FI63221B - PROSTANSYRADERIVAT FOER ANVAENDNING SAOSOM ANTIKONCEPTIONELLA MEDEL ELLER FOER ICKE-TERAPEUTISK KONTROLL AV HUSDJURENS OESTRISKA CYKEL - Google Patents

Description

r ^ frZri rBl an ADVERTISEMENT PUBLICATION, -, Q ~ - jBTa lbj (11) utlAggninosskrift οόΖΖΊ C (45) Patent ay Previously 10 05 1533 Patent noddclst ^ ^ (51) Kv.lk.3 / tm.d.3 C 07 c 177/00 FINLAND —FINLAND (21) - Ρμ · μ · μΜι * ι «1333/72 (22) Htkemtoptlvi - Amölcnlngtdlf 10.05.72 ^ (23) Primary Cloud - Tribe | h« t * dt | 10.05 72 (41) Tullut) ulklMktl - Latches offwtllg 22] _j_ 72

National Board of Patents and Registration (44) Date of issue. - _

Pitt · * · och registerstyrelsen Astekin utiagd och utUkritam pubtkond. ul. 03 (32) (33) (31) Requested Muoikous-toiIrS reports 11.05.71 O5.OI.72 England-England (GB) 1 ^ 139/71 »396/72 (71) Imperial Chemical Industries Limited, Imperial Chemical House,

Millbank, London S.W.l, England-England (GB) (72) Jean Bowler, Macclesfield, Cheshire, Neville Stanton Crossley,

Macclesfield, Cheshire, England-England (GB) (Jh) Oy Kolster Ab (5 ^) Prostatic acid derivatives used as contraceptives or non-therapeutic control of the estrous cycle in domestic animals

The invention relates to novel cyclopentane derivatives and in particular to novel cyclopentane derivatives analogous to naturally occurring compounds known as prostaglandin 3a prostaglandin E2 and the new compounds have a similar spectrum of pharmacological properties and are useful for similar purposes. However, the relative potency of these new compounds differs from that of the aforementioned naturally occurring prostaglandins with respect to certain of the pharmacological effects shown, and in particular they are more potent as luteolytic agents than the corresponding natural prostaglandins. That is, the prostaglandin analogs of the invention are more potent than naturally occurring prostaglandin and the prostaglandin E1 analogs of the invention are more potent 2,63221 than naturally occurring prostaglandin. These new compounds are similarly more potent uterine smooth muscle stimulants than the corresponding naturally occurring prostaglandin. , and the prostaglandin E2 analogs of the invention are very valuable in this regard. These new compounds are therefore preferred contraceptive agents for determining pregnancy or regulating the menstrual cycle as hypotensive agents. These new compounds according to the invention are also useful as fertilization additives when used for the artificial insemination of domestic animals, whereby the likelihood of fertilization is increased, especially in the case of pigs.

The cyclopentane derivatives described in this specification are called prostanoic acid derivatives having the formula: 9 H 7 5 3 1

COOH

10/8 6 4 2 \ / 20 11; 13 15 17 19

B

More particularly, the invention relates to prostanoic acid derivatives of the formula α2 n * for use as a contraceptive, or for non-therapeutic control of the estrous cycle of domestic animals.

v R

. ^ -A-CH (OH) -X-Y-R

HO

wherein R * is a hydroxymethyl or carboxyl group or an alkoxycarbonyl group having up to 5 carbon atoms 2; either R is a hydroxy group or an alkanoyloxy group having 1 to 4 carbon atoms 3 63221 3 2 3 and R is a hydrogen atom, or R and R together form an oxo group; A is an ethylene or vinylene group; X is an alkylene group having 1 to 3 carbon atoms optionally substituted with one or two alkyl groups having 1 to 3 carbon atoms; Y is an oxygen or sulfur atom, a sulfinyl group (-SO-) or an alkylimino group having up to 1+ carbon atoms (-N-alkyl); is a phenyl, naphthyl, benzyl or furfuryl group optionally substituted by halogen, hydroxy, phenyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkenyl, halogen - (- C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or di-C 1 -C 4 alkylamino, and optionally having one alkyl group of up to 1+ carbon atoms in the 2-position, and pharmaceutically acceptable salts of compounds of formula I wherein R is a carboxyl group.

A preferred meaning of R when it is an alkoxycarbonyl radical having up to 5 carbon atoms is, for example, a methoxycarbonyl, ethoxycarbonyl or n-butoxycarbonyl group.

2

When R is an alkanoyloxy radical having 1 to 1 + carbon atoms, it may be, for example, an acetoxy or propionyloxy radical.

When X is an alkylene radical having 1 to 3 carbon atoms substituted by 0, 1 or 2 alkyl radicals each having 1 to 3 carbon atoms, it may be, for example, a methylene, ethylene or trimethylene radical having 0, 1 or 2 methyl substituents, e.g. a methylene, ethylidene, isopropylidene or trimethylene radical.

When Y is an alkylene imino radical having up to 1+ carbon atoms, it may be, for example, a methylimino (CH 2 -N <.) Radical.

A is preferably a trans-vinylene radical.

Suitable halogen atom substituents include, for example, chlorine, bromine and fluorine. Suitable alkyl, alkoxy or alkenyl substituents containing 1-1 + carbon atoms of R 1 are, for example, methyl, t-butyl, allyl or 1+ ....

methoxy group. Suitable haloalkyl substituents having 1 to 1 carbon atoms of R include, for example, a chloroalkyl and fluoroalkyl group, for example a trifluoromethyl group. Suitable di- (C 1 -C) alkylamino radicals in which each. The alkyl of 1+ sacs has 1 to 3 carbon atoms and which may be substituents on R is, for example, a dimethylamino group.

63221

Suitable substituted phenyl or naphthyl groups include, for example, chlorophenyl, chloronaphthyl, bromophenyl, fluorophenyl, tolyl, xylyl, methylnaphthyl, t-butylphenyl, methylchlorophenyl, trifluoromethylphenyl, hydroxyphenyl, hydroxyphenyl, methoxynaphthyl, biphenylyl, dimethylaminophenyl and tetrahydronaphthyl.

The most preferred aryl radicals do not contain more than 2 substituents i, as described above. R can thus in particular be a radical such as phenyl, benzyl, furfuryl, 1-naphthyl, 2-naphthyl, 2-, 3- and U-chlorophenyl, 1 + bromophenyl, 2-, 3- and lt-fluorophenyl, 2 , 3-, 2,2-, 2,5-, 2,6-, 3, * + and 3,5-dichlorophenyl, 2-, 3- and tolyl, 2,3-, 3- and 3,5-xylyl, N-butylphenyl, 3-allylphenyl, 3-trifluoromethylphenyl, N-hydroxyphenyl, 2-, 3- and N-methoxyphenyl, U-biphenylyl, 3-dimethylaminophenyl, 2-chloro-1 + methylphenyl, 1-chloro-2-naphthyl,? -Chloro-2-naphthyl, 6-methyl-2-naphthyl, 6-methoxy-2-naphthyl and 5,6,7,8-tetrahydro-2-naphthyl.

A suitable alkyl radical having up to k carbon atoms and which may be present as a substituent on carbon atom 2 is, for example, a methyl radical.

Examples of basic addition salts are ammonium, alkyl ammonium having 1 to U alkyl radicals each having 1 to 6 carbon atoms, alkanol ammonium having 1 to 3 2-hydroxyethyl radicals, and alkali metal salts, e.g. triethylammonium, ethanolammonium, diethanolammonium , sodium and potassium salts.

It can be seen that the compounds of formula I contain at least 5 asymmetric carbon atoms, namely carbon atoms 8, 9 »11» 12 and 15, of which the space structures of four, 8, 9 »11 and 12 are shown in formula I, and that the carbon atoms 2, 3 and k may also be asymmetrically substituted so that it will be appreciated that such compounds may exist in at least two optically active forms. It will be appreciated that the useful properties of the racemate may exist in varying amounts in the optical isomers and that the invention relates to the racemic form of the compounds of formula I and any optically active form having the above useful properties, and it is well known how to obtain and determine optically active forms. corresponding biological properties.

63221

It is also to be understood that the above definition includes both C-15 epimers, and that all of the chemical formulas set forth in this specification use the same specific stereochemistry for carbons 8, 9, 11, and 12 as in Formula I.

Although both C-15 epimers of the compound of the invention have advantageous pharmacological properties, the epimer is more polar in thin layer chromatography, more active in e.g. a luteolytic experiment, and more polar C-15 epimers are therefore more preferred.

A preferred group of cyclopentane derivatives according to the invention, due to their strong luteolytic or smooth muscle stimulating activity, are those compounds in which R is a chlorophenyl, fluorophenyl, trifluoromethylphenyl or unsubstituted naphthyl radical, in particular those in which R is , methoxycarbonyl ....... * 1

or a hydroxymethyl radical, and in particular those compounds in which R

is a 3- or 1 + -chlorophenyl, 2- or 1 + -fluorophenyl, 3-trifluoromethylphenyl or unsubstituted naphthyl radical. A very preferred subgroup are those compounds wherein R 1 is a carboxy, methoxycarbonyl or hydroxymethyl radical, R is a hydroxyl radical and R is a hydrogen atom, • 2. 3 or R and R together form an oxo radical, A is a vinylene radical, ..... X is a methylene or isopropylidene radical, Y is an oxygen atom and R is a 3- or 1 + chlorophenyl-2- or U-fluorophenyl radical, -trifluoromethylphenyl or 2-naphthyl radical optionally having a methyl substituent on carbon 2.

The cyclopentane derivatives of the invention can be prepared as follows: (a) for the preparation of compounds in which R 1 is a carboxy radical, a compound of the formula 6 63221 b 2 K 3 '' vC ./

Cl / ^ A-CH-X-Y-R ^ B ^>. ·. 2 3. U.

or an anhydride thereof, wherein A, X, Ϊ, R, R and R have the same meaning As above, 6 and R and R each represent a tetrahydropyran-2-yloxy radical or an acyloxy radical having 1 to 6 carbon atoms or a mixed anhydride of a compound of formula II , hydrolyzing, the salt of which, if desired, reacting the product with a base, or (b) for the preparation of compounds in which R 1 is an alkoxycarbonyl radical having 1 to 5 carbon atoms, an acid of formula R 3 R 2. /

'' ./ ^ (CH.) - COOH

rA-CH-X-Y-R1 * / i * 2 3 U. ..

wherein A, X, Y, R, R and R are as defined above, is reacted with a diazoalkane of the formula R, Ng wherein R is an alkyl radical having 1 to 5 carbon atoms, or (c) to prepare compounds wherein has 1 to 5 carbon atoms. An alkoxycarbonyl radical, a salt of an acid of formula II, for example a silver salt, is reacted with an alkyl halide having 1 to 5 carbon atoms, for example an alkyl iodide, or (d) to prepare compounds in which R 1 is a hydroxymethyl radical and Y is an oxygen or sulfur atom or an alkylimino radical, an ester of formula I wherein R 1 is an alkoxycarbonyl radical, for example an alkoxycarbonyl radical having 1 to 5 carbon atoms, reduced with, for example, a complex metal hydride such as lithium aluminum hydride, or 63221 (e) wherein Y is a sulfinyl radical, a thio compound of formula cc,.

i do, 1 o O 11 wherein r, Rc} r · 3 t r, A and X have the same meaning as in claim 1, is oxidized, for example, with sodium periodate.

A suitable mixed anhydride is a mixed anhydride with a lower alkanoic acid, for example an alkanoic acid having up to 8 carbon atoms, for example acetic acid

The hydrolysis process (a) can be carried out under either acidic or basic conditions, for example in aqueous acetic acid or in an aqueous or alcoholic solvent of an alkali metal carbonate, for example in a methanolic solution of potassium carbonate, and can be carried out at ambient temperature or at an elevated temperature of up to 60 °.

The starting material of formula II wherein A is a vinylene radical and Y is an oxygen or sulfur atom and used in the process of the invention can be prepared by reacting a known aldehyde V (Ac = acetyl or p-phenylbenzoyl) with a phosphonate of formula (CH_O ) pP + 0. CH.CO.X.Y.R1 * (VI) (prepared from dimethylmethylphosphonate. J ... 4. ....

and an ester of the formula R 1 Y.X.COO-alkyl in the presence of butyllithium) 1+

or phosphorane of the formula Ph ^ CH.CO.X.Y.R

(prepared from triphenylphosphine and a compound of formula (R 1 .YXCOCH 1) to give unsaturated ketone VII. This ketone VII is reduced with zinc borohydride to the corresponding unsaturated alcohol VIIC and the acyl protecting group is then removed with methanolic potassium carbonate of formula IX. Diol IX is protected as a bis-tetrahydropyranyl ether and the lactone ring is reduced with diisobutylaluminum hydride to give lactol XI or alternatively diol IX is reduced with diisobutylaluminum hydride to give a triol which can be acylated and selectively hydrolyzed to give This lactol X [is reacted with a phosphonium yldi anion obtained from (U-carboxybutyl) triphenylphosphonium bromide and a strong base to give a carboxylic acid of formula II.

The starting material of formula II wherein A is an ethylene radical and Y is an oxygen or sulfur atom and used in the process of the invention can be obtained by hydrogenating an unsaturated ketone VII in the presence of a 5-, palladium on carbon catalyst or using nickel boride to give a saturated ketone and repeating the above treatment using said saturated ketone instead of unsaturated ketone VII.

. 2

A starting material of formula II wherein R is alkanoyloxy radical. . 2 potassium, can be obtained from the corresponding compound in which R is a hydroxy radical by acylation with an acid anhydride in pyridine to give 9-ester-1-mixed anhydride.

2. 3

The starting material of formula I, II or III in which R and R together form an oxo radical can be obtained from the corresponding 0 * 3 starting material of formula II in which R is hydroxy and R is hydrogen by oxidation with Jones reagent (in chromic acid acetone), which then, if necessary, the tetrahydropyranyl protecting group is hydrolyzed and the carboxylic acid group is esterified.

It will be appreciated, of course, that the optically active compound of the invention may be obtained either by resolution of the corresponding racemate or by carrying out the above-mentioned reaction step from an optically active medium, for example an optically active aldehyde of formula V (Ac = acetyl or p-phenylbenzoyl).

1 9 63221 9

(H o H

^ + (MeO) 2.P-CH.CO.X.Y.R ^ L * R *

AoO ^ ||

O

V VI VII

A ό -> W -5> \ —f \ Y Y R4 \ _ X.Y.R4 / -

Ac <r T HO '

OH ÖH

VIII IX

0

1 OH

-> <Ö -> ό

X XI

Ac is an acyl radical, 10 63221

As mentioned above, the compounds of the invention have anti-fertilization properties that differ from those of naturally occurring prostaglandins and E. coli. For example, 16- (Hf fluorophenoxy) -9C (, 11? (> 15-trihydroxy-17 * 18,19,20-tetranor-5-cis-13-trans-prostadienoic acid is approximately 200-fold more active than prostaglandin in a luteolytic experiment in hamsters ( oral administration) and about 10 times more active as a smooth muscle stimulant compared to prostaglandin F 2.

When a compound of the invention is used to regulate the menstrual cycle in animals, the compound may be used in combination with or concomitantly with a gonadotrophin, for example PMSG (pregnant mare serum gonadotrophin) or HCG (human fetal choroidal gonadotrophin) to accelerate the onset of the next cycle.

The prostanoic acid derivative of the invention may be used in combination with a pharmaceutically or veterinarily acceptable diluent or carrier.

The active ingredient-containing compositions may be suitable for oral administration, for example as tablets or capsules, in a suitable form for inhalation, for example as an aerosol or spray solution, in a suitable form for parenteral administration, for example as a sterile, injectable, aqueous or oily solution, or as a suppository, suppository, or for vaginal use.

The following examples illustrate the invention: 63221 11

Example 1

A solution of 9,6-hydroxy-16-phenoxy-11,15-bis (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (120 mg) 1, In 5 ml of a 2: 1 mixture of acetic acid and water, stirred at 50 ° C for 4 hours. The solvents were evaporated, the residue was dissolved in dilute aqueous sodium bicarbonate (2 ml) and extracted with ethyl acetate (3 x 2 ml) and the extracts discarded. The aqueous solution was acidified to pH 3-4 with 2N aqueous oxalic acid and the acidified solution was extracted with ethyl acetate (4 x 5 mL). The ethyl acetate extracts were washed with a 1: 1 mixture of saturated brine and water and then dried. After evaporation of the ethyl acetate, a residue of a mixture of C-15 epimers of 90 ° C (15) (> 15-trihydroxy-16-phenoxy-17,18,19,20-tetranor-5-cis-13-trans-pro-thienic acid) was formed. on silica gel plates manufactured by Merck, Darmstadt, using a mixture of benzene, dioxane and acetic acid (20: 10: 1) as the developing solution, the C-15 epimers with Rp values of 0.3 and 0.4, respectively, were separated. Rg values were obtained on silica gel plates manufactured by Merck, Darmstadt, and compound ages were detected either by fluorescence or by spraying the plates with a sulfuric acid solution of cerium ammonium nitrate.) The NMR spectrum (deuterated acetone) of each isomer showed the following characteristic bands (<i-value) 6-6.1, broad multiplet, 5 aromatic protons 4.2-4.8, broad multiplet, 4 olefin protons 2.9-3.8, broad multiplet, 3H, HC-0, and four exchangeable protons.

The bis-tetrahydropyranyl ether used as a starting material can be prepared as follows.

To a solution of dimethylmethylphosphonate (10.3 g) in dry tetrahydrofuran was added n-butyllithium (69 mL of a 1.2 M hexane solution) at -70 ° C under nitrogen. After 10 minutes of wedging, a solution of phenylacetyl chloride (4.1 g) in dry tetrahydrofuran (20 ml) was added dropwise and the mixture was stirred at -78 ° C for 4 hours. The reaction mixture was neutralized with acetic acid and the solvents were removed under reduced pressure. The residue was shaken with a mixture of ether (100 ml) and water (20 ml) and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was distilled on a road apparatus at an oven temperature of 160 ° C and a pressure of 0.1 nm to give dimethyl 2-oxo-3-phenoxypropyl phosphonate.

A solution of dimethyl 2-oxo-3-phenoxypropylphosphonate (1.01 g) in dry 1,2-dimethoxyethane (20 mL) was treated with n-butyllithium (2.75 mL of a 1.2 M solution in hexane) at 7878 ° C. and the mixture was stirred for 15 minutes. To this mixture of 12,63221 was added N, N-formyl-2,3,3a (5,6a / 3-tetrahydro-2-oxo-5 (R) -p-phenylbenzoyloxy) cyclopenteno [1] furan (1.95 g). solution in 1,2-dimethoxyethane (10 ml), and after 1 hour the reaction mixture was neutralized with glacial acetic acid and all solvents were removed by evaporation under reduced pressure at a temperature below 35 ° C. The residue ✓ was chromatographed on a "Florisil" column using ethyl acetate in methylene chloride as eluent to give the product as an unsaturated ketone as a white solid. * 0.6 (1: 1-ethyl acetate} benzene $.

To a solution of the unsaturated ketone (500 mg) in dry 1,2-dimethoxyethane (20 ml) at 0 ° C was added 1.5 ml of a 0.5 M solution of zinc borohydride in 1,2-dimethoxyethane. The mixture was stirred at room temperature for 30 minutes and then saturated sodium hydrogen tartrate solution was added until the effervescence ceased. Ethyl acetate (100 ml) was then added, the organic layer was separated, washed with a 1: 1 mixture of saturated brine and water, and dried. The solvents were evaporated to give a mixture of epimeric unsaturated alcohols (Rf »0.3 (1: 1 ethyl acetate / benzene)).

A mixture of epimeric unsaturated alcohols (500 mg) was stirred vigorously for 2 hours with finely divided anhydrous potassium carbonate (10 mg) in ethanol (10 ml). 1N Hydrochloric acid (2.1 ml) was then added, followed by ethyl acetate (50 ml). The organic layer was separated, washed successively with saturated sodium bicarbonate solution and saturated brine, and dried, and the solvents were evaporated. The residue was chromatographed on a "Flori8il" column (20 g). Elution with ether removed the by-products and subsequent elution with ethyl acetate gave a mixture of diols of C-15 epimers / 1ips0.2 (ethyl acetate).

To a solution of the diol of the epimers (316 mg) in methylene chloride (3 mL) under nitrogen was successively added distilled 2,3-dihydropyran (1.2 mL) and a solution of anhydrous toluene-p-sulfonic acid in tetrahydrofuran (0.1 mL; 1 L solution).

. After 10 minutes, pyridine (3 drops) was added followed by ethyl acetate (50 mL). The solution was washed successively with saturated sodium bicarbonate solution and saturated brine, and dried. Evaporation of the solvents gave a mixture of bis-tetrahydropyranyl ethers of epimers as a clear oil / Ry »0.6 (ethyl acetate.

To a solution of the bis-tetrahydropyranyl ethers of the epimers (U20 mg) in dry toluene (10 mL) at -78 ° C was added 1 mL of a 2.2 nmol / mL solution of diisobutylaluminum hydride in toluene. After 13 minutes 63221 13 'the reaction was quenched by dropwise addition of methanol (3 ml) and after standing for 15 minutes at room temperature a mixture of a 1: 1 mixture of saturated brine and water (25 ml) was extracted with ethyl acetate (3 x 50 ml). The extract was washed with saturated brine and dried, and the solvents were evaporated to give 2,3,3-3,6a, N-tetrahydro-2-hydroxy-N, N-phenoxy-3- (tetrahydropyran-2-yloxy) -1-trans -butenyl) 5 * Cr (tetrahydropyran-2-yloxy) cyclopenten [b) a mixture of furan epimers (Rf = 0.1 U (1: 1 ethyl acetate / benzene)).

Fine (U-carboxybutyl) triphenylphosphonium bromide (1.11 g) was heated at 100 ° C under vacuum for 1 hour. The bracketed reaction vessel was filled with dry nitrogen, the solid was dissolved in dimethyl sulfoxide (5 mL) and the solution was cooled to room temperature. To this solution was added dropwise 2.35 ml of a 2-m solution of methanesulfinylmethane sodium in dimethylsulfoxide, followed by a solution of a mixture of cyclopenteno furan-bis-tetrahydropyranyl ether epimers (1 x 00 mg) in a mixture of dimethylsulfoxide (10 ml) and benzene (2 ml). This solution was stirred for 3 hours and the solvent was removed by evaporation under reduced pressure at a temperature below 1 * 0 ° C. The residue was shaken with water (10 ml) and ethyl acetate (10 ml) and the aqueous phase was separated, extracted with ethyl acetate (2 x 10 ml) and extracted and discarded. The aqueous solution was acidified to pH 3 with aqueous 3-H 2 oxalic acid and extracted with an equal volume of ether and petroleum ether (b.p. U0-60 ° C) (5 x 10 mL). The organic phase was separated, washed with brine and dried. Evaporation of the solvents gave 9-hydroxy-16-phenoxy-11β-bis (tetrahydro-pyran-2-yloxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid as a clear oil 0.5 (ethyl acetate)) '.

Example 2

The work-up of Example 1 was repeated using the corresponding phosphonate reagent to give the compounds shown below. The products were identified by NMR spectroscopy and examined either by Ry on a thin layer chromatograph or by accurately measuring the mass with a mass spectrometer for either molecular ion or (M + - methyl) ion, whichever was more appropriate, and using a tetra (trimethylsilyl) derivative which was prepared by adding bis-trifluoromethylsilyl-trifluoroacetamide containing 1% trimethylchlorosilane (trademark Regisil) to the compound to be measured and allowing the mixture to stand for 1 hour. In a few cases, a phosphonate reagent or an unsaturated ketone intermediate has also been studied and the values obtained from these compounds have also been reported.

iU

63221 A-CH (OH) -X-OR1 *

? H

Well. PA A X

1 phenyl -CH: CH- -CH2-2 phenyl -CH: CH- -CH (CH3> -3 phenyl -CH: CH- -C (CH3> 2-4 phenyl -CH: CH- - (CH2-5) bentyl -CH: CH- -CH2-6-naphthyl -CH: CH- "CH2-7 4-chlorophenyl -CH: CH- -CH2-8 U-chlorophenyl -CH2CH2 ~ -CH2-8 3-chloro phenyl -CH : CH- 10 2-chlorophenyl -CH: CH- -CH2-11,2,5-dichlorophenyl -CH: CH- -CH2- 12k-bromophenyl -CH: CH- -CH2-13k-fluorophenyl -CH : CH- "CH2 - 14 U-tolyl -CH: CH- -CH2- 3 3-tolyl -CH: CH-" CH2 "16 1 * t-butyl phenyl -CH: CH- -CH2 ~ 17 trifluoroyl - -CH: CH- -CH2-phenyl 18 4-methoxy phenyl -CH: CH- - CH2 - 19 2-methoxyphenyl -CH: CH- -CH2 ~ 20 U-biphenylyl -CH: CH- "CH2- 63221 15

Missaspektri

Phosphonate Enone W: o Isomer * Found L Calculated kp (C / sp. (C) mm) 1 sec Μ + · 6 78.3610 678.3625 178-185 / 0.0 '155-158 lp M + e6 78 2 mp M + -CH - 677.35 A5 175 / 0.2 677.35A0 lp M + -692 692 3 s * os M + -CH - 691.3703 130 / 0.1 691.3660 A mp Μ + · 706.3921 706.3938 166-168 / 0.1 120-122 lp M + -706 5 mixture Μ + · 692.3753 692.3781 170 / 0.1 99-101 6 sec M + -728.37AA 728.3781 ΡΡ. - 185-187 85-86 ° C.

7 sec M + -CH „- 697.3001 170-173 / 0.1 132-135 697.29A8 lp M +« 712 712 8 mp (a) M + -71A.3399 71A.3391 170-173 / 0.1 132-135

lp (a) M + «71A

9 mp M + -CH »697.3000 180 / 0.2 697.2297 lp M + -712 712 10 mp M + -712.3216 712.3235 17A-178 / 0.1 129-132 lp M +« 712 11 mp M + -CH - 731.2609 - 136-138 731.2599 12 mixture M + - CH - 7A1.2A97 7AI.2A85 13 mp M + «696.3A6 8 696.3529 - 162 lp M +« 696 l6 '.

63221

Mass spectrum Phosphonate Enone kp (° c / (° C). T ·· j .. mm; li: o Isomer Calculated Found ___, __I_____ _ I .. - I ___ <14 Mixture M + “692.3738 692.3781 164 / 0.05 149 15 sec M + ** 692.3752 692.3781 180 / 0.5 140-141 lp H + -692 16 Mixture M + “734.4213 734.4251 17 mp M + = 746.3467 (b) 746.3499 115-117 lp c) 18 mp M + ** 708.3717 708.3731

Ip M + -708 19 sec Μ + · 708.3710 708.3731 lp M + -708 20 sec H + «754.3944 754.3938 m.p. - 63-64 ° C.

lp M + -754

i ------ J

* mp «than the more polar, lp» less polar isomer in thin layer chromatography on silica gel.

(a) products obtained synthetically from the more polar and the less polar enol intermediate, respectively.

b) Rp-O → 5 after two treatments on silica gel gel by thin layer chromatography using 5-ethyl acetate in ethyl acetate.

O yo, 50 after two treatments on silica gel gel thin layer chromatography as in b).

^ 63221

In the preparation of compounds 8 in which A is an ethylene radical, the unsaturated ketone intermediate is reduced to the saturated ketone as follows: (1 + -chloro phenoxy-3-hydroxybut-1-enyl) -2,3,3a, 6α / 3-tetrahydro-2-oxo A more polar epimer (epimers in the butenyl carbon chain C-3) of -5- (p-phenylbenzoyloxy) cyclopenteno / b-furan (360 mg) was dissolved in ethanol (25 ml) and the solution was added to nickel boride previously prepared from nickel acetate (620 mg) and sodium borohydride. 5 ml of a 1 M solution) The mixture was shaken with hydrogen for 3 hours and filtered and the filtrate was evaporated to dryness to give U / 5- (n-t-chlorophenoxy-3-hydroxybutyl) -2,3,3a / 3 ', 6a N-tetrahydro-2-oxo-5 - ((p-phenylbenzoyloxy) cyclopenteno [b] furan Rf »U (50% ethyl acetate in toluene) A saturated ketone was then used instead of the unsaturated ketone in the remaining Example 1. in the reading described.

Example 3

To a solution of the more polar C-15 epimer of 16- (1-chlorophenoxy) -9?, 13,15,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (15 mg ) in methanol (1 ml) at 0 ° C, an excess of ethereal diazomethane was added. After 10 minutes, the solvents were evaporated to give the only C -15 ~ epimer as a clear oil Rp »0.3 (ethyl acetate). The NMR spectrum showed the following characteristic bands (S-values): 6.8-7.2, k aromatic proton 5.3-5.7, U olefin proton 3.6, C00CH3.

Example U

The treatment according to Example 1 was repeated using the corresponding phosphonate

U

reagents or equivalent phosphorane R CH 2 .CO.CH 2 PPh 2 to give the compounds shown below. The products were identified by NMR spectroscopy and have been identified below either by Rp thin layer chromatography or by mass measurement by mass spectrometry using the molecular ion of the corresponding fully protected (trimethylsilyl) derivative prepared by adding bis-trimyl to the compound to be measured. -trifluoroacetamide containing 1% trimethylchlorosilane (trademark "Regisil") and allowing the mixture to stand for 1 hour. In a few cases, a phosphonate reagent or an unsaturated ketone intermediate has been studied and the corresponding values for these compounds have also been reported.

v / ^ 1 Ν ^ = γ "// Λν ^ Λ ^> <; οοη CH (OH) -X- Y-R1 * ilo 18 63221 ί Other t

Well. R * X Y

prostanoic acid substituents 21 phenyl -CH 6 - -N (CH 2 O) -22 i * -chloro phenyl-O (O 2) 2 '-O-23 4-chlorophenyl -CH 2 - -S-2M 3-fluorophenyl-Cl 2 -O-2-fluorophenyl-CE 2 - ~ 0 ~ -.

26 3,4-dichlorophenyl -CE 2 -O-27 2,5-dichlorophenyl -CE 2 -O-28 2-tolyl-O-29 2,3-xylyl -CH - -O-3,5 3,5-xylyl -CH 2 - -O-31 2-chloro-4-methylphenyl-CH 2 -O-32 3-dimethylaminophenyl -CH 2 -O-33 1-naphthyl "CH 2 -O-3¾ U-chloro-1-naphthyl -CE 2 -O-n-2-methyl-2-naphthyl-CH 2 -O-O-36--6-methyl-2-naphthyl-Cl 2 -N-6-methoxy- 2-naphthyl -CH 2 "-O-38 3-chlorophenyl -CH 2 - -O-2-methyl-4,39 2,3-dichlorophenyl -CE 2 -O-

ZjO 2,6-dichloro phenyl -CH2- -O-

Jq 3,5-dichlorophenyl -CH2- -O-4-chloro-3-methylphenyl [-CE2-O-2j3 3-methoxyphenyl] -1 | 1 | 1-Chloro-2-naphthyl-O-η 5,6,7,8-tetrahydro-2-naphthyl-CH 2 -O-η-63221 19

Mass spectrum Phosphonate Enoni, x bp. (° C / m.p. (° C) No. Isomer Found Calculated in mm) 21 mp M + = 691.3991 »691.3940 (b) 145-150 lp 691; 22 sec M-CH 2+ = 725.3313 150 / 0.05 (c) 725-3302 lp 23 sec M + = 728.2977 728.3006 (b) 135-138 lp 24 sec 1 ^ = 696.3496 696.3531 (d) 138-139 lp 696 25 mp M + = 696.3510 696.3531 (e) 144 lp 696 j 26 mp M + = 746.2791 746.2844 i (f) 150-152 lp 746 27 mp M + = 746.2799 746.2844 (g) 187-190 lp 746 28 mp M + = 692.3813 692.3781 154-160 / 165 -167 0.05 lp 692 29 mp M + = 706.3971 706.3935 I80 / O.15 166-168 lp 706 30 mp M + = 706.3922 706.3935 - 140-142 lp 706 31 mp M + = 726 726 - 113-115 lp 7 26 32 mp M + = 721.4020 721.4047 (b) j 138-145 pp, 721! 33 sec M + = 728.3830 728.3781 (h) 185-187! lp 728 34 mp M + = 762.3356 762.3388 (i) (j) lp 762 1 i 20 63221

Maesspectrum. (a) T Poefonate Enone No. Isomer Calculated Found kp. (° C / m.p. (° C) mm) 35 mp ^ = ^ 2.39 ^ 6 742.3937 mp85-86 185-187 36 RK * mi · 3902 7 * 12 * 3937 mp71-72 153 37 mp M + = 758.3910 758 * 3887 mp58-59 195 lp 758 38 mp M + = 726.3346 726.3391 180 / 0.2 (k) lp 726 39 mp M + -CH, = 731.2609 175 / 0.03 153-155. 731.26¾¾ lp M -CHj = 73l ^ 0 mp M + = 746.2844 7¾6.28¾¾ mp89-90 140-142 lp 7¾ 6 ¾l mp M + = 746.2829 7¾6.28¾¾ mp80-82 138-139 lp 746 42 mp M + = 726.3397 726.3391 - 143 lp 726 43 mp M + = 708.3745 708.3730 (1) 129-130 lp 708 44 M + = 762.3402 762.3391 mp61-62 195 1.5 gSi

I --------- J

(a) mp · more polar, lp »less polar (b) These compounds were prepared synthetically from phosphoranes (not phosphonates) prepared as described below.

(e) Rp »0.5 (sontic ethyl acetate in toluene).

(d) Rf-0.2 (40¾ ethyl acetate in methylene dichloride).

63221 21 (e) RF-0.1i (5% acetic acid in ethyl acetate) (f) Rp * 0.3 (50% ethyl acetate in chloroform) (β) Rp® 0.23 (50% ethyl acetate in chloroform) (h) Rf »0.3 (50% ethyl acetate in methylene chloride) (i) Rp * 0.1 * (10% methanol in ethyl acetate) (j) Rp * 0.8 (50% ethyl acetate in toluene) ( k) Rp »0.6 (50% ethyl acetate in toluene) (l) Rp = 0.1 * (50% ethyl acetate in methylene chloride) (®) Rp® 0.25 (3% acetic acid in ethyl acetate) (n ) Rp® 0.30 (3% acetic acid in ethyl acetate) (m) and (n), £ 6.8 (1H, aromatic), 6.6 (2H, aromatic), 5Λ (2H, olefinic) and 5, 7 (2H, olefinic).

An example of the preparation of phosphorane used in the preparation of the cyclopentane derivative according to the invention instead of a phosphonate is the preparation of (3- (3-dimethylaminophenoxy) acetonylidene) -triphenylphosphorane, which is carried out as follows:

To a solution of 3-dimethylaminophenol (685 mg) in dimethoxyethane (20 mL) was added n-butyllithium (3.5 mL of a 1.3 mL solution in hexane) at -70 ° C under nitrogen. The solution was allowed to warm to room temperature, a solution of 3-iodoacetonylidene-triphenylphosphorane (2.22 g) in benzene (100 ml) was added thereto, and the mixture was heated under reflux for 2 hours.

The mixture was then diluted with toluene (100 ml), washed with water (2 x 50 ml) and dried, the solvents evaporated off and the residue triturated with ether to give (3- (3-dimethylaminophenoxy) acetonylidene) triphenylphosphorane, m.p. 110-115 ° C.

In a similar manner, analogous N-methylanilino (resin) and 1 * -chlorophenylthio (m.p. 15-165 ° C) phosphoranes were prepared.

Example 5

The procedure of Example 3 was repeated using the corresponding more polar C-15 epimer 16- (U-chlorophenoxy) -?,?, 11?, 15 "trihydroxy-17,18,19,20-tetraolino-5- instead of the more polar C-15 epimer of cis-13-trans-prostadienoic acid, the following methyl esters were obtained as separate C-15 epimers: a) for methyl-16- (U-fluorophenoxy) -9e (15-trihydroxy-17,18 , 19,20-tetra-nor-5-cis-13'-trans-prostadienoate, Rf »0.3 (5% methanol in toluene), 6.8-7.2 (aromatic), 5.3-5, 7 (N-olefinic proton), 3.6 (methyl ester).

b) methyl 9,11β / 15-trihydroxy-16- (2-naphthyloxy) -17,18,19,20-tetrano-5-c18-13-trans-prostadienoate, M + <670.35 ^ 2 (calculated 670,35 ^ 1).

22 63221 c) methyl 9 <*, 11θ (, 15'-trihydroxy-2-methyl-16- (2-naphthyloxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M = 684 , 3678 (calculated 681 +, 3697).

d) methyl 90 (11,15,15-trihydroxy-16- (6-methyl-2-naphthyloxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M + = 684.3739 (calculated 684.3698).

e) methyl 9c, 11¾, 15-trihydroxy-16- (6-methoxy-2-naphthyloxy) -17,18,19,20-tetrano4-5-cis-13-trans-prostadienoate, M + = 700, 3681 (calculated 700.3647).

f) methyl 16- (3-chlorophenoxy) -9c (, 11 «(, 15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, RF = 0.3 (ethyl acetate ), M + = 654.2973 (calculated 654.2995).

g) methyl Δ 9,1,110,15-trihydroxy-2-methyl-16- (3-chlorophenoxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, Rf = 0.4 (ethyl acetate) ), M + = 668.3133 (calculated 668.3151) ·

Example 6 16- (4-Chlorophenoxy) -9β, 1M, 15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostanoic acid (20 mg of the more polar C-15 epimer) was treated with excess with dilute aqueous ammonia to form the ammonium salt. Excess ammonia was evaporated off under reduced pressure and the residue was treated with a stoichiometric amount of silver nitrate to form a silver salt. The silver salt was filtered off, dried, dissolved in n-butyl iodide (0.5 ml) and stirred at room temperature for 1 hour. The solution was extracted with ethyl acetate, the ethyl acetate extract evaporated to dryness and the residue chromatographed on Florisill (1 g) using 50-5% ethyl acetate in toluene as eluent to give n-butyl-16- (4-chlorophenoxy) -9 &. , 15 ′ tri-hydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate, M + s 696.3427 (calculated 696.3464), Rf = 0.4 (ethyl acetate).

In a similar manner, but using ethyl iodide instead of n-butyl iodide, ethyl 16- (4-chlorophenoxy) -9Λ, 1X, 15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoate was obtained. , M + = 668.3086 (calculated 668.3151) ·

Example 7

A solution of mixed acetic anhydride and the more polar 9 <X * acetoxy-16- (4-chlorophenoxy) -11 (X, 16-bis- (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor- 5-cis-trans-prostadienoic acid C-15 epimer (73 mg) in 2 ml of a 2: 1 mixture of acetic acid and water was stirred at 47 ° C under nitrogen 4. The solvents were evaporated, the residue was dissolved in dilute aqueous sodium bicarbonate solution (2 ml) and The solution was extracted with ethyl acetate (3 x 2 mL), the extracts were discarded, the aqueous solution was acidified to pH 3 with 4 2 N aqueous oxalic acid, and the acidified solution was extracted with ethyl acetate (1 x 5 mL). and a 1: 1 mixture of water and dried, and after drying the ethyl acetate, the residue was purified by thin layer chromatography on silica gel using 3 # acetic acid in ethyl acetate to give 9-cetacetoxy-16- (14-chlorophenoxy) -11β-dihydroxy-17,116. , 19,20-tetranor-5-cis-13-tra the more polar C-15 epimer of ns-prostadienoic acid, M + = 682.29 ^ 2 (calculated 682.29 months).

The bis-tetrahydropyranyl ether used as starting material can be prepared as follows: 9β-hydroxy-16- (U-chlorophenoxy) -11,15-his (tetrahydropyran-2-yloxy) -17.18.19.20-tetranor-5-c18-13-trans A solution of the C-15 epimer of β-propadienoic acid polar isomer (70 mg) in 0.15 ml of a 2: 1 mixture of pyridine and acetic acid was kept at room temperature for 16 hours. The volatile material was evaporated off and cyclohexane (10 ml) was added and the residue evaporated to dryness three times to leave a mixture of acetic anhydride and 9β-acetoxy-16- (U-chlorophenoxy) -H -17,18,19,20-tetranor-5 'cis-13-trans-proetadienoic acid as a yellow oil Xmax (CHCl3) 1720, 1810 cm-1.

Example 8

To a solution of 9α-acetoxy-16- (U-chlorophenoxy) -11,15-dihydroxy-17.18.19.20-tetranor-5-cis-13'-trans-prostadienoic acid (12 mg) in methanol (1 ml) at 0 ° C, an excess of ethereal diazomethane was added.

After 10 minutes, the solvents were evaporated, the residue was dissolved in ether and the solution was treated with lithium aluminum hydride (50 mg). The mixture was stirred at room temperature for 1 hour, the excess hydride was decomposed by adding water (1 ml) and the mixture was extracted with ethyl acetate to give 16- (U-chlorophenoxy) -12β-trihydroxy-17,18,19,20-tetranor-5-cis -13-Trane-prostadienol, M + = 698.3 ^ 39 (calculated 698.3 ^ 1), Rp = 0.2 (ethyl acetate).

In a similar manner there were obtained: 16- (3-chlorophenoxy) -9β, 11,4,5-trihydroxy-2-methyl-17,18,19,20-tetranor-5-cis-13-trans-prostadienol, Rf = 0.15 (ethyl acetate , M + * 712.3575 (calculated 712.3597).

9β, 11β, 15-trihydroxy-16- (6-methyl-2-naphthyloxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienol, Rf = 0.2 ( ethyl acetate).

Example 9

The work-up of Example 1 was repeated using the appropriate phosphonate reagent to give: 2k 63221 a) S, 11 '& 15'-trihydroxy-16- (U-hydroxyphenocene) -17,18,19,20-tetranor-5-eis-13- trans-prostadienoic acid, Rp = 0.2 and 0.3 (in 3N acetic acid ethyl acetate), »6.82 (UH, aromatic), 5.3-5.7 (UH, olefinic), 3.98- 5.1 (10H, CH2O and exchangeable protons), phosphonate, Rf 0.2 (10% in methanol-ethyl acetate), enone, m.p. 135 "creates ° C.

b) 16-furfuryl-9β-4,15 "trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-8-prostadienoic acid, Rf = 0.5 (3β acetic acid in ethyl acetate), J" · 1.5 (1H) and 6.3 (2H) (furyl protons) 5.1-5.6 (UH, olefinic), phosphonate, b.p. 200 ° C / 0.2 mm enone, m.p. 92-93 ° C.

c) 16- (3-allylphenoxy) -9 </ j 11 /., 15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid , M <710.3892 (calculated 718.3938), foefonate, Rf = 0.32 (ethyl acetate), enone, m.p. 110-112 ° C.

Example 10

The treatment described in Example 1 was repeated using a 9-oxo-prostanoic acid derivative instead of a 9'-hydroxy-prostanoic acid derivative to give the compounds shown below. To measure the mass spectrum, the acids were converted to methyl esters with diazomethane, the 9-oxo group was protected by methoxy conversion with methoxylamine, and in the cases shown, the hydroxy groups at C-11 and C-15 were protected as trimethylsilyl derivatives. Nmr. Spectra were measured in deuterated acetone.

0 J—— (OH) -X-Y-R ** i \ ___25 _ 63221

Well. X Y

46 phenyl -CH 2 -O-1 7 phenyl -CH (CH 2) - -O- 48 phenyl - (CH ·), - O - 2 3 49 1-naphthyl -CH 2 - -50 2-naphthyl ” CH2_-O-51 4-chlorophenyl-CH2-O-52 4-chloro-phenyl-CH2 "-S-53 3-chlorophenyl" CH2-O-54 2-chloro phenyl-^ 2 ~ -O-55 4-chloro phenyl -C (CH 2) 2 -O-55 4-bromophenyl -CH - -O - 57 4-fluorophenyl "CH 2 ~ -O-58 3-fluorophenyl" CH 2 -O-O- 2-fluorophenyl -CH2-O-60 2,4-dichlorophenyl -CH2-O- $ 1,2,5-dichlorophenyl -CH2-O-62 3,5-dichlorophenyl-cr-O-6 3 4-tolyl -CH 2 -O-64 3-tolyl-Mg-O-65 2-tolyl-CH 2 -6,6,6,5-xylyl -CH-O-6γ 4-chloro-3-methylphenyl 68 2-chloro-4-methylphenyl -CH 2 -O-6 g 3-trifluoromethyl phenyl-CH 2 -Q 4 70-methocaiphenyl, -CH 2 - -O-71 2-methocalophenyl-Cl 2 -O-72-U-chloro- 1-naphthyl -CH 2 -O-26-63221

No. Isomer * Characteristic values +6 mixture Rp * 0.2 (acetone / cyclohexane / ethyl acetate 1: 2: 2) NMR .: 46.98-7.28 (5H, aromatic), 5.1 * 8 (2H, cis-olefin), 5.78 (2H, trans-olefin), 3.5 "→ 5 (5H,> CH.O- and -COOH) 1 * 7 mixture M + b589.3267 (calculated for 589.3255 methyl ester) , 9-methoxime, 11,15-di (trimethylsilyl) derivative). Rp * 0.1 * (3 E acetic acid in ethyl acetate) U8 mixture Rp = 0.3 (3 $ acetic acid in ethyl acetate) 1 * 9 mixture Rp * 0.1 * (3 $ acetic acid in ethyl acetate).

NMR: aromatic protons at 48.3-8.5 (1H), 7.7-7.9 (1H), 7.2-7.5 (** H) and 6.8-7.08 (1H) ) 50 mixture Rp * 0.3 (3% acetic acid in ethyl acetate).

NMR: aromatic protons at 47-7.8 (3H) and 7.1-7.5 (1H).

51 HB M + * 609.2633 (calculated for 609.2709 methyl ester, 9-netoxime, 11,15-di (trimethylsilyl) derivative). Rp * 0.1 »(3% acetic acid in ethyl acetate) 52 mixture Rp * 0.5 (3% acetic acid in ethyl acetate).

NMR .: aromatic protons at wavelength <^ 7 »3 (½) 53 mp Rp = 0.3 (3 # acetic acid in ethyl acetate).

NMR: aromatic protons at 7.15 (1H) and 6.9 (3H).

5 ** mixture Rp * 0.1 »(3 # acetic acid in ethyl acetate) 55 mixture Rf 0.5 (3 # acetic acid in ethyl acetate).

NMR: aromatic protons at 7.28 (2H), 7.19 (2H) and 2 methyl at 1.25 and 1.30 (6h) 56 mixture M * 509.11 * 17 (calculated 509, 11 * 13 for methyl ester 9-ethocheme) 57 mixture Rp * 0.3 (3 # acetic acid in ethyl acetate) NMR · aromatic protons at wavelength £ 6.91 (2H) and 7.08 (2H) 58 mixture Rp * 0.3 (2 # acetic acid in ethyl acetate).

NMR: aromatic protons at $ 7.25 (1H) and 6.65 (3H) 59 mixture Rp »0.1 * (5 # acetic acid in ethyl acetate).

NMR: aromatic protons at wavelength £ 7.05 (1 * H) 27,63221 No. Isomer * Characteristic values 60 mixture Rp »0.1 * (0.25 * acetic acid in ethyl acetate) NMB .: aromatic protons at wavelength £ 7 , 12 (1H), 7.3 (1H) and 7.1 * 1 (1H) 61 mixture Rf »0.31 * (3 * acetic acid in ethyl acetate) NMR. aromatic protons at wavelengths £ 7.3 (1H), 7.15 (1H) and 6.9 (1H) 62 mixture Rp = 0.3l »(3 *; acetic acid in ethyl acetate).

NMR: aromatic protons at λ max 6.9 (3H) 63 mixture R * 0.2 (cyclohexane / ethyl acetate / acetone, Γ 2: 2: 1).

NMR: aromatic protons at wavelength ε 6.7 (2H) and 7.1 (2H), and methyl at wavelength S2.28 6k mixture Rp = 0.5 (3 * acetic acid in ethyl acetate).

NMR .: aromatic protons at wavelength

S1.05 (1H) and 6.73 (3H), and methyl at wavelength £ 2.28 65 a mixture of M + s 589.328 U calculated for 589.3251 * methyl ester, methoxime, di (trimethylsilyl) derivative.

Rf »0.35 (3 * acetic acid in ethyl acetate).

66 mixture R s 0.2 (cyclohexane / acetone / ethyl acetate-1 *: 1: 2).

Γ NMR .: aromatic protons at wavelength £ 6.5 (3H), and methyls (6h) at wavelength 2.28 67 mixture Rps 0.5 (5 * acetic acid in ethyl acetate).

NMR: aromatic protons at wavelengths £ 7.2 (1H) and 6.85 (2H), and methyl at wavelengths 2.3 68 Rpa 0.1 U (cyclohexane / ethyl acetate / acetone 1+: 2: 1).

NMR .: aromatic protons at wavelengths £ 7.18 (1H) and 6.80 (2H), and methyl at wavelength 2.2 69 mp Rp? 0.5 (5 * acetic acid in ethyl acetate) NMR .: aromatic protons at wavelength ^ 7 , 5 (1H) and 7.25 (3H) 70 mixture Rp * 0.6 (3 * acetic acid in ethyl acetate) 71 mixture Rp »0.65 and 0.7 (3 * acetic acid in ethyl acetate) 72;) eos Rf * 0.1 * (3% acetic acid in ethyl acetate).

NMR .: aromatic protons at wavelength ε 8.1 * (1H), 8.15 (1H), 7.6 (3H) and 7.08 (1H) Λ mp * more polar.

28,63221 The 9-oxo-prostanoic acid derivatives used as starting materials can be obtained by oxidizing the corresponding 9β-hydroxy compound, as exemplified below (g-oxo-1-denoxy-11β-tetretrahydropyran-4-yloxy) -17,18,19, In connection with the preparation of 20-tetranor-5-cis-13-trans-prostadienoic acid.

To a solution of 9β-hydroxy-16-phenoxy-11,15-his (tetrahydropyran-2-yloxy) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (270 mg) in acetone (5 ml) at -10 ° C, Jones reagent (chromic acid in acetone) (0.163 ml) was added. After 15 minutes, isopropanol (1 drop) was added followed by ethyl acetate (20 mL). The solution was washed with 1: 1 saturated brine / water and dried. Evaporation of the solvents and chromatography of the residue on silica using 1: 1 ether / petroleum ether (b.p. 0-60 ° C) as eluent gave the desired 9-oxo-bis- (tetrahydropyranyl ether).

Rp = 0.2 (50 2 ethyl acetate in toluene).

Example 11

The procedure of Example 3 was repeated using 11β-15-dihydroxy-16- (2-naphthyloxy) -9-oxo-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, 16- (U-chlorophenoxy) Instead of -9,11,15,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid to give methyl-11%?, 15-dihydroxy-16- (2-naphthoxy). -ethyl) -9-oxo-17,18,19-20-tetranor-5-cis-13-trans-prostadieno [m.p.], Rp * 0.3 (ethyl acetate).

Example 12

To a solution of 16- (U-chlorophenylthio) -9 {11gg14-15 trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid (12 mg) in methanol (0.5 mL) at room temperature 0 ° C, a solution of sodium periodate (5 mg) in water (0.5 ml) was added. After 18 hours, the solvents were evaporated and the residue was extracted with acetone to give 16- (U-chlorophenylsulfinyl) -9e611 / »15“ trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, 7M, 2918 (calculated 7, 2956), Rp * 0.2 (3 i acetic acid in ethyl acetate).

Example 13% w / v 16- (U-fluorophenoxy) -9? 10 (1,15-trihydroxy-17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid 0.003 sodium phosphate 2.90 sodium hydrogen phosphate 0 , 30 water for injections up to 100 63221 29

Sodium phosphate was dissolved in about 80% water, followed by dissolving the prostadienoic acid derivative and, after dissolution, sodium hydrogen phosphate. The solution was made up to the desired volume with water for injection and the pH was checked to be between 6.7 and 7.7. The solution was filtered to remove fines, sterilized by filtration, and filled into pre-sterilized neutral glass ampoules under aseptic conditions. Immediately before use, the contents of the ampoule were diluted with sodium chloride B.P. for intravenous administration.

The prostadienoic acid derivative can, of course, be replaced by an equivalent amount of another prostanic acid derivative of the invention.

Example 14

The procedure was as in Example 10, starting from the appropriate 9-oxoprostanoic acid derivative to prepare a compound of formula .CH 2 OR 1 *

HO

^ Mass spectrum (b) R Isomer (a) Found Calculated 3-chlorophenyl m.p. (M-CH 2) + s 680.2979 680 3010 l.p. 680 3-Trifluoromethylphenyl m.p. M = 729 3538 729 352 «» l.p. 729 2,4-dichlorophenyl m.p. M + = 729 2907 729 2869 l.p. 729 (a) m.p. = more polar, l.p. = less polar 9-methoxy-1,11 * 15-tris (trimethylsilyl derivative) measured in silica gel thin film chromatophin (b) The starting 9-oxoprostanoic acid derivative was prepared by oxidizing the corresponding 9-hydroxy derivative as described in the second part of Example 10.

uv '· l ·'

Claims (1)

63221 30 Prostanoic acid derivatives of the formula R2 R3 vA for use as a contraceptive or for non-therapeutic control of the estrous cycle in domestic animals. , 'A-CH (OH) -X-Y-R HO wherein R 1 is a hydroxymethyl or carboxyl group or an alkoxycarbonyl group having up to 5 carbon atoms 2; either R is a hydroxy group or an alkanoyloxy group having 3 to 3 carbon atoms and 3 is a hydrogen atom, and R and R together form an oxo group; A is an ethylene or vinylene group; X is an alkylene group having 1 to 3 carbon atoms optionally substituted with one or two alkyl groups having 1 to 3 carbon atoms; Y is an oxygen or sulfur atom, a sulfinyl group (-SO-) or an alkylimino group having up to 4 carbon atoms 4 (-N-alkyl) and R is a phenyl, naphthyl, benzyl or furfuryl group optionally substituted by halogen, hydroxy, phenyl, (C 1 -C 4) alkyl, (C 1 -C 4) alkenyl, halo- (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or di- (C ^ C3) alkylamino; and wherein the formula optionally has one alkyl group having up to 4 carbon atoms in the 2-position; and pharmaceutically acceptable salts of compounds of formula I wherein R * is a carboxyl group.