molecule enters the membrane, the hydrophilic moiety will push the prodrug into the cytoplasm. Because the prodrugs are retained for a short period of time outside the eye membrane or skin, they do not cause burning, pain, itching or swelling of the eye.

Prostaglandins can treat male erectile dysfunction (Yeager; J.L., et al, U.S. Pat. No. 6,693,135) and increase female sexual arousal (Scott, N.E. U.S. Pat. No. 6291528). However, prostaglandin formulations, when used alone, do not effectively penetrate into the skin to achieve therapeutic concentrations of the drug. A commercial prostaglandin product, alprostadil (prostaglandin E)₁) (muse.rtm, Vivus, Menlo Park Calif.), hollow tube of 3.5 mm diameter by 3.2 cm long (Padma-Nathan, h., et al., n.engl.j.med., 336: 1-7(1997)) placing the pellets in the urethra to treat impotence. The side effects of this treatment modality are penile pain and minor urethral trauma. Transurethral administration of prostaglandin E₁Or prostaglandin E₂Is a very effective way to treat impotence, but causes side effects such as burning or pain in the urethra and pain in the cavernous sinus of the genitals. Another problem with transurethral administration of prostaglandins is how to remove the composition to stop administration, which can lead to overdosing and leaving an excess of prostaglandin in the vagina of the partner.

A commercially available prostaglandin E₁The product is administered by injection through the cavernous body. Alprostadil (prostaglandin E)₁) The major side effects of the administration of the sponge injections are pain, the possibility of fibrosis andscars may be left at the injection site.

The novel prodrug can be used for treating the diseases with extremely high speed (about 1 mg/h/cm)²) Through the skin, a treatment is provided that has little side effects for treating erectile dysfunction or for enhancing female sexual arousal. About 0.01ml containing 0.0005% [ -0.05 μ g (microgram)]11, 15-dihydroxy-9-one-13-prostanoic acid N, N-diethylaminoethyl acetate, pH7.0, in phosphate buffer (0.1M) was administered once daily for 5 days to the genital area of male rats (30). The results show that the sexual impulse of the rats receiving the drug was increased 6-fold and the number of sexual intercourse was increased 4-fold compared to the rats without the drug.

Then, an equal amount of 11, 15-dihydroxy-9-one-13-prostanoic acid N, N-diethylaminoethyl acetate in phosphate buffer solution (0.1M) at ph7.0 was administered once daily for 5 days to the genital area of male rats (30) and female rats (30). The results show that the sexual impulse was 6-fold enhanced and the sexual coordination was 6-fold increased in the rats receiving the drug compared to the rats without the drug. Most importantly, the rats did not show any signs of discomfort after dosing.

Natural prostaglandin E, prostaglandin A and prostaglandin F and their synthetic analogs are useful for lowering systemic blood pressure (systolic arterial pressure). 0.02mg of 11, 15-dihydroxy-9-one-5, 13-prostadienoic acid N, N-diethylaminoethyl ester acetate (A) and 11, 16-dihydroxy-9-one 16-vinyl-5, 13-prostadienoic acid N, N-diethylaminoethyl ester acetate (B) dissolved in 0.3ml of phosphate buffer (0.1M) at pH7.0 were administered to the back of spontaneously hypertensive rats (hypertension induced by tungsten-rich food). The blood pressure of the rat was continuously recorded with a multichannel physiological recorder. The results are shown in Table 4.

TABLE 4 Effect of prostaglandin prodrugs on mean arterial blood pressure in spontaneously hypertensive rats. All data are mean. + -. SD

After transdermal administration of the prostaglandin prodrug to spontaneously hypertensive rats, the mean arterial blood pressure of the rats was significantly reduced and the administered rats did not show any discomfort.

The compounds represented by the general formula (2) 'Structure 2' described above can be prepared by reacting protected prostaglandins, prostacyclins and related compounds with the compounds represented by the general formula (3) 'Structure 3' by coupling agents including: n, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N '-tetramethyluronium tetrafluoroborate (TBTU), O- (benzotriazol-1-yl) -N, N' -tetramethyluronium Hexafluorophosphate (HBTU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), and the like.

Structural formula 3

Wherein R is₁Represents H, any one of alkyl with 1 to 12 carbon atoms, alkoxy with 1 to 12 carbon atoms, alkenyl with 1 to 12 carbon atoms, alkynyl with 1 to 12 carbon atoms, aryl or heteroaryl; r₂Represents H, any alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; r represents a branched or unbranched radical, - (CH)₂)_n-, wherein n ═ 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …, aryl or heteroaryl; x represents O, S or NH; n is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …

When X represents O, the compound represented by the general formula (2) 'structure 2' described above can be synthesized by reacting a metal salt, an organic base salt or an immobilized base salt of prostaglandin, prostacyclin and related compounds with a compound represented by the general formula (4) 'structure 4'.

Structural formula 4

Wherein R is₁Represents H, any one of alkyl with 1 to 12 carbon atoms, alkoxy with 1 to 12 carbon atoms, alkenyl with 1 to 12 carbon atoms, alkynyl with 1 to 12 carbon atoms, aryl or heteroaryl; r₂Represents H, any one of alkyl with 1 to 12 carbon atoms, alkoxy with 1 to 12 carbon atoms, alkenyl with 1 to 12 carbon atoms, alkynyl with 1 to 12 carbon atoms, aryl or heteroaryl; r₃Represents H, any one of alkyl with 1 to 12 carbon atoms, alkoxy with 1 to 12 carbon atoms, alkenyl with 1 to 12 carbon atoms, alkynyl with 1 to 12 carbon atoms, aryl or heteroaryl; r represents a branched or linear chain, - (CH)₂)_n-, where n ═ 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …, aryl or heteroaryl; z represents halogen, or p-toluenesulfonyl, A^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or any other negative ion.

Advantages of the invention

The prodrug structures of prostaglandins, prostacyclins, and related compounds of the present invention all have a lipid soluble portion and a water soluble portion (amine groups that exist in protonated form at physiological PH). The positively charged amino groups of these pro-drugs have two major benefits. First, it greatly improves the solubility of these drugs in water; when these prodrugs are administered transdermally in the form of a solution, spray, lotion, ointment, emulsion, or gel, they rapidly bind to moisture on the surface of the skin, eyes, genital area, mouth, nose, or other areas of the body. Second, the positive charge on the amino group of these prodrugs can bond to the negative charge on the phosphate head group of the biofilm. The local concentration outside the membrane will be high, thereby facilitating the passage of these pro-drugs from regions of high concentration to regions of low concentration. After the prodrug molecules enter the membrane, the hydrophilic moiety pushes the drug into the cytoplasm, a semi-liquid concentrated aqueous solution or suspension. Because these prodrugs have a short residence time in the skin, eyes, genital area, mouth, nose or other areas of the body, they do not cause itching, burning or pain. Experimental results indicate that more than 90% of the prodrug can return to the parent drug structure in a few minutes. These prodrugs are more potent than prostaglandins, prostacyclins, and related compounds in that they are more potent at the same dosage because they are more absorbable and avoid first pass metabolism of the drug by transdermal administration. Another great benefit of transdermal administration of these prodrugs is that administration is more convenient, especially to children.

Drawings

FIG. 1: 11, 15-dihydroxy-9-keto-13-prostadienoic acid N, N-diethylaminoethyl acetate solution (a, 10% solution), 11, 15-dihydroxy-9-keto-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate solution (B, 10% solution), 9, 11, 15-trihydroxy-13-prostanoic acid N, N-diethylaminoethyl acetate solution (C, 10% solution), 9, 11, 15-trihydroxy-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate solution (D, 10% solution) of human skin tissue isolated by Franz cells (N ═ 5); 9, 11, 15-Trihydroxyl-15-methyl-5, 13-Prostamadienoic acid N, N-diethylaminoethyl acetate solution (E, 10% solution), 9, 11, 15-Trihydroxyl-15-methyl-4, 5, 13-Prostamatrienoic acid N, N-diethylaminoethyl acetate solution (F, 10% solution), prostaglandin E₁Suspension (G, 10% suspension), prostaglandin E₂Suspension (H, 10% suspension), prostaglandin F_1αSuspension (I, 10% suspension), prostaglandin F_2αCumulative total amount of suspension (J, 10% suspension), carboprost suspension (K, 10% suspension), prostatallin suspension (L, 10% suspension). In each case, the carrier solution was a phosphate buffered solution (0.2M) at pH 7.4.

FIG. 2: 9, 11-dihydroxy-15-keto-20-ethyl-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate solution (a, 10% solution), 11, 16-dihydroxy-9-keto-16 methyl-13-prostanoic acid N, N-diethylaminoethyl acetate solution (B, 10% solution) of human skin tissue isolated by Franz cells (N ═ 5); (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3R) -3-hydroxy-4- [ (α, α, α -trifluoro-m-tolyl) oxy ] -1-butenyl ] cyclopentyl ] -5-heptenoic acid N, N-diethylaminoethyl acetate solution (C, 10% solution) (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (3R) -3-hydroxy-5-phenylpentyl ] cyclopentyl ] -5-heptenoic acid N, N-diethylaminoethyl acetate solution (D, 10% solution), (Z) -7- [ (1R, 2R, 3R, 5S) -3, 5-dihydroxy-2- [ (1E, 3S) -3-hydroxy-5-phenyl-1-pentenyl ] cyclopentyl ] -heptenoic acid N, N-diethylaminoethyl acetate solution (E, 10% solution), 11, 15-dihydroxy-16, 16-dimethyl-9-one-2, 13-prostadienoic acid N, N-diethylaminoethyl acetate solution (F, 10% solution), unoprostone suspension (G, 10% suspension), misoprostol suspension (H, 10% suspension), travoprost suspension (I, 10% suspension), latanoprost suspension (J, 10% suspension), bimatoprost suspension (K, 10% suspension), cumulative total amount of gemeprost suspension (L, 10% suspension). In each case, the carrier solution was a phosphate buffer solution (0.2M) at pH 7.4.

FIG. 3: 7- [ 3-hydroxy-2- (3-hydroxy-4-phenoxy-1-butenyl) -5-oxocyclopentyl of human skin tissue isolated by Franz cell (n ═ 5)]-5-heptenoic acid N, N-diethylaminoethyl acetate solution (A, 10% solution), 6, 9-epoxy-11, 15-dihydroxy-5, 13-prostadienoic acid N, N-diethylaminoethyl acetate solution (B, 10% solution), 7- [3, 5-dihydroxy-2- [ 3-hydroxy-4- [3- (trifluoromethyl) phenoxy ] ethyl acetate]-1-butenyl radical]Cyclopentyl group]-5-heptenoic acid N, N-diethylaminoethyl acetate solution (C, 10% solution), 7- [2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl]-3, 5-dihydroxycyclopentyl-5-heptenoic acid N, N-diethylaminoethyl ester acetate (D, 10% solution), 7- [3, 5-dihydroxy-2- (3-hydroxy-4-phenoxy-1-butenyl)) Cyclopentyl group]4, 5-heptadienoic acid N, N-diethylethyl acetate solution (E, 10% solution), sulprostone suspension (F, 10% suspension), prostaglandin I₂Cumulative total amount of suspension (G, 10% suspension), fluprostenol suspension (H, 10% suspension), cloprostenol suspension (I, 10% suspension), fenprostil suspension (J, 10% suspension). In each of the above examples, the carrier solution was a phosphate buffer solution (0.2M) at pH 7.4.

FIG. 4: wherein R is₁Represents H, any one of alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; r₂Represents H, any one of alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; r₃Represents H, any one of alkyl of 1 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, alkenyl of 1 to 12 carbon atoms, alkynyl of 1 to 12 carbon atoms, aryl or heteroaryl; x represents O, S, or NH; a. the^-Represents Cl^-，Br^-，F^-，I^-，AcO^-Citrate, or any other negative ion; r represents a branched or linear chain, - (CH)₂)_n-, where n ═ 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10 … …, aryl or heteroaryl; z represents an alpha (alpha) -chain and C_x-C_y-R₄Represents an omega (omega) -chain; cy represents the cyclopentyl system of the prostaglandin.

Best mode for carrying out the invention

Preparation of 11, 15-dihydroxy-9-one-13-prostanoic acid N, N-diethylaminoethyl ester acetate

37.7g (0.1mol) of sodium 11, 15-dihydroxy-9-one-13-prostataurate are dissolved in 100ml of acetonitrile. To the reaction mixture were added 26.1g (0.1mol) of 2-bromo-N, N-diethylethanamine hydrogen bromide and 8.6g of sodium hydrogen carbonate. The reaction mixture solution was stirred at room temperature overnight. The solvent was evaporated to dryness. 250ml of ethyl acetate are added to the reaction mixture and washed three times with 100ml of water each time. The organic solution was dried over anhydrous sodium sulfate. For treatingThe sodium sulfate was removed by filtration. 6g of acetic acid was added to the reaction mixture with stirring. 200ml of hexane were added. The solid product was collected by filtration. After drying, 42g of the target product, which is hygroscopic, were obtained with a yield of 81.8%. Solubility in water: 100 mg/ml; elemental analysis: c₂₈H₅₁NO₇(ii) a Molecular weight: 513.37. theoretical value (%) C: 65.47, respectively; h: 10.01; n: 2.73; o: 21.80; found value (%) C: 65.42, respectively; h: 10.03; n: 2.70 of; o: 21.85.¹H-NMR(400MHz，D₂O)：：0.96(t，3H)，1.25-1.33(m，12H)，1.48-1.53(m，4H)1.55(t，6H)，1.68(m，2H)，2.08(m，1H)，2.18(s，3H)，2.21(m，2H)，2.25(t，2H)，2.77(m，1H)，3.22(m，4H)，3.50(m，2H)，3.76(m，1H)，3.90(m，1H)，4.52(m，2H)，5.65-5.69(m，2H)。

detailed description of the preferred embodiments

Preparation method of N, N-diethylaminoethyl 11, 15-diacetoxy-9-ketone-5, 13-prostatic dienoic acid-1-amide acetate

43.7g (0.1mol) of 11, 15-diacetoxy-9-one-5, 13-prostadienoic acid are dissolved in 300ml of chloroform. 20.6g N, N' -dicyclohexylcarbodiimide was added to the reaction mixture. 11.7g N, N-diethylaminoethylamine hydrobromide was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. The solid was removed by filtration. The chloroform solution was washed twice with 100ml of 5% aqueous sodium bicarbonate solution and three times with 100ml of water. The organic layer was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. The reaction mixture was stirred with the addition of 6g of acetic acid. 200ml of hexane were added. The solid product was collected by filtration. After drying, 45g of the target product which is hygroscopic and has a yield of 85.8% were obtained. Solubility in water: 100 mg/ml. Elemental analysis: c₃₄H₅₉NO₉S; molecular weight: 657.90. theoretical value (%): c: 62.07; h: 9.04; n: 2.13; o: 21.89; s: 4.87; found (%): c: 62.02; h: 9.06; n: 2.11, O: 21.95; s: 4.86.¹H-NMR(400MHz，D₂O)：：0.95(t，3H)，1.25-1.33(m，14H)，1.54(m，2H)1.56(t，6H)，1.62(m，2H)，1.99(m，2H)，2.01(s，3H)，2.02(s，3H)，2.05(s，3H)，2.10(m，1H)，2.18(s，3H)，2.35(t，2H)，2.77(m，1H)，3.22(m，4H)，3.35(m，2H)，3.89(m，2H)，3.97(m，1H)，4.02(m，1H)，4.60(m，1H)，5.45-5.69(m，2H)。

preparation of 9, 11, 15-triacetoxy-13-prostanoic acid N, N-dimethylaminoethyl mercaptide acetate

49.9g (0.1mol) of 9, 11, 15-triacetoxy-13-prostanoic acid were dissolved in 300ml of chloroform. 20.6g N, N' -diisohexylcarbodiimide was added to the reaction mixture. To the reaction mixture was added 13.1g of dimethylaminoethyl mercaptan. The mixture was stirred at room temperature for 3 hours. The solid was removed by filtration. The chloroform solution was washed twice with 100ml of 5% aqueous sodium bicarbonate solution and three times with 100ml of water. The organic solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. 6g of acetic acid was added to the reaction mixture with stirring. 200ml of hexane were added. The solid product was collected by filtration. After drying 45g of the readily hygroscopic product were obtained, yield 85.8%. Solubility in water: 100 mg/ml. Elemental analysis: c₃₂H₅₃NO₉(ii) a Molecular weight: 657.9. theoretical value (%): c: 64.51; h: 8.97 of; n: 2.35; o: 24.17; found (%): c: 64.47; h: 8.99; n: 2.34, O: 24.20.¹H-NMR(400MHz，D₂O)：：0.95(t，3H)，1.25-1.31(m，6H)，1.54(m，2H)1.56(t，6H)，1.72(m，2H)，1.95(m，2H)，2.01(s，3H)，2.02(s，3H)，2.10(m，1H)，2.18(s，3H)，2.20(m，2H)，2.25(t，2H)，2.30(m，2H)，3.18(m，1H)，3.22(m，4H)，3.50(m，2H)，4.50(m，1H)，4.52(m，2H)，4.58(m，1H)，5.45-5.69(m，4H)。

synthesis method of 9, 11, 15-trihydroxy-5, 13-prostatic dienoic acid diethylaminoethyl ester acetate

37.7g (0.1mol) of 9, 11, 15-trihydroxy-5, 13-prostadienoic acid sodium salt are dissolved in 100ml of acetonitrile. To the reaction mixture was added 39g (0.15mol) of 2-bromo-N, N-diethylethanamine hydrogen bromide in ethyl acetate. Reaction solution in the chamberThe reaction was stirred for 3 hours. Sodium bicarbonate, 8g, was added to the reaction mixture. The mixture was stirred for an additional 2 hours at room temperature. The solvent was evaporated. 250ml of ethyl acetate were added to the reaction mixture and the mixture was washed three times with 100ml of water each time. The organic solution was dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration. To the reaction mixture was added 6g of acetic acid with stirring. 200ml of hexane were added. The solid product was collected by filtration. After drying, 45g of the target product, which is hygroscopic, were obtained with a yield of 87.6%. Solubility in water: 100 mg/ml; elemental analysis: c₂₈H₅₁NO₇(ii) a Molecular weight: 513.71. theoretical value (%) C: 65.47, respectively; h: 10.01; n: 2.73; o: 21.80; found value (%) C: 65.42, respectively; h: 10.03; n: 2.70 of; o: 21.85.¹H-NMR(400MHz，D₂O)：：0.96(t，3H)，1.25-1.33(m，6H)，1.48(m，2H)，1.55(t，6H)，1.65(m，1H)，1.72(m，2H)，1.81(m，2H)，1.92(m，2H)，1.96(m，2H)，2.26(m，1H)，2.18(s，3H)，2.25(t，2H)，3.21(m，1H)，3.23(m，1H)，3.25(m，4H)，3.52(m，2H)，3.86(m，1H)，4.52(m，2H)，5.65-5.69(m，4H)。

9, 11, 15-Trihydroxyl-15-methyl-5, 13-Prostamadienic acid N, N-diethylaminoethyl ester acetate

60g of polymer-immobilized triethylamine (3mol/g, 100-mesh 200) were suspended in 180ml of chloroform. 29.6g (0.1mol) of 9, 11, 15-trihydroxy-15-methyl-5, 13-prostadienoic acid N, N-diethylaminoethyl ester was added to the mixture with stirring. 43g (0.15mol) of N, N-diethylaminoethyl bromide hydrogen bromide were added to the mixture, and the mixture was stirred at room temperature for 5 hours. The high molecular weight polymer was removed by filtration and washed three times with 50ml of tetrahydrofuran each time. To the mixture was added 8.2g (0.1mol) of sodium acetate with stirring. Stirring was then continued for 2 hours. The solid was removed by filtration and washed three times with 50ml of chloroform each time. The solution was concentrated to 100ml in vacuo. Then 300ml of hexane was added to the solution. The solid product was collected by filtration and washed three times with 100ml of hexane each time. After drying, 47g of the target product, which is hygroscopic, were obtained with a yield of 87.8%. Solubility in water: 100 mg/ml; elemental analysis: c₂₈H₅₁NO₇(ii) a Molecular weight: 527.73, respectively; theoretical value(%): c: 66.00; h: 10.12 of the total weight of the mixture; n: 2.65 of; o: 21.22; found value (%) C: 65.96, respectively; h: 10.15; n: 2.64 of; o: 21.24.¹H-NMR(400MHz，D₂O)：：0.95(t，3H)，1.24-1.34(m，6H)，1.41(s，3H)，1.47(m，2H)，1.56(t，6H)，1.65(m，1H)，1.72(m，2H)，1.82(m，2H)，1.92(m，2H)，1.97(m，2H)，2.26(m，1H)，2.18(s，3H)，2.25(t，2H)，3.21(m，1H)，3.23(m，1H)，3.25(m，4H)，3.52(m，2H)，4.52(m，2H)，5.64-5.68(m，4H)。

industrial applicability

The prodrugs of the general formula (2) 'Structure 2' are superior to prostaglandins, prostacyclins and related compounds. They may be used to treat any condition that is treatable by prostaglandins, prostacyclins, and related compounds in humans or animals. They can be used for treating glaucoma or ocular hypertension, for treating male erectile dysfunction and improving female sexual excitation, lowering systemic blood pressure, for induced abortion, for hypotension control, for inhibiting platelet aggregation, and for treating lung diseases, gastrointestinal diseases, shock, reproductive diseases, infertility, etc.

Claims (14)

1. A compound represented by structural formula 2:

wherein R is₁Represents H, or alkyl of any 1 to 12 carbon atoms;

R₂represents H, or alkyl of any 1 to 12 carbon atoms;

R₃represents H;

x represents O or S;

A^-represents Cl^-、Br^-、F^-、I^-、AcO^-Or citrate;

r represents- (CH)₂)_n1-, where n1 is 1, 2, 3, 4, 5,6, 7, 8, 9 or 10;

Cx-Cy is-CH₂-CH₂-, or-CH ═ CH-;

z represents- (CH)₂)₆-，-CH₂-CH＝C＝CH-(CH₂)_n2-, or

Wherein n2 represents an integer between 0 and 6;

R₄represents:

or

Wherein R is₅Represents H;

X₃，X₄and X₅Represents H, OH, Cl, F, OCH₃，S-CH₃，CH₃，C₂H₅，CH＝CH₂，CH₂CH＝CH₂Or CF₃；

Y₃And Y₄：

(a) When separated, each represents a different substituent selected from H, OH, OOH, OCOCH₃，OCOC₂H₅，OCOC₃H₇，OCOC₄H₉，OCOC₅H₁₁，OCOC₆H₁₃，CH₃，CH₂OH，CH₂OCOCH₃，CH₂OCOC₂H₅，CH₂OCOC₃H₇，CH₂OCOC₄H₉Cl, F, Br and I, or

(b) Both of which are combined together to represent an O or both of which are H;

Y₅represents CH₂Or O;

m and n are integers between 0 and 8;

represents:

or

Wherein R is₅Represents H.

2. The method for preparing a compound according to claim 1, wherein the compound is prepared by reacting a prostaglandin, prostacyclin or prostacyclin with a compound of formula 3, under the action of a coupling agent comprising: n, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate, O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate,

wherein R is₁Represents H, or alkyl of any 1 to 12 carbon atoms; r₂Represents H, or alkyl of any 1 to 12 carbon atoms; r represents- (CH)₂)_n-, where n is 1, 2, 3, 4, 5,6, 7, 8, 9, or 10; x represents O or S.

3. The method for synthesizing a compound according to claim 1, wherein X in said compound is O, which is obtained by reacting a prostaglandin, or a metal salt or an organic base salt of prostacyclin with a compound represented by structural formula 4,

wherein R is₁Represents H, or alkyl of any 1 to 12 carbon atoms; r₂Represents H, or alkyl of any 1 to 12 carbon atoms; r₃Represents H; r represents- (CH)₂)_n-, where n is 1, 2, 3, 4, 5,6, 7, 8, 9, or 10; z represents halogen or p-toluenesulfonyl, A^-Represents Cl^-、Br^-、F^-、I^-、AcO^-Or citrate.

4. A compound according to claim 1 or a composition containing at least one compound according to claim 1 as active ingredient for use in the treatment of any prostaglandin, prostacyclin-treatable conditions in humans or animals by transdermal administration.

5. A compound as claimed in claim 1 or a composition containing at least one compound as claimed in claim 1 as active ingredient, characterized in that the compound or composition is used for the treatment of any prostaglandin, prostacyclin treatable conditions in humans or animals by transdermal administration in solution, spray, lotion, ointment, emulsion or gel form to any part of the body to achieve therapeutically effective plasma concentrations.

6. A compound according to claim 1 or a composition comprising at least one compound according to claim 1 as an active ingredient, characterized in that the compound or composition is used for the treatment of male erectile dysfunction or female sexual dysfunction by transdermal administration to the genital area of a human or animal in the form of a solution, spray, emulsion, ointment, emulsion or gel to a therapeutically effective concentration.

7. A compound according to claim 1 or a composition comprising at least one compound according to claim 1 as an active ingredient, wherein the compound or composition is used for the treatment of glaucoma or ocular hypertension by transdermal administration to the eye of a human or animal in the form of a solution, spray, lotion, ointment, emulsion or gel to achieve a therapeutically effective concentration.

8. A compound according to claim 1 or a composition containing at least one compound according to claim 1 as an active ingredient, characterized in that the compound or composition is used for the treatment of systemic hypertension by transdermal administration to any part of a human or animal in the form of a solution, spray, emulsion, ointment, emulsion or gel to achieve a therapeutically effective concentration.

9. A compound according to claim 1 or a composition containing at least one compound according to claim 1 as active ingredient, characterized in that the compound or composition is administered transdermally in the form of a solution, spray, lotion, ointment, emulsion or gel to the female vagina for use in induced abortion.

10. A compound according to claim 1 or a composition containing at least one compound according to claim 1 as an active ingredient, characterized in that the compound or composition is used for treating gastrointestinal ulcers and skin ulcers by transdermal administration to any part of a human or animal in the form of a solution, spray, emulsion, ointment, emulsion or gel to achieve a therapeutically effective concentration.

11. A compound according to claim 1 or a composition containing at least one compound according to claim 1 as an active ingredient, characterized in that the compound or composition treats inflammation by transdermal administration to the eye or other body part of a human or animal to achieve a therapeutically effective concentration.

12. Transdermal therapeutic application system comprising a compound according to claim 1 or a composition comprising at least one compound according to claim 1 as active ingredient for the treatment of any prostaglandin, prostacyclin treatable conditions in humans or animals.

13. The transdermal therapeutic application system of claim 12, wherein the system is a bandage or patch comprising a matrix layer containing the active substance and a non-permeable protective layer.

14. A transdermal therapeutic application system according to claim 12 or 13 wherein there is an active substance reservoir comprising a permeable skin-facing base.