NO742518L - - Google Patents

Description

Cyclopentane derivatives and method for their production.

The present invention relates to cyclopentane derivatives, and in particular relates to 5-trans-prostenic acid derivatives which have luteolytic activity. The new compounds can therefore advantageously be used as contraceptives, for inhibition of labor or termination of pregnancy or for regulation of the estrous cycle, and they. are also useful as hypotensives, for the relief of bronchospasm, and as inhibitors of platelet agglomeration or of gastric secretion. The new compounds are also usable as an additive to semen for artificial fertilization of farm animals and the number of successful fertilizations increases because of this, especially when it comes to pigs and cattle.

According to the present invention, the cyclopentane derivative is prepared with the formula:

where R is a hydroxymethyl or carboxy radical, or an alkoxycarbonyl radical with up to 11 carbon atoms and R 2 is either a hydroxy radical or an alkanoyloxy radical with up to 4 carbon atoms and R 3 is a hydrogen atom, or R<2> and R 3 together form an oxo- radical; A is an ethylene or trans-vinylene radical; Y is a direct bond or an alkylidene or alkylideneoxy radical of 1 to 5 carbon atoms, where the alkylidene part of the latter group is attached to the carbon atom of the -CH(OH) group and the oxygen atom is attached to R^; and R^ is a phenyl or naphthyl radical which may be unsubstituted or substituted with halogen atoms, nitro, hydroxy or phenyl radicals, alkyl, alkenyl, haloalkyl, alkoxy, alkenyloxy or acylamino radicals with up to 4 carbon atoms, or dialkylamino radicals wherein each alkyl group contains 1 to 3 carbon atoms; as the compound contains 0 or 1. alkyl radical containing 1 to 4 carbon atoms at carbon atom 2, 3 or 4;

and for those compounds where R"" is a carboxy radical, pharmaceutical and veterinary acceptable salts thereof.

A suitable meaning for R<*> when it is an alkoxycarbonyl radical is for example a methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical, especially an alfoxycarbonyl radical with up to 5 carbon atoms. ;A suitable meaning for R when it is an alkanoyloxy radical with 1 to 4 carbon atoms is, for example, an acetoxy ;or propionyloxy radical.;A suitable meaning for Y when it is an alkyl radical, or for the alkylidene part of Y when it is an alkylideneoxy radical is for for example a methylene, ethylidene, isopropylidene, propylidene, 1-methylpropylidene or 1-ethylpropylidene radical, and especially such a radical with 1 to 3 carbon atoms and especially a methylene or isopropylidene radical. Suitable halogen atoms as substituents in R^ are, for example, chlorine, bromine or fluorine atoms. Suitable alkyl, alkoxy, alkenyl, alkenyloxy or acylamino substituents with up to 4 carbon atoms in R^ are, for example, methyl, t-butyl, allyl, methoxy, allyloxy or acetamido radicals. Suitable haloalkyl substituents with 1 to 4 carbon atoms for R 4 are, for example, chloroalkyl or fluoroalkyl radicals, for example trifluoromethyl radicals. Suitable dialkylamino radicals, where each alkyl group contains 1 to 3 carbon atoms and which can be substituents for R^, are for example dialkylamino radicals where the two alkyl radicals are the same, for example the dimethylamino radical., ;Suitable substituted aryl radicals are thus for example chlorophenyl-, chloronaphthyl-, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl and tetrahydronaphthyl radicals. Preferred aryl radicals containing no more than two substituents are indicated above. Special meanings for R^ are therefore phenyl-, 1-naphthyl-, 2-naphthyl-, 2-, 3- and 4-chlorophenyl, 4-bromophenyl, 2-, 3- and 4-fluorophenyl, 2,3- 2 ,4-, 2,5-, 2,6-, 3,4- and 3,5-dichlorophenyl-, 2-, 3- and 4-tolyl-, 2,3-, 3,4- and 3, 5-xylyl-, 4-t-butylphenyl-, 3-allylphenyl-, 3-trifluoromethylphenyl-, 4-hydroxyphenyl-, 2-, 3- and 4-methoxyphenyl-, 4-biphenylyl-, 3-dimethylaminophenyl-, 2- chloro-4-methylphenyl-, 1-chloro-2-naphthyl-, 4-chloro-2-naphthyl-, 6-methyl-2-naphthyl-, 6-methoxy-2-naphthyl- and 5,6,7,8 -tetrahydro-2-naphthyl radicals. Particularly preferred aryl radicals are phenyl, 3- and 4-chlorophenyl and 3- and 4-trifluoromethylphenyl radicals. A suitable meaning for the alkyl radical with up to 4 carbon atoms, which can be a substituent at carbon atom 2, 3 or 4 is, for example, methyl radical, and particularly preferred at carbon atom 2. Examples of pharmaceutically and veterinary medicinally acceptable salts are ammonium, alkyl-ammonium containing 1 to 4 alkyl radicals with one to six carbon atoms, alkanol-ammonium containing 1 to 3 2-hydroxyethyl radicals, and alkali metal salts such as triethylammonium, ethanolammonium, diethanolammonium, sodium and potassium salts. It will be seen that the compounds of formula I contain at least 4 asymmetric carbon atoms, namely carbon atoms 8, 11, 12 and 15, the relative configurations of three of these, 8, 11 and 12, are given in formula I, and that the carbon atoms 2, 3, 4, 9 and 16 also; may be unsymmetrically substituted, so that it is clear that such compounds may exist in at least two optically active forms. It will be understood that the useful properties of the racemate can be present to varying extents in the optical isomers, and that the present invention relates to the racemic form of the compounds of formula I and possibly optically active forms which have the above-mentioned useful properties, as it is commonly known how the optically active forms can be obtained and their respective biological properties can be determined. ;It will also be understood that the definition above also includes both G-15 epimers and that in all the chemical formulas shown the same stereochemistry at C-8, 9, 11 ;and 12 as shown in formula I is implied.;A special group of cyclopentane derivatives according to the invention comprises compounds with the formula I where [is a carboxy or methoxycarbonyl radical, in particular a carboxy radical, R 2 is a hydroxy radical and R 3 is a hydrogen atom or R<2> and R<3> together form an oxo radical , A is a trans-vinylene radical, Y is a direct bond or a methylene, isopropylidene, methyleneoxy or isopropylideneoxy radical and R<4>is a phenyl, 3- or 4-chlorophenyl or 3- or 4-trifluoromethylphenyl radical, and for these compounds where fR^. is\ a carboxy radical, pharmaceutically or veterinary acceptable salts thereof as indicated above. A preferred group of compounds according to the invention, due to their high luteolytic effect, comprises cyclopentane derivatives of the formula I where Y is a methyleneoxy radical and R<4> is a phenyl or naphthyl radical which may optionally be substituted with one chlorine, fluorine - or trifluoromethyl radical, and in particular those cyclopentane derivatives where R"'" is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R 2 is a hydroxy radical, ;R 3 is a hydrogen atom, A is a trans-vinylene radical, Y is a methyleneoxy radical and R 4 is a 3- or 4-chlorophenyl or 3-; or 4-trifluoromethylphenyl radical.; A preferred group of cyclopentane derivatives according to the invention due to their ability to inhibit gastric secretion comprises compounds of formula I where Y is an isopropylideneoxy radical and R<4> is a chlorophenyl or trifluoromethylphenyl radical, and especially compounds where R"^ is a carboxy, methoxycarbonyl, or ethoxycarbonyl radical, especially carboxy, R 2 is a hydroxy-;3 2 3 radical and R is a hydrogen atom, or preferably R and R together form an oxo radical, A is a trans-vinylene radical, Y is an isopropylideneoxy radical and R<4> is a chlorophenyl radical, especially a 4-chlorophenyl radical. The particularly preferred cyclopentane derivative of formula I is 16-(3-chlorophenoxy)-9a, 11a, 15-trihydroxy-17,18,19,20-tetra-nor-5-trans\7yl 3-trans-prostadienoic acid, 9a ,lla,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor-5- transftl3- trans-prostadic acid, 16-(4-chlorophenoxy)-lia,15-dihydroxy -16-methyl-9-oxo-18,19,20-trinor-5-trans,13-trans-prostadic acid, 9a,11a,15-trihydroxy-16-phenyl-17,18,19,20-tetranor-5 - trans,13-trans-prostadic acid, 11a,15-dihydroxy-9-oxo-16-phenyl-17,18,19,20-tetra-nor-5-. trans ,13- trans -prostadioic acid and 11a , 15-trihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5- trans ,13- trans -prostadioic acid. The new cyclopentane derivatives according to the invention can be prepared according to known methods for the preparation of chemical analogues/compounds. The compounds according to the invention can be prepared by: (a) separating a mixture of the 5-trans-cyclopentane derivative of formula I and the corresponding 5-cis-isomer; (b) for the preparation of compounds where R 2 is a hydroxy radical and R is a hydrogen atom, reduce an enone of the formula: ; where R<4> has the above meaning, R<5> is an alkoxycarbonyl radical with up to 11 carbon atoms, and R and R independently of each other are a hydroxy radical or a protected hydroxy radical, and then when R 6 and R 7 are protected hydroxy radicals , removes the protecting groups, and to obtain a compound where R<1>; is a carboxy radical, the product obtained is hydrolyzed with a base, ; or for the preparation of a compound of formula I where R"*"

is a hydroxymethyl radical, the product obtained reduces, for example, with a complex metal hydride such as lithium aluminum hydride;

(c) for the preparation of compounds where R 2 is a hydroxy radical and R is a hydrogen atom, thermolysis of a phosphonium betaine of the formula:

14 3

where R , R , A and Y have the above meanings, R is a hydrogen atom, R is an aryl radical, for example a phenyl radical, R 9 is an alkyl radical with 1 to 6 carbon atoms, for example a methyl or ethyl radical, and R< 1>^ is a tetrahydropyran-2-yl radical and then the protected tetrahydropyranyl radicals R10 are hydrolysed.

A suitable method for separating the 5-trans compounds according to the invention from a mixture of the 5-cis and 5-trans compounds according to method (a) is by means of chromatography, for example on silica gel impregnated with silver nitrate, but other conventional methods for separating cis-trans mixtures can also be used, for example fractional crystallization.

The mixture of cis- and trans-isomers from which the trans-isomer can be separated according to method (a) can be obtained, for example, by reacting a lactol with the formula:

where A, Y and R<4> have the meanings given above and R<11> and R<1>^ are independent of each other, for example tetrahydropyran-2-yl-

or alkanoyl radical, with a ylide prepared from a (4-carboxy-butyl)triphenylphosphonium salt, for example the bromide, by means of butyllithium in a solvent, for example sulfo[lane, followed by hydrolysis of the protected groups R<11>and R 12. While this reaction gives predominantly the cis compound when the ylide is prepared using a sodium base, the use of butyl lithium in sulfolane gives a mixture of cis and trans isomers containing up to 40 1 of the trans isomer. The protective ones are then removed

11 12

the groups R and R , by treatment with an acid, for example acetic acid, or with a base, for example potassium carbonate in methanol.

Alternatively, the mixture of cis- and trans-isomers used as starting material in method (a) can be obtained by photolysis of the more readily available cis-isomer, for example by irradiation of an oxygen-free benzene/methanol solution of the cis-isomer, which contains 2 equivalents of diphenyl sulphide, using light V^|ol length 350 nm for 24 hours.

Method (b) according to the invention reduction can be carried out by using, for example, zinc borohydride, aluminium-tri-. isopropoxide or diisobio/rnyloxy aluminum isopropoxide. A suitable meaning for R 6 or R 7 when it is a protected hydroxy radical is for example an acyloxy radical, for example acetoxy or 4-phenylbenzoyloxy radical. Preferred enones as starting materials of the formula II are those where R<6> and R 7 are both hydroxy radicals or both 4-phenylbenzoyloxy radicals, or where R 6 is a 4-phenylbenzoyloxy radical and R 7 is a hydroxy radical. The protecting group can be removed from such a protected hydroxy radical, for example by hydrolysis with a base. It will of course be understood that the hydrolysis conditions can be chosen so that the ester group R^ is also hydrolyzed or so that the group is left unchanged.

The starting material with the formula II which is used in the process according to the invention can be obtained, for example, by treating the known iodo-lactone V with tributyltin hydride, and deiodinated lactone VI is obtained. The hydroxy group is protected as tetrahydropyran-2-yl ether VII, the lactone is reduced to lactol VHI using diisobutyl aluminum hydride, the lactol is reacted with

(4-carboxybutyl)-triphenylphosphonium bromide, and the acid IX is obtained. The acid IX is esterified, for example with diazdmethane, and the ester X is obtained, which is epoxidized with m-chloroperbenzoic acid, while simultaneously removing the tetrahydropyranyl group, and the epoxide diol XI is obtained. The two hydroxy radicals are protected as tetrahydropyranyl ethers XII, and reaction with lithium diphenyl phosphide gives a diphenyl phosphine derivative XIII of uncertain structure. Reaction of XIII with methyl iodide gives a phosphonium betaine XIV, which readily undergoes thermal elimination, and trans-olefin XV is obtained. The two tetrahydropyranyl groups are removed with acid, and the diol XVI (R 6 g R 7 = hydroxy) is obtained, treatment

with a strong acid, the acetal group hydrolyzes, and one obtains the aldehyde XVII (R 6 = R 1 = hydroxy), and the reaction of the aldehyde XVII with a phosphonate derivative of the formula (CH_0)9P0.CH-CO.YR 4 in the presence of a strong base gives the starting material II , (R 5 = methoxycarbonyl, R 6 = R 7 = hydroxy).

f\ 7

Alternatively, the diol XVI (R = R = hydroxy) can be transferred to the bis-ester, for example XVI (R 6 = R 7 = 4-phenylbenzoyloxy) which is hydrolysed to the aldehyde XVII (R6 = R<7>= 4-phenyl- benzdyloxy), which is then reacted with the phosphonate derivative, and a starting material with the formula II is obtained (R 6 = R 7 = 4-phenylbenzoyloxy).

Alternatively, the tetrahydropyranyl ether XII is transferred to a trithiocarbonate with the formula:

for example with potassium methyl xanthate, and the trithiocarbonate XX is desulphurised, for example with trimethyl phosphite, and the trans-olefin XV is obtained.

f\ 7

•The compound XVI (R = R = 4-phenylbenzoyloxy) can alternatively be obtained from the cis compound XIX, by oxidative cleavage, for example with osmium tetroxide and sodium periodate,

and you get the aldehyde XX which is reacted with a phosphonate of the formula (CH30)2PO.CH2CO(CH2)2COOH in the presence of a strong base, and you get an enone XXI. The enone is reduced to the olefin XXII by preparing a thioketal which is then desulphurised, for example with Raney nickel. The olefin XXII is then esterified, and the desired compound XVII is obtained (R<6>= R<7>= 4-phenylbenzoyloxy).

In method (c) according to the invention, phosphonium betaine III, which is used as starting material, can be obtained from the known bis-(tetrahydropyranyl ether) with the formula:

rf\7

XVI (R = methoxycarbonyl, R = R = 4-phenylbenzoyloxy)

PB = 4-phenylbenzbyl.

by selective epoxidation of the cis-double bond with m-chloroperbenzoic acid, esterification of the carboxyl radical and protection of the 9-hydroxyl radical, also as a tetrahydropyranyl ether, followed by reaction of the protected epoxide with a lithium diaryl phosphide, LiP(R 8)9 and quaternization with a alkyl halide,

9 10

R halogen. The protected tetrahydropyranyl radicals R are suitably removed by acid hydrolysis, for example with acetic acid.

The. it will of course be understood that an optically active compound according to the invention can be obtained either by dissolving the corresponding racemate or by carrying out the above-described method starting from an optically active starting material.

As indicated above, the cyclopentane derivatives according to the invention have a luteolytic effect. 16-(3-Chlorophenoxy)-9a,11a,15a-trihydroxy-5-transfTl 13-trans-prostadic acid is, for example, approx. 50 times more effective than prostaglandin-F2a in a luteolytic experiment with hamsters by subcutaneous dosing.

The compound according to the present invention is therefore useful, for example, for inducing labor pains and is used for this purpose in the same way as, for example, the naturally occurring prostaglandin-E^ and -E2, i.e. by administering a sterile,

mainly aqueous solution containing from 0.01 to 10ug../ml,

preferably 0.01 to lyg./ml of active compound, in the case of intravenous,

extraovular or intra-amniotic administration until labor begins. For this purpose, the compounds according to the present invention can be used in combination, or at the same time, with a stimulating agent for the uterus, for example oxytocin, in the same way as it is known to use prostaglandin-F2a in combination, or at the same time, with oxytoxin for inducing labor .

When a compound according to the invention is used to regulate the estrous cycle in animals, they can be used in combination, or at the same time, with a gonadotropin, for example PMSG (prime serum) or HCG (human chorionic gonadotropin) to on-rush the beginning of the next cycle.

It is thus a feature of the invention to provide a pharmaceutical or veterinary medicine preparation containing a cyclopentane derivative according to the invention, together with a pharmaceutical or veterinary medicine acceptable diluent or carrier.

The preparations may be in a form suitable for oral administration, for example tablets or capsules, in a form suitable for inhalation, for example an aerosol or a solution suitable for spraying, in a form suitable for parenteral administration, for example sterile injectable aqueous or oily solutions or suspensions, or in the form of a suppository, suitable for anal or vaginal use.

The preparations according to the invention can be prepared by conventional means and conventional excipients can be added.

The following examples illustrate the invention:

Example 1

A mixture of 16-(3-chlorophenoxy)-9α,11α,15α-trihydroxy-17,18,19,20-tetranor-5-cis, 13-trans-prostadic acid and the corresponding 5-trans-, 13-trans- compound was thin-layer chromatographed on silica gel GF 254 plates (Merck Darmstadt) which are impregnated with silver nitrate before use. The plates are developed with 101 acetic acid in ethyl acetate, and the separated compounds are located by removing a strip from the edge of a plate, spraying the strip with cerium sulfate solution and developing the strip by heating. The trans-isomer showed = 0.4 and the cis-isomer R^ = 0.3. The required strips corresponding to the trans isomer were removed from the plates, and the desired 16-(3-chlorophenoxy)-9a,11a,15a-trihydroxy-17,18,19,20-tetranor-5- trans, 15,- trans -prostadic acid was eluted. The nuclear magnetic resonance spectrum in deuteriochloroform showed the following characteristic peaks (6 values):

2.28, 2H, triplet, -CH2-COOH

3.98, 3H, multiplet

4,16, 1H, multiplet >CH.O-

4.46, 1H, multipletJ

5,50, 2H, multiplet, 5,6- trans-olefinic protons 5,70, 2H, multiplet, 13,14- trans-olefinic protons 6,8-7,4, 4H, multiplet, aromatic protons.

The mass spectrum of the tetra(trimethylsilyl) derivative showed (M-CH3)<+>= 697.3000 (calculated for C34H61C106Si4= 697.3017).

The mixture of the 5-cis, 13-trans and 5-trans, 13-trans compounds used as starting material can be obtained as follows:

(4-carboxybutyl)-triphenylphosphonium bromide (156 mg,

0.35 mmol) was dried at 60°C. in vacuo for 1 hour and was then dissolved in sulfolane (2.7ml) in an inert atmosphere. n-Butyl lithium (290 µl of a 2.29 M solution in hexane) was added dropwise and the mixture was stirred at 35°C for 45 minutes. 43-[4-(3-Chlorophenoxy)-3a-(tetrahydropyran-2-yloxy)-but-1-trans-enyl]-2,3,3ag,6ag-tetra-„ hydro- 2-hydroxy-5a-( (tetrahydropyran-2-yloxy)cyclopenteno-.[b]furan (67 mg, 0.13 mmol) was subjected to azeotropic distillation with toluene and dried in vacuo. A mixture of sulfolane (0.8 ml) and toluene (0.27 ml) was then dissolved in OH and added to the phosphorane solution. After two hours the mixture was diluted with water (10 mL) and extracted with ether (4 x 10 mL) and the ether extracts were dissolved. The aqueous solution was adjusted to pH /3/.0 with 2N oxalic acid. and extracted with 1:1 ether/pentane (5 x 10 mL). The combined extracts were dried and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel GF 254 plates with 5% methanol in methylene chloride, and a mixture of 16-(3-chlorophenoxy)-9a-hydroxy-11a,15a-bis-(tetrahydropyran-2-yloxy)- 17,18,19,20-tetranor-5-cis,13-trans-prostadic acid and the corresponding 5-trans,13-trans compound, R£ = 0.3.

The mixture of bis-(tetrahydropyranyl ethers) (63mg) was dissolved in tetrahydrofuran (0.46ml), a 2:1 mixture of acetic acid and water (5.7ml) was added and the mixture was heated at 50°C for 2 hours. The residue was dried by azeotropic distillation with toluene, and the desired mixture of 5-cis, 15-trans-

and 5- trans, 15- trans compounds.

Example 2

The procedure described in the first part of example 1 was repeated by using the corresponding 16-(5-trifluoromethyl-phenoxy) as starting material instead of 16-(5-chlorophenoxy), and one obtains 9a,11a,15-trihydroxy- 16-(5-trifluoromethylphenoxy)-17,18,19,20-tetranor-5-trans,15-trans-prostadienic acid, Rp = 0.4 (10% acetic acid in ethyl acetate on silica gel impregnated with silver nitrate). The nuclear magnetic resonance spectrum in hexadeutrioacetone showed the following characteristic features (5 values):

2.28, triplet, 2H, -CH2.CO2H

5.9-4.6, multiplet, 5H, )CH-0-

5.45, multiplet, 2H, 5.6- trans olefinic protons 5.65, multiplet, 2H, 15.14- trans olefinic protons 7.1-7.8, multiplet, 5H, aromatic protons.

lThe starting material, 16-(5-trifluoromethylphenoxy) ,

which was used in the above method was prepared according to the method indicated in the second part of Example 1 by using the corresponding 3-(triflugrmethylphenoxy)butenyl-cyclopenteno[b]furan derivative instead of the 5-chlorophenoxy compound.

Example 5

The procedure described in the first part of example 1 was repeated by using the corresponding 16-phenyl starting material instead of 16-(5-chlorophenoxy), and one obtains 9a,11a,15a-trihydroxy-16-phenyl-17, 18,19,20-tetranor-5-trans, 15-trans-prostadienic acid, Rp = 0.55 (10% acetic acid in ethyl acetate on silica gel impregnated with silver nitrate). The nuclear magnetic resonance spectrum in hexadeuterioacetone showed the following characteristic features (6 values):-

2.28, triplet, 2H, -CH2COOH

2.8, multiplet, 2H, -CH2Ph

3.5-4.5, multiplet, 7H, ^,CH-O- and -OH

5.5, multiplet, 4H, olefinic protons

7.2, singlet, 5H, aromatic protons.

The mass spectrum of the tetra(trimethylsilyl) derivative showed M<+>= 647.3360 (calculated for<C>33<H>59<0>5<Si>4 = 647.3443).

The mixture of the 5-cis, 13-trans and 5-trans, 13-trans compounds which were used as starting material can be obtained as described in the last part. in Example 1 using the mixed side-chain C-3 epimers of 2,3,3α3,6α3-tetrahydro-2-hydroxy-43-[4-phenyl-3-(tetrahydropyran-2-yloxy)-but -1- trans-enyl]-5 α-tetrahydropyran-2-yloxy)cyclopenteno[b]furan, and a mixture of mixed C-15 epimers of 9α-hydroxy-16-phenyl-lla,15-bis- (tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-cis,15-trans-prostadic acid and the mixed C-15 epimers of the corresponding 5-trans,13-trans compound.

The mixture of bis-(tetrahydropyran-2-yl ether yeast)

(200mg) was dissolved in tetrahydrofuran (4.2ml), a 2:1 mixture of acetic acid and water (11.5ml) was added and the mixture was heated for 1 hour at 50°C. The residue was dried by azeotropic distillation. with toluene, and a mixture of the mixed C-15 epimers of 9a,11a,15-trihydroxy-16-phenyl-17,18,19,20-tetranor-5-cis,13-trans-prostadic acid and the mixed C-15 epimers of the corresponding 5-trans, 13-trans compound.

This mixture of the two pairs. epimers were separated by means of thin-layer chromatography on silica gel GF.254 plates, (Merck, Darmstadt) developed with 3% acetic acid in ethyl acetate, and a mixture of the more polar C-15 epimers of 5-cis,13-trans- and the 5-trans,13- trans compounds R„ = 0.25, the desired starting material, and a mixture of the less polar C-15 epimers of 5- cis,13- trans and 5- trans,13- trans -compounds, Rp = 0.35.

Example 4.

The procedure described in the first part of example 1 was repeated by using the corresponding 9-oxo-16-phenyl starting material instead of 16-(3-chlorophenoxy), and one obtains lia,15a-dihydroxy-9-oxo- 16-phenyl-17,18,19,20-tetranor-5-trans, 13-trans-prostadienic acid, Rp = 0.35 (101 acetic acid in ethyl acetate on silica gel impregnated with silver nitrate). The nuclear magnetic resonance spectrum in hexadeuterioacetone showed the following characteristic features (6 values):

2.85, multiplet, 2H, -CH2Ph

3.5-4.5, multiplet, 5H,)CH-O- and -OH

5,4, multiplet, 2H, 5,6- trans olefinic protons 5,6, multiplet, 2H, 15,14- trans olefinic protons

7.2, singlet, 5H, aromatic protons.

The mass spectrum of the triis[(trimethylsilyl)-9-methoxyme derivative showed

M<+>= 617.5558 (calculated for C32H55N05Si3617.5588).

The mixture of the 5-cis, 15-trans and 5-trans, 15-trans compounds which were used as starting material can be obtained as follows: The mixture of the mixed C-15 epimers of 9a-hydroxy-16-phenyl-lia, 15-bis(tetrahydropyran-2-yloxy)-17,18,19,20-tetranor-5-7£is, 13- trans -prostadic acid and the mixed C-15 epimers of the corresponding 5- trans , 15- trans -compound (757mg), prepared as indicated in the second part of Example 5, was dissolved in pure acetone (16ml), and cooled to 0°C, Jones' reagent (chromic acid in acetone, 0.45ml) was added and the solution was stirred for 15 minutes at 0°C. Isopropanol (5 drops) was added, followed by ethyl acetate. The solution was washed with saturated saline and dried, and the solvent was evaporated to give a mixture of the mixed C-15 epimers of 9-oxo-16-phenyl-11a,15-bis-(tetrahydropyran-2-yloxy)- 17,18,19,20-tetranor-5-cis,15-trans-prostadienic acid and the blued C-15 epimers of the corresponding 5-trans,15-trans compound, Rp = 0.5 (5% methanol in methylene dichloridej_.

A solution of these mixed epimers (761mg) in a mixture of acetic acid (29ml), water (15ml) and tetrahydrofuran (16ml) was stirred at 50°C for 1h, and the solvents were evaporated to give a residue consisting of a mixture of the mixed C-15 epimers of lia, 15α-dihydroxy-9-oxo-16-phenyl-17,18,19,2[01-tetranor-5-cis,15-trans-prostadienic acid and the mixed C -15-epimers of the corresponding 5-trans, 15-trans compound. C-15 epimers were separated according to the procedure described in the last part in example 5, and the mixture of more polar C-15 epimers of the 5-cis, 15-trans and 5-trans, 15-trans compounds was obtained, the desired starting material.

Example 5

A mixture of methyl-15-(4-trifluoromethylphenyl)-9-oxo-11a,15a-dihydroxy-16,17,18,19,20-pentanor-5-cis, 15-trans-

prostadienonate and the corresponding 5- trans, 13- trans compound were thin-layer chromatographed on silica gel GF 254 plates, (Merck, • Darmstadt) which were impregnated with silver nitrate before use. Plates were developed by diluting twice with 33% acetone in methylene chloride,

and the separated compounds were located by removing a strip along the edge of a plate, spraying the strip with cerium sulfate solution, and developing the strip by heating. The trans isomer showed Rp = 0.58 and the cis isomer Rp = 0.54. The trims corresponding to the trans isomer were removed from the plates, and methyl-11a,15a-dihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-trans, 13- trans-prostadienonate was eluted. The nuclear magnetic resonance spectrum in hexadeutrioacetone showed the following characteristic peaks (S values):

3,6, singlet, 3H, -COOCHj

4.0-4.8, multiplet, 3H, C-IIg proton and -OH

5,3-5,5, multiplet, 3H, 5,6-trans olefinic protons

plus C-153 proton

5.8-6.0, multiplet, 2H, 13,14- trans -olefinic protons

7.65, singlet, 4H, aromatic protons.

The mass spectrum of the bis(trimethylsilyl)-9-methoxyme derivative showed M+ 613.2889, (calculated for C 30 H 46 F 3 NO 5 Si 2 = 613.2867).

The mixture of methyl 15-(4-trifluoromethylphenyl)-9-oxo-11a,15a-dihydroxy-16,17,18,19,20-pentanor-5-cis,13-trans-prostadienoate and the corresponding 5-trans, 13- trans compound used as starting material was prepared as follows: To a solution of 5a-hydroxy-2-oxo-4g-[3-(4-trifluoromethylphenyl)-2,3,3ag,6ag-tetrahydro -3-Hydroxy-1-trans-propenyl]-cyclopentenotb]furan (300mg) in toluene (10ml) in an atmosphere of nitrogen at 0°C was successively added redistilled 2-methoxy-propene (0.9ml) and a solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran (0.04 ml of a 1% solution). The solution was heated to room temperature and after 25 minutes pyridine (0.002ml) was added. The solution was cooled to -78°C and di-isobutyl aluminum hydride (0.9ml of a 1.95M solution in toluene) was added. After 10 minutes, the reaction was stopped by the dropwise addition of methanol (0.2 ml) and heated to room temperature. The reaction mixture was added to ethyl acetate (25ml), which was quickly washed with a mixture of 1:1 saturated saline/water (2x5ml) and dried. The solvent was evaporated and a mixture of epimeric lactols was obtained, 2,3,3α3,6α3-tetrahydro-2-hydroxy-5α-(1-methoxy-1-methylethoxy)-43-[3-(1-methoxy- 1-methylethoxy)-3-(4-trifluoromethylphenyl)-1-trans-propenyl]cyclopenteno[b]furan, R„ = 0.4 (1:1 ethyl acetate/toluene).

(4-Carboxybutyl)-triphenylphosphonium bromide (1.03g, 2.33mmol) was dried at 70°C in vacuo for 1 hour and was then dissolved in sulfolane (20ml) in an inert atmosphere. n-Butyl lithium (3.1ml of a 1.42M solution in hexane) was added dropwise and the mixture was stirred at 35°C for 30 minutes. The above epimeric lactols (503mg, 0.88mmol) were subjected to azeotropic distillation with toluene, dried in vacuo, dissolved in sulfolane (2ml) and added to the phosphorus solution. After 1 hour the mixture was diluted with water (10ml) and extracted with ether (3 x 20ml) and the ether extracts were discarded. The aqueous solution was adjusted to pH 5.0 with a saturated aqueous solution of oxalic acid and extracted with 1:1 ether/pentane. (5 x 20ml). The combined extracts were dried and the solvent evaporated under reduced pressure to give a mixture of the mixed C-15 epimers of 9α-hydroxy-11a,15-bis-(1-methoxy-1-methylethoxy)-15-( 4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5- cis , 13- trans -prostadic acid and the mixed C-15 epimers of the assimilating 5- trans , 13- trans compound Rp = 0, 29 (5% methanol in methylene chloride) together with some residual sulfolane.

A solution of the above mixture of the prostadiic acid derivatives (300mg) in methylene chloride (2ml) was added to the Collins [chromium trioxide (480mg) added to pure dry methylene chloride (1Oml) and pyridine (0.774ml) and stirred before use at room temperature for 15 minutes] and stirred at room temperature for 10 minutes. Isopropanol (3 drops) was added, the reaction mixture was filtered through "Celite" (trademark), evaporated to dryness and further dried by azeotropic distillation with cyclohexane. The residue was dissolved in ether and filtered through "Celite" and the solvent was evaporated to give a mixture of the mixed C-15 epimers of 11a,15-bis(1-methoxy-1-methyl-ethoxy)-9 -oxo-15-(4-trifluoromethylene-phenyl)-16,17,18,19,20-pentanor-5-cis,13-trans-prostaS5:enoic acid and the mixed C-15 epimers of the corresponding 5 - trans, the 13-trans compound, Rp = 0.44 (101 methanol in methylene dichloride) together with some residual sulfolane.

The above mixture was dissolved in 3.3 ml of pH 3 citric acid buffer and 6.6 ml of acetone and stirred at room temperature for 18 hours. The solvents were evaporated, and the residue was dried by azeotropic distillation with toluene and. subjected to column chromatography on CC4 silica gel (Mallinckrodt Chemical Works) (35g), eluting with a gradient of increasing amounts of ethyl acetate in cyclohexane, and the more polar C-15-epimers of the mixture of 11a,15a-dihydroxy- 9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,15-trans-prostadioic acid and the corresponding 5-trans,13-trans compound Rp = 0.27 (3 % acetic acid in ethyl acetate).

To a solution of this mixture of the more polar C-15 epimers of 5-cis, 15-trans and 5-trans[7|13-trans compounds (26mg) in ether (5ml) at 0°C. was added an excess of diazomethane in ether. After 15 minutes, the solvents were evaporated, and a mixture of methyl-11a,15a-dihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5-cis,15 was obtained - trans-prostadienoate and the corresponding 5-trans, 15-trans compound, the desired starting material.

Example 6

A solution of the mixed C-15 epimers of 16-(4-chlorophenyl)-16-methyl-9-oxo-lia,15-bis(tetrahydropyran-2-yloxy)-18,19,' 20-trinor-5 - trans,15-trans-prostadic acid (78.4mg) in a mixture of acetic acid (5.7ml), water (0.92ml) and tetrahydrofuran (1.8ml) was stirred at 50°C for 5| hour. The solvents were evaporated under reduced pressure and the residue was dried by azeotropic distillation with toluene to give the mixed C-15 epimers of 16-(4-chlorophenyl)-11a,15-dihydroxy-16-methyl-9-oxo-18 ,19,20-trinor-5-trans,15-trans-prostadic acid. C-15 epimers were separated by thin layer chromatography on silica gel GF 254 plates, (Merck, Darmstadt), eluting twice with 1% acetic acid in ethyl acetate. The necessary strips corresponding to the more polar epimer were removed from the plates, and the single epimer of 16-(4-chlorophenyl)-11a, 15-dihydroxy-16-methyl-9-oxo-1(8!, 19 ,20- trinor-5-trans,15-trans-prostadienoic acid, Rp = 0.4, was eluted.The nuclear magnetic resonance spectrum in hexadeutrioacetone showed the following characteristic peaks (6 values):

1.25, doublet, 6H, -CH(OH)-C(CH3)2~0-

2.25, triplet, 5H, -CH^COOH

4.15, multiplet, 2H, C-llg proton

5,4, multiplet, 2H, 5,6-trans- olefinic protons 5,85, multiplet, 2H, 15,14- trans olefinic protons 7,15, quartet, 4H, aromatic protons.

The mass spectrum for the 9-methoxy-tris(trimethylsilyl) derivative showed (M-<CH>3)<+><=>680.3046 (calculated for C25H4gN05Si3= 680.3025).

The mixed C-15 epimers used as starting material in the above procedure were prepared as follows: (4-carboxybutyl.l)triphenylphosphonium bromide (9.92g) was dissolved in sulfolane (136ml) under nitrogen, and n-butyl -lithium (23.4mlPav a 1.42M solution in hexane) was added with stirring. After 30 minutes at 30°C, a solution of 4g-dimethoxy-■ methyl-2,3,3ag,6ag-tetrahydro-2-hydroxy-5B-(tetrahydropyran-2-yloxy)-cyclopenteno[b]furan (2 ,Og) in a mixture of sulfolane (24 mL) and toluene (8 µl). After stirring for 1 hour, water (400 ml) was added and the mixture was extracted with ether (5 x 400 ml). The aqueous solution was acidified with oxalic acid to pH 5 and extracted with 50% ether in pentane (4 x 400ml). The organic phases were combined and dried, and the solvent was evaporated under reduced pressure. The residue was subjected to dry column chromatography on silica gel (300g), eluting with ethyl acetate, and a mixture of 5-cis- and 5-trans-isomers of 7-[2g-dimethoxymethyl-3a-hydroxy-5a-(4-phenylbenzoyloxy) is obtained cyclopent-la-yl]hept-5-enoic acid, Rp =

0.33 (5% methanol in methylene dichloride). The nuclear magnetic resonance spectrum in deutriochloroform showed the following characteristic features (6 values):

3.4, singlet, 6H, -OCH3

5.5, multiplet, 2H, olefinic protons To a solution of the mixture of cis- and trans-isomers (2.47g) in ether (25ml) was added an excess of a solution of diazomethane in ether. After 20 minutes at room temperature, the excess diazomethane was evaporated in a stream of argon, and the ether solution was evaporated in vacuo. The residue was subjected to dry column chromatography on silica gel (240g), eluting with 50% ethyl acetate in toluene and the product obtained was chromatographed again on a dry column of silica gel (450 µg impregnated with silver nitrate (54g), eluting with 50% ethyl acetate in /tbluen, and methyl 7-[2g-dimethoxymethyl-5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-cyclopent-la-yl]hept-5-trans-enoate is obtained as a clear oil,

Rp = 0.7 (50% ethyl acetate in toluene on silica gel impregnated with silver nitrate.) The nuclear magnetic resonance spectrum in deuteriochloroform showed the following characteristic features (6 values):

3.37, singlet, 6H, ) C-(OCH_3) 2

3.63, singlet, 3H, -COOCH3

4.65, multiplet, 1H, tetrahydropyranyl C-2 proton 5.49, multiplet, 2H, trans olefinic protons. Methyl 7-[2g<->dimethoxymethyl-5a-hydroxy-3a-(tetrahydropyran-2-yloxy)cyclopent-la-yl]hept-5-trans-enoate

(379mg) was dissolved in dry pyridine (4.4ml) under argon, and treated with p-phenylbenzoyl chloride (411mg) and the mixture was stirred for 17 hours. Water (150ml) was then added and stirring was continued for 2 hours. The mixture was evaporated under reduced pressure and toluene was added to facilitate the azeotropic removal of pyridine. The residue was partitioned between toluene (30ml) and saturated sodium bicarbonate solution (15ml). The entire mixture was filtered through "Hyflo" (trademark) and the organic phase was separated. The aqueous layer was extracted with toluene (15ml), the organic extracts were combined, washed with brine (10ml), dried over sodium sulfate, filtered and the solvent evaporated to give methyl 7-[2£-dimethoxymethyl-5a- (4-Phenylbenzoyloxy)-3α-(tetrahydropyran-2-yloxy)cyclopent-la-yl]-hept-5-trans-enoate as a clear oil, Rp = 0.57 (251 pentane in ether). The nuclear magnetic resonance spectrum in deutriochloroform showed the following characteristic features (6 values):

3.41, multiplet, 6H, )C(OCH 3 ) 2

3.6, singlet, 3H, -COOCH3

5.3-5.5, multiplet, 3H, trans olefinic and C-5B protons

7.1-7.7, multiplet, 7H, aromatic protons

8.08-8.21, multiplet, 2H,

A solution of methyl 7-[23-dimethyloxymethyl-5α-(4-phenylbenzoyloxy)-3α-(tetrahydropyran-2-yloxy)cyclopent-la-y|J]/hept-5- trans -enoate (550mg) in dry methanol (12ml) was stirred under argon at room temperature with toluene-p-sulfonic acid (1.6ml of a 1% solution of anhydrous toluene-p-sulfonic acid in dry tetrahydrofuran for 17 hours. Pyridine (2 drops) and toluene were added (40ml) and the solvent was evaporated under reduced pressure, the residue was partitioned between ethyl acetate (50ml) and water (25ml), the organic phase was separated, washed successively with saturated sodium bicarbonate

(2 x 15ml) and saturated salt solution (15ml), dried and the solvent evaporated to give methyl-7-[23-dimethoxymethyl-3a-hydroxy-5a-/T4-phenylbenzoyloxy)cyclopent-la-yl] hept-5-trans-enoate as a clear oil, Rp = 0.47 (10% ethyl acetate in methylene dichloride).

The nuclear magnetic resonance spectrum in deuteriochloroform showed the following characteristic features (6 values): 3.43<>>

singlets, 6H, 7C(OCH_3)2

3.48j

3.61, sgn<g>lett, 3H, -COOCH3

4.17-4.48, multiplet, 2H, -CH(OCH3)2 and C-33 protons 5.3- 5.5, multiplet, 3H, olefinic and C-53 protons 7.4- 7.75. multiplet.7H. aromatic protons

8.07-8.2, multiplet

Methyl 7-[2B-dimethoxymethyl-3a-hydroxy-5a-(4-phenylbenzoyloxy)cyclopent-la-yl]nept-5-trans-enoate (306mg)

was vigorously stirred under argon for 10 minutes in a two-phase system consisting of 2% isopropanol in chloroform (12ml) and concentrated hydrochloric acid (6ml). The entire reaction mixture was poured into an excess of saturated bicarbonate and the organic layer was separated.

The aqueous solution was extracted with ethyl acetate (3 x 50ml),

the combined organic extracts were washed with brine (50ml), dried and evaporated to give methyl-7-[2B-formyl-3a-hydroxy-5a-(4-phenylbenzoyloxy)cyclopent-la-yl]hept-5- trans -enoate as a clear oil, Rp = 0.4 (50% ethyl acetate in toluene).

Dimethyl-2-oxo-3-methyl-3-(4-chlorophenoxy)-butylphosphonate (486mg) and methyl-7-[23-formyl-3a-hydroxy-5a-(4-phenylbenzoyloxy)-cyclopent-la-yl] hept-5-trans-enoate (269mg) was suspended under argon in a mixture of toluene (9ml). Aqueous 1M sodium hydroxide solution (1.2ml) was added and the two phase mixtures were vigorously stirred for 16 hours. The reaction mixture was shaken with ethyl acetate (20ml) and brine (20ml) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 40ml), the combined organic extracts were dried and the solvent was evaporated. Dry column chromatography using silica gel (150g) and 50% ethyl acetate in toluene and eluent gave the enone methyl-16-(4-chlorophenoxy)-11a-hydroxy-16-methyl-15-oxo-9a-(4-phenylbenzoyloxy) )-18,19,20-trinor-5-trans, 13- trans -prostadienoate, Rp = 0.66 (ether) as an oil.

The nuclear magnetic resonance spectrum in deuteriochloroform showed the following characteristic features (6 values):

1.52, singlet, 6H, two methyl groups

3.61, singlet, 3H, -OCH3

5,2-5,5, multiplet, 3H, 5,6-trans-olefinic and

C-93 protons

6,7-7,7, multiplet, 13H, aromatic and 15,14- trans

olefinic protons

8.0-8.2, multiplet,

The enone (225mg) was stirred under argon at room temperature with a 0.56M solution of diisobornyloxyaluminum isopropoxide in toluene (5.84ml, 6 equivalents). After 16 hours the mixture was partitioned between water and ethyl acetate, filtered through "Hyflo" and the filter cake was washed with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and the solvent evaporated to give an impure product, which was purified by dry column chromatography over silica gel (120g), eluted with 50% ethyl acetate in toluene ,

and a mixture of epimeric diols was obtained, methyl-16-(4-chlorophenyl)-11a,15-dihydroxy-16-methyl-9a-(4-phenylbenzoyloxy)-18,19,20-tri-nor-5-trans , 15-trans-prostadienoate, together with the corresponding iso-propyl esters.

To a solution of the epimeric diols (152mg) in methylene dichloride (2ml) in a nitrogen atmosphere at 0°G was sequentially added redistilled 2,5-dihydropyran (175mg), followed by a solution of toluene-p_-sulfonic acid (50ml) in a 1% solution in tetrahydrofuran). After 10 minutes a drop of pyridine was added and the solution was washed successively with saturated sodium bicarbonate solution and saturated saline solution and was then dried. Evaporation of the solvents gave a mixture of C-15-epimer bis(tetrahydropyranyl ether), Rp = 0.8 (25% ethyl acetate in toluene).

The crude epimeric bis(tetrahydropyran-2-yl ethers)

(170mg) was stirred at room temperature under argon in a mixture of methanol. (2ml.), water (2ml) and 1,2-dimethoxyethane (1.5ml) with potassium hydroxide (2.05ml of a 1M solution in methanol, 10 equivalents) for 16 hours. Glacial acetic acid was added to adjust the pH of the solution to 7 and the solvents were evaporated under reduced pressure.

The residue was partitioned between water and ethyl acetate and extracted with ethyl acetate (2 x 30 ml). The combined organic phases were washed with brine and dried, leaving the solvent. evaporated and mixed C-15 epimers of 16-(4-chlorophenyl)-16-methyl-11a,15-bis(tetrahydropyran-2-yloxy<y>)-18,19,20-trinor-5- trans , 13- trans-prostadienic acid, Rp. = 0.5 (ethyl acetate), together with a small amount of 4-phenylbenzoic acid.

The above mixture (127mg) was dissolved in pure acetone (2.8ml), was cooled to -0°C, and Jones' reagent (chromic acid in acetone, 0.67ml) was added and the solution was stirred for 15 minutes at 0 °C. Isopropanol (3 drops) was added, followed by ethyl acetate. The solvent was washed with saturated saline and dried, and the solvent was evaporated to give the mixed C-15 epimers of 16-(4-chlorophenyl)-16-methyl-9-oxo-lla,15-bis(tetrahydropyran-2 -yloxy)-18,19,20-trinor-5- trans,13- trans -prostadic acid, Rp =

0.7 (ethyl acetate), which is the desired starting material.

Example 7

Sodium phosphate was dissolved in approx. 80% water, aftermoisture of the prostadic acid derivative, and when this had dissolved, sodium hydrogen phosphate. The solution was diluted to the correct volume with water for injection, and the pH was adjusted between 6.7 and 7.7. The solution was filtered to remove particulate matter, sterilized by filtration and filled into pre-sterilized neutral glass ampoules under aseptic conditions. Immediately before use, the contents of an ampoule were diluted in sodium chloride B.P. for administration by intravenous infusion.

The prostadic acid derivative can of course be replaced by an equivalent amount of another prostanic acid derivative according to the invention.

Example 8

The procedure described in Example 7 was repeated omitting sodium phosphate B.P. and sodium hydrogen phosphate B.P., and one obtains ampoules containing a sterile aqueous solution of 16-(4-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5- trans, 13- trans -prostadienoic acid, which can be used in the same way as described in example .7.

The prostadic acid derivative can be replaced with an equivalent amount of another prostadic acid according to the invention to give other sterile aqueous solutions.

Claims (28)

1. Cyclopentane derivative with the formula: where R is a hydroxymethyl or carboxy radical, or an alkoxycarbonyl radical with up to 11 carbon atoms; R 2 is either a hydroxy radical or ( §' t alkanoyloxy radical with 1 to 4 carbon-3 2 3 atoms and R is a hydrogen atom or R and R together form an oxo radical; A/e? is an ethylene or trans-vinylene radical; Y is a direct bond or an alkylidene or alkylideneoxy radical with 1 to 5 carbon atoms, where the alkylidene moiety in the latter is bonded to the carbon atom of the -CH(OH) group <p> and the oxygen atom is bonded to R <4> ; and R <4> is a phenyl or naphthyl radical which may be unsubstituted or substituted with halogen atoms, nitro, hydroxy or phenyl radicals, alkyl, alkenyl, haloalkyl, alkoxy, alkenyloxy or acylamino radicals containing up to 4 carbon atoms , or dialkylamino radicals where each alkyl group contains from 1 to 3 carbon atoms; the compound inside holds 0 or 1 alkyl radical of 1 to 4 carbon atoms at carbon atom 2, 3 or 4; and for compounds where R"" is a carboxy radical pharmaceutically or veterinary acceptable salts thereof. 2. Cyclopentane derivative as stated in claim 1, characterized in that R<1> is a hydroxymethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, n-butoxycarbonyl or n-decyloxycarbonyl radical; R 2. is a hydroxy, acetoxy or propionyloxy radical and R is a hydrogen atom or R and R 3 together form an oxo radical; A is an ethylene or trans-vinylene radical; Y is a methylene, methyleneoxy, ethylidene, ethylideneoxy, isopropylidene, isopropylideneoxy, propylidene, propylideneoxy, 1-methylpropylidene, 1-methylpropylideneoxy, 1-ethylpropylidene or 1-ethylpropylideneoxy radical; and R <4> is a phenyl or naphthyl radical which may optionally be substituted with chlorine, bromine or fluorine atoms, or with methyl, t-butyl, allyl, methoxy, allyloxy, acetamido, chloroalkyl, fluoroalkyl or dimethylamino radicals; the compounds containing 0 or 1 methyl substituent at carbon atom 2, 3 or 4; and for compound wherein R1 is a carboxy radical, ammonium, alkylammonium containing 1 to 4 alkyl radicals each containing 1 to 6 carbon atoms alkanol-ammonium containing 1 to 3 2-hydroxyethyl radicals and alkali metal salts thereof. 3. Cyclopentane derivative as stated in claim 2, characterized in that R <4> is a phenyl, naphthyl, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl-, trifluoromethylphenyl-,. hydroxyphenyl, methoxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl or tetrahydronaphthyl radical. 4. Cyclopentane derivative as specified in claim 3, characterized in that R4 is a phenyl-, 1-naphthyl-, 2-naphthyl-, 2-, 3- or 4-chlorophenyl-, 4-bromophenyl-, 2-, 3- or 4 -fluorophenyl-, 2,3- 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl-, 2-, 3- or 4-tolyl-, 2,3-, 3,4- or 3,5-xylyl-, 4-t-butylphenyl-, 3- allylphenyl, 3-trifluoromethylphenyl, 4-hydroxyphenyl-, 2-,. 3- or 4-Methoxyphenyl-, 4-biphenylyl-, 3-dimethylaminophenyl-, 2-chloro-4-methyl-phenyl-, 1-chloro-2-naphthyl-, 4-chloro-2-naphthyl-, 6-methyl-2- naphthyl, 6-methoxy-2-naphthyl or 5,6,7,8-tetrahydro-2-naphthyl radical. 5. Cyclopentane derivative as stated in claims 2, 3 or 4, characterized in that R^ is a carboxy radical which is a triethylammonium, ethanolammonium, diethanolammonium, sodium or potassium salt. 6. Cyclopentane derivative as stated in claim 1, characterized in that Y is a direct bond or a methyleneoxy radical. 7. Cyclopentane derivative as stated in claim 1, characterized in that R" <*> " is a carboxy or methoxycarbonyl radical, R <2> is a hydroxy radical and R is a hydrogen atom or R <2> and R 3 together form an oxo -radical, A is a trans-vinylene radical, Y is a direct bond or a methylene-, isopropylidene-, methyleneoxy- or isopropylideneoxy radical and R <4> is a phenyl-, 3- or 4-chlorophenyl- or 3- or 4-trifluoromethyl-phenyl radical, and for those compounds where R"<*>" is a carboxy radical, pharmaceutically or veterinary medicinally acceptable salts thereof. 8. Cyclopentane derivative as stated in claim 1, characterized in that Y is a methyleneoxy radical and R 4 is a phenyl or naphthyl radical which may optionally be substituted with chlorine, fluorine or trifluoromethyl radical. 9. Cyclopentane derivative as stated in claim 8, characterized in that R 1 is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R is a hydroxy radical, R 3 is a hydrogen atom, A is a trans-vinylene radical, Y is a methyleneoxy radical and R<4> is a 3-or 4-chlorophenyl or 3- or 4-trifluoromethyl-phenyl radical. 10. Cyclopentane derivative as stated in claim 1, characterized in that Y is an isopropylideneoxy radical and R <4> is a chlorophenyl or trifluoromethylphenyl radical. 11. Cyclopentane derivative as stated in claim 10, characterized in that R'<*>" is a carboxy, methoxycarbonyl or ethoxycarbonyl radical, R 2 is a hydroxy radical and R <3> is a hydrogen atom or R <2> and R < 3> together form an oxo radical, A is a trans-vinylene radical, Y is an isopropylideneoxy radical and R4 is a chlorophenyl radical. 12. Cyclopentane derivative as stated in claim 11, characterized in that R <2> . and R <3> together form an oxo radical. 13. Cyclopentane derivative as stated in claim 11 or 12, characterized in that R <4> is a 4-chlorophenyl radical. 14. Cyclopentane compound as stated in claim 1, characterized in that the compound is 16-(3-chlorophenoxy)-9a,11a,15-trihydroxy-17,18,19,20-tetranor-5-trans, 13-trans-prostadic acid. 15. Cyclopentane derivative as stated in claim 1, characterized in that the compound is 9a,11a,15-trihydroxy-16-(3-trifluoromethylphenoxy)-17,18,19,2-tetran <p> r-5-transCk3- trans-prostadienic acid . 16-(4-chlorophenoxy)-lia, 15-dihydroxy-16-methyl-9-oxo-18,19,20-trinor-5- trans,13- trans -prostadic acid, 9a,lia, 15-tr.ihydroxy- 16-phenyl-17,18 ,19 ,20-tetranor-5-trans ,13-trans-prostadienoic acid ,lla,15-dihydroxy-9-oxo-16-phenyl-17 ,18 ,19 ,-20-tetranor -5- trans,13- trans -prostadic acid, 11a,15-dihydroxy-9-oxo-15-(4-trifluoromethylphenyl)-16,17,18,19,20-pentanor-5- trans,13-trans -prostadic acid . 16. Cyclopentane derivative as stated in any one of claims 1 to 15, characterized in that the racemic form is present. 17. Cyclopentane derivative as set forth in any one of claims 1 to 15, characterized in that it is in a luteolytically active, optically active form. 18. Process for the production of a cyclopentane derivative as stated in claim 1, characterized in that (a) separating a mixture of the 5-trans-cyclopentane derivative with the formula I and the corresponding 5-cis-isomer; (b) for the production of compounds where R 2. is a hydroxyl radical and R <3> is a hydrogen atom, reduces an enone with the formula: where R 4 has the meaning stated in claim 1, R 4 is an alkoxycarbonyl radical with up to 11 carbon atoms, and R 6 and. R 7 is independently a hydroxy radical or a protected hydroxy radical, and then when R 6 and R 7 are protected hydroxy radicals, removing the protecting groups, and then preparing a compound of formula I where R is a carboxy radical, hydrolyzing the product obtained with a base, or for the preparation of a compound of formula I where R<1> are hydroxymethyl radicals, reduces the product obtained; or (c) for the preparation of compounds where R 2 is a hydroxy radical and R is a hydrogen atom, thermolyze a phosphonium betaine of the formula:e where R., R., A and Y have the meaning stated in claim 1, R is a hydrogen atom, R^ is an aryl radical, R^ is an alkyl radical with 1 to 6 carbon atoms, and R"<*>" ^ is a tetrahydropyran-2-yl radical and then hydrolyze the protected tetrahydropyran radicals R^. 19. Method as stated in claim 8, characterized in that a mixture of the 5-trans-cyclopentane derivative with the formula I and the corresponding 5-cis-isomer is separated by means of chromatography or fractional crystallization. 20. Method as stated in claim 19, characterized in that silica gel impregnated with silver nitrate is used for the chromatography. 21. Method as stated in claim 18, characterized in that the reduction of the enone with formula II is carried out by using zinc borohydride, aluminum tri-isopropoxide or di-isobornyloxy-aluminium isopropoxide. 22. Process as set forth in claim 18 or 21, characterized in that a starting material of formula II is used, R 6 and R 7• are hydroxy radicals or both 4-phenylbenzoyloxy radicals, or R^. is a 4-phenylbenzoyloxy radical and 7 R is a hydroxy radical. 23. Method as stated in claim 18, characterized in that a starting material of formula III is used, R 8 is a phenyl radical and R 9 is a methyl or ethyl radical. 24. A pharmaceutical or veterinary medicinal preparation containing a cyclopentane derivative as set forth in claim 1 together with a pharmaceutical or veterinary medicinal acceptable diluent or carrier. 25. Preparation as stated in claim 24, characterized in that it is available in the form of a tablet, capsule, aerosol, a solution suitable for injection-inhalation, a sterile, injectable aqueous or oily solution or suspension or suppository. 26. Cyclopentane derivative as stated in claim 6, essentially as described in Example 1. 27. Cyclopentane derivative as stated in claim 1, substantially as described in any of Examples 2 through 6. 28. Preparation as stated in claim 25, essentially as described in Example 7 or 8.