HU199415B - Process for producing antiasthmatic aromatic prostacyclin analogues and pharmaceutical compositions containing them as active components - Google Patents

Abstract

The present invention relates to the preparation of aromatic prostacycline analogs of formula (I) by reacting a compound of formula (II) with a compound of formula (III) in the presence of an acid catalyst, or (b) reacting a compound of formula (IV) with (V). and treating the resulting enone with a reducing agent, optionally hydrolyzing the protecting groups and / or saponifying the compound. The compounds of formula (I) have anti-asthma activity. ΓοΊ A-CO? R1 $ OR5 Ff CH-CH-CH-R® NR5 Ul Ul IE) r?)> P-CH-C-R6 & 0 0 a-co2r '(VI (IVI Y' CHO A-COzR1) Scope of the description: 9 pages, 10 formulas (. (^ CH-CH-C-R6 (VI. »-1-

Description

The present invention relates to a process for the preparation of aromatic prostacyclin analogs of formula (I) and pharmaceutical compositions containing them.

In the formula (I), the substituents have the following meanings:

R * is hydrogen, C 1-4 straight or branched alkyl,

A is - (CH ₂ ) n -, n is 2, 3, 4, 5 or 6,

R ³ is a hydroxyl group of α or β, benzoyloxy group or tetrahydropyranyloxy group,

^R5 is hydrogen or tetrahydropyranyl,

R ⁶ is C 3 -C 8 cycloalkyl.

The compounds of the invention may be racemates or optically active compounds.

The compounds of formula (I) wherein the substituents are as defined above, is prepared by ^a) (II) - wherein the substituents are as previously megádotakkal - (III) with a compound an acid catalyst, or

b) reacting a compound of formula IV wherein the substituents are as defined above with a phosphorane of formula V wherein R ⁶ is as defined above, and then forming a compound of formula VI wherein the substituents are as defined above, with - enont alkali metal, alkaline earth metal hydrides or borohydrides, zinc borohydride or quaternary alkylammonium borohydrides or alkylaluminum hydrides or potassium tri-sec.butylborohydride, sodium tri-sec.butyl with tri-sec.butylborohydride, lithium triisamoylborohydride, sodium triisisoamylborohydride, potassium triisamoylborohydride or aluminum alkoxides.

i) then optionally preparing the compounds of formula (I) wherein R ³ is hydroxy and R ⁵ is hydrogen and the resulting compound of formula (I) wherein R ³ is benzoyloxy or tetrahydropyranyloxy and / or R ⁵ is tetrahydropyranyl If desired, compounds of formula known per se, preferably reacted with boron trifluoride etherate in methanol or methanolic potassium carbonate, or ii) R is * is H, R ³ is hydroxy, for preparing compounds of formula (I) ⁵ is hydrogen, R is obtained Compounds of formula (I) wherein R ¹ is C 1-4 straight or branched alkyl, R ³ is hydroxy, and R ⁵ is hydrogen are basically hydrolyzed and / or saponified in a manner known per se.

The compounds of the present invention having the general formula (I) are considered to be a stable and effective analogue of prostacyclin. However, their pharmacological profile differs significantly from that of natural prostacyclin. While the most potent effect of prostacyclin is in inhibiting platelet function and its haemodynamic effects (see, e.g., Drugs of Today, 19, 603 (1983)), piriprost (9-deoxy-6, 9-N-Phenylamino-A ^{6, e-} PGI (Drugs of the Future, 8, 877 (1983)) does not have such effects, but the effect that LTC ₄ and thus other SRS-As appear to be medically useful. inhibits the formation component and the competitive antagonist of LTC ₄ production of the compounds (Prostaglandins, 1983 26211-221;.. and publications have appeared in the biological and medical effects (Prostaglandins and thromboxanes Research 11: 39-44 1983).

According to their pharmacological profile, their beneficial effects can be used in the treatment of diseases which are mediated by SRS-A. These include many allergic diseases, the most severe being allergic asthma.

It has been found that the compounds of the formulas described in the present invention (I) - wherein the substituents are as above defined, - inhibit the formation of LTC _4, LTC ₄ and the competitive antagonists.

The compounds of the present invention have the advantage that they are stabilized before the major metabolic pathways known to prostacyclin (C-15 oxidation, ω-oxidation). This greater stability is achieved by the large space-consuming cycloalkyl group having no methyl end-chain.

The compounds of formula I according to the invention were prepared in two ways.

In process variant (a), the 6-keto-PGI compounds of formula (II), wherein the substituents have the same meanings as described above, are subjected to the well-known Paal-Knorr cyclization (see, e.g., RAJones, GPBean, The Chemistry of Pyrroles, Vol. 34 in the Series of Organic Chemistry (Academic Press, 1977). 0.01 to 1.0 equivalents of organic sulfonic acids, preferably pyridine salt of p-toluenesulfonic acid (PPTSA), inorganic acids, preferably anhydrous hydrochloric acid, sulfuric acid and their salts, preferably pyridine hydrochloride, Lewis acids, preferably boron trifluoride, titanium tetrachloride. Suitable solvents are chlorinated hydrocarbons, preferably dichloromethane, chloroform, carbon tetrachloride, and alcohols, preferably ethanol, aromatic hydrocarbons, preferably

-2HU 199415 Β Benzene, toluene, xylene. The reaction is carried out at a temperature of -70 to 150 ° C, preferably 30 to 60 ° C. It is particularly preferred that the condensation be carried out in the presence of pyridine hydrochloride catalyst in chloroform at 40-50 ° C. ·

The hydroxyl groups of the compounds of the general formula (f) prepared above may also be deprotected and / or the ester group may be saponified and / or a salt may be formed from the free acid. The starting material of the reaction is a compound of formula (II) wherein the substituents have the same meanings as described above.

K.C. Nicolau et al., J.Am.Chem.Soc. 101, 766 (1979).

In process variant b), an aldehyde of formula (IV) wherein the substituents have the same meanings as described above is reacted with a phosphorane of formula (V) wherein R ⁷ is phenyl, substituted phenyl and the other substituents have the same meaning as previously defined. The reaction solvent may be an aromatic hydrocarbon, preferably dichloromethane, chloroform, carbon tetrachloride, an ethereal solvent, preferably diethyl ether, tetrahydrofuran. The reaction temperature is -20 to 100 ° C, preferably 20 to 30 ° C. In the reaction, 1.0 to 10 equivalents, preferably 2.0 to 3.0 equivalents (V) are used. phosphorane of the general formula. Acid catalysts, in particular benzoic acid, in an amount of 0.01-0.5, preferably 0.1-0.5 equivalents, may be advantageously employed in some instances. The compound of formula (V) obtained above may be converted into the desired compound of formula (I) using one of the reducing agents known in the art. Suitable reducing agents are alkali metal, boron or aluminum hydrides, preferably zinc borohydride, sodium borohydride, lithium trimethoxy aluminum hydride, lithium tributoxy aluminum hydride, quaternary alkylammonium boride. butyl borohydride, lithium triisoylamyl borohydride, aluminum alkoxides may be used. Solvents for the reaction include alcohols, preferably methanol, ethanol, tert-butanol, etc .; ether type solvents, preferably diethyl ether, tetrahydrofuran, dimethoxyethane. The reduction may be carried out at from -70 ° C to 50 ° C, depending on the reducing agent, the solvent and the particular compound of formula (V).

The C-15 isomers may be separated, if necessary, by chromatography.

The protecting groups and / or ester groups of the compounds of the formula I obtained by the above processes a) or b) can be removed and, if necessary, formed into salts.

Examining the biological activity of the compounds of the present invention, it has been found that the compounds of our invention possess glutathione-S-transferase inhibitory activity. The assays were performed using a method known in the art (C.Wu et al., 1983, Biochem. Biophys. Commun. 112: 980;

HWHabig et al., J. Biol. Chem., 41, 827 (1974)). Thus, the 16, 17, 18, 19, 20-pentanor-1-yl-cyclohexyl-6,9-deoxy-6,9-phenylimino-α ^{, 8-} prostaglandin-I, Formula I of Example 3 wherein R '= hydrogen, A = - (CH 2) - -, n = 4, R ³ = hydroxy-purged, R ⁵ = hydrogen, R ^e = cyclohexyl). ICM value. In addition, the compounds antagonize the activity of LTC _{4 in} guinea pig ileum, as reported by MKBach. Prostaglandins 25 no. 5, 759-770 (1983). According to the results obtained above, the IC ₅₀ of 16,17,18,19,20-pentanor-15-cyclohexyl-6,9-deoxyphenyl-imino-Δ ^{6, ε-} prostaglandin-I, is 2.4 μΜ. The compounds of formula I described in this application, according to the pharmacological profile described above, are useful in the treatment of various allergic symptoms in both human and veterinary medicine. The most preferred area of application for asthma patients is prevention or reduction of seizures. In addition, the compounds of our invention are useful in the treatment of any allergic disorder in which the development of a deleterious process is mediated by SRS-A (see, for example, Orange. RP; Austen, KF .: Adv. Immunol. Austen, KF: J. Immunol., 121, 793 (1978). The preferred therapeutic amount is 0.001 to 10 mg / kg, depending on the particular compound, the patient's condition, gender, age, and mode of administration.

Preferably, the compounds are administered parenterally, orally or by inhalation in a single dose. Dosages as well as the most convenient route of administration will be readily determined by one of ordinary skill in the art. In the preparation of pharmaceutical compositions, customary filler, diluent, taste and odor-influencing, formulation-facilitating, absorption-promoting additives may be used.

The compounds of formula (I) of the present invention may be used alone or in combination with another agent.

The following examples illustrate the preparation of compounds of formula IV:

Reference Example I

2-Phenyl-3- (4 '- (methoxycarbonyl) -butyl) -7a-tetrahydropyranyloxy-6β- (tetrahydropyranyloxymethyl) -2-azabicyclo (3,3,0) octa-Δ Δ ^{3 , 4-} diene (compound of formula VII)

500 mg (0.22 mmol) of n-6-oxo-7 - ((2-p-tetrahydropyranyloxymethyl-4-a-tetrahydropyranyloxy-5-oxo) -cyclopentyl-heptanoic acid methyl ester in 5 ml of chloroform and 0.1 ml of ethyl alcohol and 1.02 ml of aniline and 0.3 ml of a 2 mg / ml solution of pyridinium hydrochloride in dichloromethane are added. The reaction mixture was allowed to stand at room temperature for 3 days. Ethyl acetate (30 ml) was added and the mixture was washed successively with 5 ml of water, 5 ml of sodium hydrogen sulfate, 5 ml of water, 5 ml of saturated sodium bicarbonate, 5 ml of water, 5 ml of saturated brine, and finally magnesium sulphate. dried. Flash column chromatography (50 g of silica gel G silica gel, eluting with 2 hexane 1-ethyl acetate / 233 mg) gave the title compound as a colorless oil.

R f (hexane-ethyl acetate 1: 1): 0.49

Ή NMR: δ (ppm, CDCl ₃ ): 3.65 (s, 3H), 4.72 (m, 2H), 5.75 (s, 1H), 7.1-7.5 (m, 5H)

Reference Example 2

2-phenyl-3- (4 * - (methoxycarbonyl) -rbutil) -7 <x-hydroxy-6? (Hidroxtmetil) 2-azabicyclo (3.3.0) octa-Δ ¹ · ^{5, M} - diene (compound of formula VIII)

The bis-tetrahydropyranyl compound (1.0 g, 1.96 mmol), obtained as the final product of Example 1, was stirred in acetic acid-water-tetrahydrofuran (20: 10: 3) (33 mL) at 40 to 50 ° C for 1 hour. After cooling to room temperature, diethyl ether (200 ml) was added. The separated organic layer was washed successively with 50 ml of water, 3-4 times with 50 ml of sodium carbonate solution (pH 8-9), finally with 50 ml of water and 50 ml of saturated brine. The crude reaction mixture dried over magnesium sulfate was purified by short column chromatography (200 g silica gel G, eluent: ethyl acetate-hexane 5: 1). This gave 500 mg of the title compound as a yellow oil.

TLC

R; (ethyl acetate) = 0.38

I Rf i I m

3400, 1740, 1600, 1500.

1 H NMR (CDCl ₃ ) δ (ppm) = 5.83 (1H, s), 4.7 (1H, m), 3.88 (2H, m).

Reference Example 3

2-phenyl-3- (4'-methoxycarbonyl-r-butyl) -7oc-hydroxy-63-thiophenyl-methyl-2-azabicyclo (3.3.0) octa-Δ ¹ · ^{5, 3,4} -diene ( Compound (XI)) (Formula (I) wherein Q = -CO 2 R, R '= methyl, A = - (CH ₂ ) ₂ -, n = 3, R ² = -OR ³ R ³ = H, R ⁴ = -CH ₂ X R ⁶ , X = S, R ⁵ = R R = phenyl)

Triphenylphosphine (0.317 g, 1.21 mmol) was dissolved in 1 mL of abs. Acetonitrile. The solution was cooled to 0 ° C with ice-water. Under constant stirring at this temperature, 0.056 mL (0.1758 g; 1.1 mmol) of Br _{2 in} 2 mL abs. acetonitrile solution is added dropwise to the reaction mixture. Then, to the acetonitrile suspension was added simultaneously 330 mg (1.0 mmol) of the final product of Example 2 in 2 ml of abs. acetonitrile solution. After heating to 40-50 ° C, the mixture was treated with 1 ml (1.0 mmol) of sodium thiophenolate abs. ethanol solution for 3 hours 4. Chromatography on a short column of ethyl acetate gave 0.224 g of a dark yellow oil.

R1 (ethyl acetate) = 0.5.

IRFU »L3420. 1735, 1600, 1505 (cm ')

Ή NMR (CDCl ₃ ) δ = 5.8 (S, LH)

Reference Example 4

2-Phenyl * 3- (4'-methoxycarbonyl-t-butyl) -7-cyanobenzyloxy-66- (thiophenylmethyl) -2-azabicyclo (3.3.0) octa-Δ, ^S ' ^4- diene ( Compound (X)

200 mg (0.46 mmol) of the final product of Example 3 in 5 mL of abs. dissolved in benzene and 0.05 ml of pyridine was added dropwise. While stirring, 67.4 mg (0.48 mmol) of benzoyl chloride in 1 mL of abs. benzene solution was added and stirring was continued for 3 hours at 40-50 ° C. After cooling to room temperature, the precipitate of pyridinium hydrochloride was filtered off and washed with benzene. The benzene layer was washed with 1 x 10 mL water, dried over MgSO ₄ , evaporated. The crude product was purified by column chromatography with ethyl acetate-hexane (1: 1).

Yield: 0.210 g

Rf = 0.45 (ethyl acetate-hexane 1: 1)

IR: 1720, 1600, 1450, cm ^-1

Reference Example 5

2-phenyl-3- (4'-methoxycarbonyl-t-butyl) -7a-benzoyloxy-6? -Formyl-2-azabicyclo (3.3.0) octa-A ^{, s} ,

^3,4- diene (Formula (IV) where R '= methyl, A = - (CH ₂ ) n - where n = 3, R ³ = benzoyl)

200 mg of the final product of Example 4 are dissolved in 3 ml of anhydrous dichloromethane and cooled to 0 ° C in an ice-water bath under argon. 49.5 mg (0.37 mmol) of N-chlorosuccinimide are added over 5 minutes and the mixture is stirred for 30 minutes. After adding 3 ml of dichloromethane and 1 ml of water, 300 mg (1.1 mmol) of mercuric chloride and 240 mg (1.1 mmol) of mercuric oxide are added. After removing the ice bath, they are vigorously stirred for 3.5 hours. The mercury salts was removed by filtration, washed with 10 ml of dichloromethane, and the dichloromethane layer was finally washed with 1x10 ml of water, dried on _MgSO4 and evaporated. Purify by column chromatography on ethyl acetate-hexane (1: 1).

Yield: 110 mg

R f = 0.3 (ethyl acetate-hexane, 1: 1)

IRfito »: 1735, 1720, 1650 (αιτ ')

Ή NMR (CDCl 3) δ = 5.82 (s, 1H)

Further details of the present invention are illustrated by the following examples, without limiting our claims.

Example 1

11,15-a * tetrahydropyranyl-1,6,17,18,19,20-pentanor-1S-cyclohexyl-6,9-deoxy-6,9-phenyl-imino-A ^{e, 8} -prostaglandin- ₁₁ -methyl ester / (I) p-4HU 199415 Β where A = - (CH ₂ ) - - group, n = 4, R '= methyl radical, R ² = phenyl group, R ³ = = tetrahydropyranyloxy- group, ^R5 = tetrahidtopranil group C = bond, R® = cyclohexyl 1 = alkyl /

2.0 g (3.56 mmol) of 6-keto-11,15-tetrahydropyranyloxy-16,17,18,19,20-pentanor-15-cyclohexyl-prostaglandin-E, methyl ester (Formula II (Lahol A = - (CH 3 -, n = 4, R ¹ = methyl, T - = tetrahydropyranyloxy, B = - CH = CH, R ⁵ - tetrahydropyranyl, C = chemical bond, R (= cyclohexyl) dissolved in 20 ml of anhydrous ethanol, 3.2 ml (35.6 mmol) of freshly distilled aniline are added dropwise and 0.1 g (0.09 mmol) of dried pyridinium hydrochloride are added, stirred for 15 minutes and then 40 hours. After dilution with ethyl acetate (200 ml), the mixture was partitioned between 20 ml of 1M sodium bicarbonate solution, 2 x 30 ml of water and 30 ml of saturated sodium chloride solution, dried over magnesium sulphate and purified by chromatography. hexane-ethyl acetate, 7: 1, to give 1.16 g of the title compound as a yellowish oil.

R f (hexane-ethyl acetate, 5: 1) = 0.3

Ή NMR (CDCl ₃ ) δ: 5.85 (1H, s), 3.68 (3H, s)

Example 2

16.17.18.19.20- -cyclohexylbenzo pentanor-15-6,9-deoxy-6,9-fenllimino-A ^{e '8} prostaglandin-I, methyl ester / (I) wherein wherein A = - (CH ₂ ) "- group, n = 4, R '= methyl radical, R ³ = = hydroxyl radicals, R ⁵ = hydrogen atom, C = chemical bond, R ⁶ = cyclohexyl group /

A solution of the compound obtained in Example 1 (1.16 g, 1.87 mmol) in 15 mL of anhydrous methanol was added dropwise to 5 mL of a 10% solution of boron trifluoride etherate in methanol (4.11 mmol) with stirring. After 2 hours, 1.0 ml of triethylamine was added dropwise. Dilute with 10 mL of ethyl acetate and shake again with 10 mL of 1 N sodium hydrogen sulfate solution, 20 mL of water, 10 mL of saturated sodium bicarbonate, 2 x 20 mL of water, and finally with 20 mL of saturated sodium chloride solution. After drying over magnesium sulfate, it is chromatographed on a short column with 2: 1 hexane-ethyl acetate.

0.431 g of the title compound is obtained in the form of a yellowish oil.

Rf in ethyl acetate-hexane, 2: 1 = 0.48 HNMR (CDCl ₃₎ δ = 5.75 (1H, s), 3.73 (3H, s)

Example 3

16.17.18.19.20-Pentanor-15-cyclohexyl-6,9-deoxy-6,9-phenylimino-α- ^8- prostaglandin-1,1 (I) wherein A = -CH ₂ ) - - , n = 4, R '= hydrogen, R ² = phenyl, R ³ = hydroxy, R ⁵ = hydrogen, R® = cyclohexyl /

0.431 g (0.855 mmol) of the compound obtained in Example 2 is dissolved in 5 ml of methanol and added with vigorous stirring.

14.3 mL (14.3 mmol) of 1 N sodium hydroxide solution. After stirring for 2 h, the mixture was diluted with ethyl acetate (50 mL) and extracted with water (2 x 10 mL). The aqueous phases were combined and 1M sodium hydrogen sulfate solution was added with stirring until the pH of the solution was 4-5 (about 15 mL). The reaction mixture was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were washed with water (3 x 5 mL), brine (3 x 5 mL). After drying over magnesium sulfate, it was purified by short column chromatography. The eluent was 1.25 parts hexane - 1 part acetone saturated with water. The product thus obtained can be recrystallized from acetone-hexane to give a light brown crystalline solid.

Yield: 0.31 g R, (A IX) = 0.35

1 H NMR: δ, δ: δ = 5.7 (s, 1H); Mp: 160-161 ° C.

Example 4

U-benzoyl * 15-oxo-16,17,18,19,20-pentanor-15-cyclohexyl-6,9-deoxy-6,9-phenylmino-A ^e ' ⁸ -prostaglandin-1,1-methyl ester / (IV ) wherein A = - (CH ₂ ) n -, n = 4, R '= methyl, R ³ = benzoyloxy, R = Cyclohexyl /

1.6 g (3.59 mmol) of 2-phenyl-3- (4'-methoxycarbonyl-r-butyl-7-benzoyloxy-6p-formyl-2-azabicyclo (3.3.0) ^{okfa-l, 5} - ^3,4 -diene A (formula IV, wherein A = - _(CH2) "- group, n is 4, R '= methyl, ^R2 = Ph, ^R3 = benzoyloxy group) dissolved in 25 ml of distilled benzene kaiciumhidridről was added 1.52 g (3.95 mmol) was stirred triphenyl-2-oxo-2-cyclohexyl-ethylidene phosphorane (formula V, where R ⁷ = phenyl, R® = cyclohexyl) at room temperature under vigorous stirring Protected from light for 20 hours and chromatographed without processing (300 g silica gel G adsorbent, 3 hexane-1 ethyl acetate) to give 1.41 g of the title compound as a pale yellow oil, Rf 0.38 (1 hexane-1). ethyl acetate in an eluent)

Ή NMR (CDCl ₃ ): δ = 5.80 (s, 1H)

Example 5

11-benzoyl-16,17,18,19,20-pentanor-15-cyclohexyl-6,9-deoxy-6,9-phenylimino-A ^{, 8} prostaglandin-1,1-methyl ester (Formula I), wherein A = - (CH ₂ ) n -, n = 4, R '= methyl, R ³ = benzoyloxy, R ⁵ = hydrogen, R ® = cyclohexyl /

1.41 g (2.55 mmol) of the compound obtained in Example 4 is dissolved in 20 ml of distilled ethanol and cooled to 0 ° C. Sodium borohydride (0.578 g, 15.3 mmol) was added with vigorous stirring and after stirring for 15 min.

Acetic acid (1.5 ml) was added and the temperature was allowed to return to room temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and washed successively with saturated sodium bicarbonate solution (30 mL), water (30 mL), and brine (30 mL). Dry over magnesium sulfate. The crude product thus obtained is hexane5

-5HU 199415 Β

ethyl acetate (2: 1), chromatographed on 250 g of silica gel. This gave 1.09 g of the title compound as a yellow oil.

R f = 0.27 (1 hexane-1 ethyl acetate)

Example 6

^{16,17,18,19,20-pentanor-15-cyclohexyl-6,9-phenylimino-A-E8} prostaglandin l -methyl / general formula (I), wherein A = - _(CH2) "- group, n = 4, R '= methyl, R ^{3 *} = hydroxy, R ⁵ = hydrogen, R ⁶ = cyclohexyl /

From the compound obtained in Example 5, 1.09 g (1.96 mmol) was dissolved in 15 mL of distilled methanol and 0.4 g (2.9 mmol) of freshly annealed potassium carbonate was added under vigorous stirring. After stirring vigorously at room temperature for 6 hours, half the methanol was evaporated, diluted with diethyl acetate (200 mL), and then with sodium bicarbonate (20 mL), water (20 mL), saturated sodium bicarbonate (20 mL), and water (2 x 20 mL). Wash with 20 mL of saturated brine. Dry over magnesium sulfate. It was chromatographed on 100 g of silica gel in hexane-ethyl acetate (1: 1).

R f = 0.20 (1 hexane - 1 ethyl acetate; two isomers) δ NMR: 5.75 (1H, s), 3.73 (3H, s)

Claims (6)

A process for the preparation of aromatic prostacyclin analogues of formula I wherein R ¹ is hydrogen, C 1-4 straight or branched alkyl, A is - (CH ₂ ) n -, n is 2, 3, 4, 5 or 6, R ³ is a hydroxyl group of α or β, a benzoyloxy group or a tetrapyranyloxy group; ^R5 is hydrogen or tetrahydropyranyl, R® is a C3-8 cycloalkyl group - preparation, characterized in that ^a) a compound of formula (II) - wherein the substituents are as defined above - is reacted with a compound (III) an acid catalyst, or b) reacting a compound of formula IV wherein the substituents are as defined above with a phosphorane of formula V wherein R ⁶ is as defined above, and then forming a compound of formula VI wherein the substituents are as defined above - enont alkali metal, alkaline-earth metal hydrides or borohydrides, zinc borohydride or quaternary alkyl ammonium borohydrides or alkyl ammonium hydrides or potassium tri-sec.butyl10-borohydride, sodium tri-tri-butyride -sec.butylbromohydride, lithium triisoamylborohydride, potassium triisoamylborohydride, sodium triisisoamylborohydride 5 or with aluminum alkoxides, if desired i) for the preparation of compounds of formula I wherein R ³ is hydroxy and R ⁵ is hydrogen, the compound of formula I wherein R ³ is benzoyloxy or tetrahydropyranyloxy and / or R ³ is tetrahydropyranyl reacting the compound with boron trifluoride etherate in methanol or methanolic potassium carbonate, or, if desired, ii) R @ ¹ is hydrogen, R @ ³ is hydroxy, R @ ⁵ is hydrogen to give R @ 20. place Compounds of formula (I) having a linear or branched C 1 -C 4 alkyl group, R ³ is hydroxy and R ⁵ is hydrogen Undergo hydrolysis. Process a) according to claim 1, characterized in that the catalyst is 0.01 - The reaction is carried out at a temperature of from 70 to 150 ° C, preferably from 30 to 60 ° C, using 1.0 equivalents of organic sulfonic acids, inorganic acids or equivalent salts thereof, preferably 0.5-1.0 equivalents of pyridinium hydrochloride. a. Process b) according to claim 1, Characterized in that 2.0 to 3.0 equivalents of phosphorane (V) are carried out in benzene at 20 to 30 ° C. Process b) according to claim 1, characterized in that the reaction is carried out in ethanol at 0 ° C using sodium borohydride as a reducing agent. The method of claim 1, 16,17, 18,19,20-pentanor-15-cyclohexyl-6,9-deoxy-6,9 '-phenylimino- ^6,8- prostaglandin-1, methyl ester, characterized in that the appropriately substituted starting materials are used. 6. A? The method of claim 1, 16,1 50 18,19,20-pentanor-15-cyclohexyl-6,9-deoxy-6,9-phenylimino-A ^6,8- prostaglandin-I, characterized in that the appropriately substituted starting materials are used. 7. A process for the preparation of a pharmaceutical composition comprising one or more compounds of the formula I as claimed in claim 1, wherein R 1 -R ⁶ , A, B, C, n and m are θθ 1. A compound according to claim 1, which is mixed with one or more excipients conventionally used in the manufacture of a pharmaceutical composition.