HU184831B - Process for producing 16-methoxy-16-methyl-prostaglandin-e-1 down derivatives - Google Patents

Abstract

The present invention relates to novel horse methoxylmethyl-prostaglandin derivatives of the formula I, wherein R is C1-C4 alkyl or a non-toxic pharmaceutically acceptable cation. The compounds of formula I according to the invention are prepared by starting from appropriately substituted compounds and converting them into the desired end products by conventional methods in prostaglandin chemistry. The compounds of the present invention are effective in reducing the production of germic acid, and also protect the mucous membrane of the mammalian stomach at low doses against ulceration. -1-

Description

The present invention relates to novel horse-methoxy-16-methyl-prostaglandin-E1 derivatives and their use as gastrointestinal agents, which includes all possible forms of industrial applications, including the preparation of pharmaceutical compositions from the novel compounds, which compositions are also within the scope of the invention.

The present invention relates to a process for the preparation of a compound of formula I wherein R is an alkyl group containing from 1 to 4 carbon atoms.

In formula I, a dashed line is used to denote a substituent below the plane of the molecule being drawn (α-configuration), and a substituent above the plane of the molecule (O-configuration) is denoted by an expanding continuous valence line.

There are two chiral (asymmetric) centers on the lower side chain of the prostaglandin-like compounds of formula I, C-15 and C-16. Therefore, 4-4 isomers of the compounds of formula I are possible in which the configuration of C-15 and C-16 may be as follows: (15-R, 16-S), (15-S, 10-R) (15-R, horse-R) and (15-S, 16-S).

The compounds of the present invention have a significant inhibitory effect on the production of gastric acid (secretion), especially when administered orally (orally) and, at very low oral doses, have a strong cell protective effect.

Prostaglandins are a class of natural substances that are studied in detail because of their various pharmacological (inducing, secretory, antihypertensive and bronchodilatory) effects and because they are involved in a variety of biological processes [W. Losert et al., Arzneimitteiforschung (Drug Research, 25, No. 2, p. 135, 1975), therefore, the literature in this field is enormous, and there are numerous patents and patent applications which require "synthetic" prostaglandin derivatives, wherein these novel derivatives differ in their cyclopentane ring and / or one or the other side chain from naturally occurring prostaglandin slag products (see, for example, U.S. Patent Nos. 1,409,841, 1,506,816 and 1,345,993, Belgian Patent 827,529). and U.S. Patent 4,029,698).

The prostaglandin derivatives of the general formula I according to the present invention, although completely novel in themselves, fall within the scope of U.S. Patent No. 837,865. Belgian No. 1,495,152; United Kingdom Patent Nos. However, the aforementioned Belgian patent does not disclose any 16-methyl-16-methoxy-prostaglandin-E1 derivative which contains a saturated bond at the 5,6-position, while the 1,495,152-denominated linkage does not. United Kingdom Patent Nos. 6,166,194 and 2,16,16-dimethyl-prostaglandin-E. describes a derivative which additionally contains an oxygen atom instead of the methylene group at the 17-position, which in turn has a propyl or pentyl group attached, and compounds c have a cis-substituted double bond at the 5,6-position.

The compounds of the present invention are prepared by methods known per se which are commonly used in the art and are disclosed in U.S. Patent No. 837,865. Belgian Patent No. 5,481,900. The starting material for the preparation of the compounds of the invention is represented by formula II wherein R is as defined above and

R 1 and R ₂ represent a protecting group for hydroxyl hydroxycarbonate, cyclopentane alcohols. For the process of the present invention it is preferred when aliphatic R contains 2 to 4 carbon atoms is acilcsopcít., And • R ₂ is tetrahydro-1H-pyran-2-yl.

Starting cyclopentane aldehydes may be prepared by methods described in the literature (see, for example, Belgian Patent Nos. 807,161 and 837,855).

To prepare the prostaglandin-like compounds of the present invention, the aldehydes of formula II are first prepared by

K ₃ is an alkyl group of 1 to 4 carbon atoms, reacted with phosphonate reagents to form a compound of formula IV wherein

R is as defined above,

Ri and _R2 is an aliphatic acyl group and R ₂ is tetrahydro-H-pyran-2-yl group containing a hydroxyl group, a protecting group, and preferably R is 2-4 carbon atoms, to give intermediate.

This condensation is carried out under substantially the same conditions as the chemical literature has generally shown to be prepared from cyclopentane aldehyde intermediates and phosphorus-containing reagents. In practice, the reaction is carried out in an inert organic solvent such as tetrahydrofuran, dimethoxyethane, benzene, dioxane or the like, at a temperature between 0 ° C and 80 ° C.

In order to effect condensation, the phosphonate reagent must be converted to the corresponding anion using about one equivalent of an alkali metal hydride relative to the phosphonate of formula III. The phosphonates of formula III have a chiral center (denoted by an asterisk in formula III) and may be used in their optically active form or as a mixture of the two possible isomers. Therefore, when the aldehyde II is reacted with a mixture of two isomers of the phosphonate III, a mixture of two possible isomers of the compound IV is obtained, where the absolute configuration at the 16 carbon atoms of the two components of the mixture is opposite (one R another S), while using the optically active form of the phosphonate of formula III gives a compound of formula IV wherein s has a C16 configuration (R or S). When the above reaction results in a mixture of the C16 isomers of the compound of formula IV, these isomers may be separated by methods known per se, for example, by chromatography. Although not necessarily necessary, it is advisable to separate the isomers of the intermediate of Formula IV prior to further transformation.

As a second step in the reaction sequence, the 15-oxo derivative is reduced to the corresponding 15-hydroxy derivative using a commonly used reducing agent such as sodium borohydride, zinc borohydride, diphenyltin hydride or lithium trialkd borohydride.

184,831

Considering that the reduction of the oxo group at position 15 creates an additional chiral center in the molecule, and that the reduction is preferably carried out as described above with the pure isomers of the compounds of Formula IV, both two products of formula V are formed in which the configuration of the carbon atom 16 is the same (R or S) and the configuration of the carbon atom 15 is the opposite (R and S).

A mixture of the two isomers of the compound of formula V thus obtained may be carried on to the next reaction without separation, or it may be carried out by separating the two isomers and reacting them separately. Accordingly, in the former case, a mixture of isomers of the final product of formula I is obtained, the components of which may optionally be separated, whereas in the latter case, starting from a pure isomer of the absolute configuration at C 15 and C 16, Only one of the possible isomers of the compound of formula Ia is obtained.

In some cases, one of the C 15 isomers, usually the more polar isomer, is obtained in very small amounts. Surprisingly, it has been found that when the reaction is carried out a a compound of formula IV, wherein R ₂ represents a protective group of a hydroxyl group, preferably tetrahydro-lH-pyran-2-yl, then the two isomers formed in about equal amounts. In such cases, separation of the isomers after reduction in a manner known per se, such as silica gel column chromatography or silica gel preparative thin layer chromatography, affords pure isomers of the compounds of formula V wherein the hydroxy group at the pyran-2-yl ether. However, depending on the configuration of the carbon atom 16, it may be necessary to reconstitute the hydroxyl group at position 11-cs before chromatographic separation of the mixture.

Subsequent reduction of the oxo group at position 15 gives the corresponding compound of formula V (as defined in C15, as a mixture of isomers), where Γ < ₂ is tetrahydro-1H-pyran-2-yl. If desired, the resulting mixture of carbon 15 isomers may be separated by the methods described above. The mixture or the pure isomers are then converted to give the final product of formula (I). To obtain the final product of Formula I from a compound of Formula V, the hydroxy group at position 15 of the compound of Formula V above is first protected, for example, by the use of a protecting group, preferably 3,4-dihydro-2H-. with pyran, then the compound of formula V having a protected hydroxyl group at position 15, where R 1 is an aliphatic acyl group containing from 2 to 4 carbon atoms, is hydrolyzed under mild conditions, for example with sodium carbonate or potassium carbonate, and The hydroxy group at position 9 is then freeed, then the hydroxy group at position 9 is oxidized to an oxo group by a conventional oxidation method (e.g., Collins reagent, i.e., a pyridine-chromium trioxide complex) and finally the protecting groups at positions 11 and 15 are removed.

When tetrahydro-1H-pyran-2-yl is used as a protecting group for the hydroxy groups at positions 11 and 15, they are preferably removed by acid hydrolysis with a 19: 11: 3 by volume mixture of acetic acid, water and tetrahydrofuran. At 40-45 ° C.

If the reaction steps described above are carried out starting from a mixture of compounds of formula V (wherein the isomers of the mixture have the same absolute configuration of carbon 16 and the configuration of carbon 15 is opposite), the final product of formula I is two ( (C15) isomer mixture. If desired, the mixture thus obtained may be separated into the pure isomers by conventional chromatography as described above.

The starting phosphorus-containing reagent of formula III is prepared by reacting a compound of formula VI wherein

R ₃ is C 1-4 alkyl, lower alkyl phosphonic acid ester of formula VII wherein

X is -0R ₃ radical or a chlorine atom, O-thiomethyl-a-methoxy-hexanoic acid (rövidszénlácú) alkyl chloroformate (or corresponding acid chloride) was condensed.

To this end, the methyl phosphonate of formula VI is first converted to the corresponding anion by adding butyl lithium to a solution of the compound of formula VI in tetrahydrofuran at -78 ° C, followed by the addition of the compound of formula VII and at the same temperature. When an optically active form of the phosphonate of the general formula III is required, the racemic form of α-methyl-α-methoxyhexanoic acid is first resolved by the conventional method to the two antipodes (optical isomers, e.g., by an optically active base such as efcdrine). , atropine or amphetamine, the corresponding salts are formed which are separated by fractional crystallization.

The pure antipodes are then converted to the corresponding optically active esters or acid chlorides (Formula VII) which are then condensed with the methyl phosphonates of Formula VI.

The compounds of the present invention are also effective in inhibiting gastric acid secretion (acid secretion) when administered orally to experimental animals. The extent of this biological activity could not have been predicted by those skilled in the art, since the corresponding compounds having a double bond at the 5-position, as disclosed in U.S. Patent No. 837,865. Belgian Patent Application No. 5,198,197, shows much less activity in the oral (oral) range. In other words, it has been found that by modifying the structure of such compounds remarkably and advantageously the biological activity of the compounds is altered. The inhibitory effect of these compounds on oral gastric acid secretion was evaluated on the basis of their ability to inhibit lysamine-induced hyperacidity (increased gastric acid production) in dogs. In these experiments, histamine, which effectively enhances gastric acid secretion, is described in Bertaccini et al., Eur. Journ. Pharmacol., 28, 360 (1974)], as a continuous intravenous infusion.

184,831

Five mongrel dogs were used for the experiment. The dogs' stomachs were operated according to the method of Bertacchni et al., Supra, and thus each animal had an innervated (non-denervated) main stomach or, in other words, a non-innervated (denervated) stomach or Haidenhain's small stomach. , We placed a cannula in both the main stomach and the small stomach of Haidenhain, through which the gastric juice could drip.

The draining gastric juice was separately titrated with 0.1 N sodium hydroxide solution using an automatic titrator (Radiometer, Copenhagen). After a 4-5 week post-operative rest period, the five dogs were first given only a secretion-enhancing agent (the dose of histamine was gradually increased every half hour from the initial dose of 40 gg / kg / hr to 320 pg / kg / hr). in the stomach and in the small stomach of Haidenhain induced an increase in gastric acid secretion. Every half hour, the gastric juices dripping from the two stomachs were collected and titrated as above. The mean values thus obtained for the five dogs were considered as "control values". The inhibitory effect of the compounds of the present invention on oral gastric acid secretion was measured by administering the compounds to the gastrointestinal tract at a dose of pg / kg / h as described below, one hour prior to administration of the secretagogue. Subsequently, a continuous intravenous infusion of the gastric acid secretion enhancer, the dose of which was varied as described above, was collected every half hour and the gastric juice drained from the two stomachs was titrated. Thus, a simple calculation could determine the percent inhibition of secretion at a given dose of histamine and active compound.

Experiments with the compound obtained as described in Example 1F show that when administered at a dose of 25 µg / kg / h and 100 µg / kg / cra, this histamine is 40 µg / kg / h and 160 µg / kg / h. hourly dose-induced increase in gastric acid secretion in the main stomach by about 35% to about 95%, while in the Haidenhain gastric stomach it is inhibited by about 30% to about 60% compared to the control.

Under the same experimental conditions, the corresponding double-bonded compound at position 5 is nearly inactive. In another experiment under the same conditions, histamine was administered at a single dose of 160 pg / kg / hr; in this case, the compound prepared as described in Example 1F inhibits gastric acid secretion by about 60%, while the corresponding compound having a double bond at position 5 is inactive. The compounds of the present invention are effective in inhibiting increased gastric acid production even when administered intravenously. To demonstrate this, we measured the extent to which the compounds of the present invention inhibit histamine-induced increased gastric acid production in anesthetized rats following a single intravenous administration. These experiments are essentially those of Ghosh and Schilld [Brit. J. Pharm., 13, 54-61 (1958)]. In this method, rats are anesthetized with urethane and a dilute solution of sodium hydroxide (about 1 mL of 1/4000 N sodium hydroxide solution per minute) is administered through the esophagus and a solution of 4 pH is added directly through a cannula discharged from the pylorus (lower stomach) with a pH meter and a writing device! continuously measured using a connected glass electrode. The dilute sodium hydroxide solution introduced into the stomach is sufficiently buffered in the stomach to form an approximately linear buffer system over a given range, so that the change in pH can be considered as the degree of acid secretion. If the animals. no secretion enhancer is added, then the initial pH of the sodium hydroxide solution collected from the stomach is about 6-6.5 (pH ₀ ). Subsequently, the secretory enhancer, in this case histamine, is administered to the animals by continuous intravenous infusion at a dose of 1.5 mg / kg / h. A few minutes after the start of the infusion, the pH starts to drop and after about 10-20 minutes the acid15 secretion reaches its maximum and the pH of the fluid draining from the stomach reaches its lowest level (pHhistamine) which is constant as a result of the continuous infusion of histamine remains. The compound to be tested is then administered intravenously and the pH is continuously measured. The highest pH observed in this way indicates that the maximum amount of secretion inhibitory effect achieved by the test compound was reached (.pyristine + halogen). From the above pH values, the% inhibition of gastric acid secretion can be simply calculated:

Phthistamine drug ^- P histamine ~ p histamine

According to this 100% effect means that the test compound at a given dose of histamine took back pH excited gastric histamine is not excited gastric pH value in the basic state, while the 0% and _l5 effect means that the test compound. administration did not affect histamine-induced increased gastric acid production.

With the compound prepared as described in Example 1F, the following results were obtained:

Dose (.Mu.g / kg) % Inhibition of gastric acid secretion 2.5 15 10 63 20 90 50 100

Further experiments have shown that the compounds of the present invention have remarkable cell protection activity after very low oral doses. More specifically, the cell protective effects of the compounds of the invention were demonstrated by examining the ability of the compounds of the invention to produce high levels of 1 '(para-chlorobenzoyl) -5'-methoxy-2-methyl-3H-indolylacetic acid (indomethacin). prevent or attenuate severe ^OU of the formation of gastric ulcers induced by doses of oral dosages that are much smaller than those which can reduce gastric acid secretion. In this experiment, the rats were starved for one day but received water as needed. The test compounds were administered orally to 5 to 5 animals per dose in 5% needles in 0.5% aqueous methylcellulose solution,

-4184,831 indomethacin was administered intraperitoneally (in the abdominal cavity) at a dose of 10,000 mg / kg in the same medium. Another group of animals (the control group) was treated with ulcerogenic (ulcerative) agent only. The degree of cellular protection of the compounds of the present invention is expressed as% inhibition of ulcers relative to control. This inhibition is calculated using the formula:

^ control ~ Managed χ jqq ^ control where:

^ control mean number of ulcers in the stomach ^of control animals, and

Mean gastric ulcers ^of animals treated ^with both indomethacin and test compound were treated. '

The average ulcer numbers were reported by Thuillier et al., Chim. Ther., 3 53 (1968)), determine whether the stomachs of each experimental animal are screened for ulcers and score individual stomachs according to the severity of the observed ulcers: 0 indicates no stomach ulcer And 4 indicates perforated ulcers. The number of ulcers on each stomach is then determined and the value obtained for each animal on the stomach is averaged.

. In these experiments, the compound obtained as described in Example 1F was already very active at very low doses. The 3 µg / kg dose of this compound (the lowest dose used in this set of experiments) inhibited ulcer formation by about 43% compared to the control, while the ED ₅₀ value (the chemical dose that inhibited ulcer formation by 50%) ) according to extrapolation calculations: 6 µg / kg.

It is clear from the above that these compounds protect the gastric mucosa through one or more mechanisms which are independent of inhibition of acid secretion, as is evident from the experiment described above, since this compound exerts its protective effect at much lower doses than the dose required to inhibit acid secretion.

It follows from the above results that the prostaglandin derivatives of the present invention can be used in mammals to reduce or regulate excessive gastric acid production, and to provide small doses of protection for the gastric mucosa to reduce or eliminate gastrointestinal ulceration. Thus, the present invention also encompasses human and veterinary pharmaceutical compositions containing the prostaglandin-like compounds of Formula I as an active ingredient.

The novel compounds of the present invention are preferably administered in the form of oral, capsules, dragees or syrups. If desired, injectable solutions for parenteral (gastro-intestinal) administration may be prepared. These pharmaceutical formulations may be prepared by methods well known to those skilled in the art (see, e.g., Rcmington, Pharma- ceutical Sciences, 13th Edition, Mack Pub- lishing Co., Easton, Pennsylvania). These formulations contain from about 5 pg to about 100 pg, preferably from about 10 pg to about 60 pg of the active ingredient. Capsules and dragees may contain, in addition to the active ingredient, conventional pharmaceutically acceptable excipients such as diluents, lubricants, and disintegrating agents. Syrups may contain the usual suspending, wetting, buffering, flavoring and preserving agents. The dosage range of the prostaglandin-like compounds of the present invention required to exert antipruritic activity depends on a number of factors, including the type, age and weight of the mammal to be treated. However, good results can be obtained when the prostaglandin derivatives of the present invention are administered in a daily dose of about 10 mg to about 300 pg, preferably in divided doses. However, it will be appreciated that a daily dose outside the above range may be used, depending upon the condition of the subject being treated.

The present invention is illustrated by the following non-limiting examples.

Example I '1α, 15-Dihydroxy-16-methyl-9-oxo-prost-13 (E) -en-1-acid methyl ester (15-R, 16-R) and (15- S, 16-R), brain (15-R, 16-S), and (15-S, 16-S)

A. A solution of 870 g (0.030 mol) of optically active 3-methoxy-3-methyl-2-oxo was added dropwise to a mixture of 770 mg of a 81.8% sodium hydride suspension in mineral oil (0.026 mol) and 30 ml of anhydrous dimethoxyethane. -heptylphosphonic acid dimethyl ester = + 41.2 ° (C = 1%, CHCl ₃ )] in 40 ml of dimethoxyethane. After standing at room temperature for a quarter of an hour, 4.08 g (0.013 mol) of 7- (5a-acetoxy-2β-boiling-3a-hydroxy-cyclopent-1-yl) -heptanoic acid methyl ester (50 mL) were added in 50 mL of anhydrous dimethoxy. ethanolic solution.

The reaction mixture was allowed to stand at room temperature for 6 hours, then poured into saturated aqueous sodium dihydrogen phosphate solution and diethyl ether. shaken. The diethyl ether was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by chromatography on silica gel (eluent: diethyl ether / petroleum ether 1: 1 v / v). This gives 3.9 g of 9a-acetoxy-11a-hydroxy-methylmethoxy-16-methyl-15-oxo-prost-13 (E) -en-1-acid ester, the absolute configuration of which is 16. or S. [α] D 20 = + 53.8 ° (C = 081%, CHCl ₃ ).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.89, 1.1-2.1, 1.29, 2.08, 2.30, 2.4-2.6, 3.21, 3.68, 4, 11, 5.23, 6.87.

B) 9 g of 9a-acctoxyl-11a-hydroxy-16-methoxy-16-methyl-15-oxo-prost-13 (E) -en-1-acid methyl (5 g, 0.0113 mol) obtained in the same manner as in step A). Dissolve the ester in 150 ml of anhydrous benzene and add a solution of 2.6 ml (0.0285 mol) of 2,3-dihydropyran and 70 mg of p-toluenesulphonic acid in 50 ml of anhydrous benzene at a temperature of about 5-10 ° C. Keep at room temperature for 10 minutes. The reaction mixture was then washed with a saturated aqueous sodium bicarbonate solution and then with water, and the solvent was distilled off. The residue was purified by column chromatography over silica gel eluting with petroleum ether / diethyl ether 7: 3 by volume.

A mixture of -5384-831 was used. This way. 5 g of 9a-acetoxy-16-methoxy-16-methyl-15-oxo-11a-J- (tetrahydro-1H-pyran-2-yl) -oxy] -Poly-13 (E) -en-1- an acid methyl ester is obtained wherein the absolute configuration of the carbon atom 16 is R or S.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 088, 1.1-3.0, 1.25, 2.06, 3.23, 3.3, 4.8, 3.72, 5.20, 6.8- 7.1.

C) To a solution of 13.5 g of sodium borohydride in 400 ml of methanol is added dropwise at -20 ° C 5 g (0.0093 mol) of 9a-acetyl xyl 6-methoxy-16-methyl-15-oxo obtained as described in B). -1a [(tetra hydro-1H-pyran-2-yl) oxy] -prost-13 (E) -en-1-acid diethyl ester.

The reaction mixture. After 2 hours at -20 DEG C., the reaction mixture was poured into saturated aqueous sodium dihydrogen phosphate solution and extracted with diethyl ether. The ether portion was dried over sodium sulfate and the solvent was distilled off. The residue is Sa-acetoxy-15-hydroxy-16-methoxy-16-methyl-Ua - [(letrahydro-11,11-pyran-2-yl) -oxy] -7-prost-13 (E) -en-1-acid methyl is a mixture of two isomers of carbon 15. These isomers were separated by first eluting the chromatography column with petroleum ether / diethyl ether (8: 2 v / v) and then with petroleum ether / diethyl ether (6: 4 v / v). The first eluted product (2.05 g pure product, this less polar isomer) had an NMR (CDCl ₃ ) of 0.90, 1.13, 1.12.9, 2.07, 3.28, 2, 5-4.3, 3.73, 4.67, 5.20, 5.7-5.9.

The second eluted product (2.1 g pure product, this is the more polar isomer) had an NMR (CDCl ₃ ): 3, 1.07, 1.1-2.9, 2.07, 3.28. 3.2-4.2 3.72, 4.67, 5.20, 5.7-5.9.

In the two products thus obtained, the absolute configuration of the carbon 16 is the same (R or S) and the configuration of the carbon 15 is the opposite. Thus, these products may be the following isomeric pairs: (15-R, 16-R) and (15-S, 16-R), or (15-R, 16-S) and (15-S, horse-S) .

Subsequent chemical transformations leading to the products of formula I do not alter the stereochemistry of the carbon atoms of 15 and of horse.

D) 9a-Acetoxy-15-hydroxy-16-methoxy-16-methyl-11a - ((tetrahydro-1H-pyran-2-yl) oxy] - prost-13 (E) -en-1-acid The more polar isomer of methyl ester (2.1 g), prepared as described in Step C), is dissolved in 150 ml of anhydrous benzene. After cooling, 1.3 ml (0.0142 mole) of 2,3-dihydropyran was added, followed by a solution of 75 mg of p-toluenesulfonic acid in 40 ml of anhydrous benzene, and the reaction mixture was allowed to stand for a quarter, then with aqueous sodium hydrogen. The benzene portion was separated, dried over sodium sulfate and the solvent was distilled off. The residue was purified by chromatography on a silica gel column using petroleum ether / diethyl ether (7: 2 v / v) as the eluent. 2.1 g of 9a-acetoxyl-6-methoxy-16-methyl-11a, 15-bis [(tetrahydro-1H-pyran-2-yl) oxy] -prost-13 (E) -en-1-acid- yields a methyl ester having the configuration of the carbon atoms of 15 and 10 in one of the four possible combinations described in step C) above.

Nuclear Magnetic Resonance Spectrum (CDCl3): 0.92. 1.12, 1.15, 1.1-3.0, 2.07, 3.25, 3.32, 3.2-4,?, 3.70, 4.5-5.2, 5, 3 -5.6.

The product obtained above is dissolved in 200 ml of anhydrous methanol and 2.1 g of anhydrous potassium carbonate are added.

After stirring for 24 hours at room temperature, the reaction mixture was poured into saturated aqueous sodium dihydrogen phosphate solution and the aqueous mixture was extracted with diethyl ether. The diethyl ether portion was triturated with sodium sulfate and the solvent was distilled off. In this way, 1.95 g of pure 9α-hydroxy-16-methoxy-6-methyl-11,15-bis [(tetrahydro-1 H -pyran-2-yl) -ol] -propyl-3 (E) -ene are obtained. -I-acid-methyl retester is obtained.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.92, 1.0-2.9, 1.10, 1.13, 3.25, 3.32, 3.2-4.4, 4.6-5. 0, 5.4-5.9.

E) 6.38 g of celite, 7.25 g of Collins reagent (pyridine-chromium trioxide complex), 1.95 g of 9a-hydroxymethyl

A mixture of 16-methyl-11a, 15-bis [(tetrahydro-1H-pyran-2-yl) -3xi] -prost-13 (E) -en-1-acid methyl ester and 180 ml of dichloromethane. stirring at room temperature for one hour. The mixture was then poured into 1200 ml of diethyl ether and filtered through a pad of celite. The filtrate was clarified with activated carbon and the solvent was distilled off. 1.77 g of 16-methoxy-16-methyl-9-oxo-1α-15-bis [(tetrahydro-1H-pyran-2-yl) oxy] were obtained. - prost - 13 (E) -en-1-acid methyl ester is obtained.

Nuclear Magnetic Resonance Spectrum (CE? Cl ₃ ): 0.93, 1.0-2.9, 1.12, 1.15, 3.1-4.9, 3.25, 3.32, 3.70, 5.4-5.8,

F) The product obtained in Step E (1.77 g) is suspended in a mixture of acetic acid, water and tetrahydrofuran (19: 11: 3 by volume) (100 ml). The mixture is stirred for 2 hours at 45 ° C and then with water. dilute and adjust the pH to 7.2 by addition of sodium bicarbonate.

The aqueous mixture was then partitioned between diethyl ether and the diethyl ether distilled off; This gave 1.19 g of crude product which was purified by column chromatography on silica gel using diethyl ether as eluent.

This gives 780 mg of pure IIa, 15-dihydroxy-1-methoxy-16-methyl-9-oxoprost-13 (E) -en-1-acid methyl ester, where carbon atoms 15 and 16 are obtained. absolute configuration based on X-ray analysis (15-R, 16-R).

Product Features:

[α] ^β θ - measured on a Perkin Elmer 241 polarimeter - -50.3 ° (0.96, chloroform C.).

NMR (CDC1 _3): 0.92, 1.1-1.7, 1.11, 1.9-2.8, 2.29, 3.1-3.3, 3.24, 3, 63, 4,07,4,12, 5,69.

The uniformity of the product, m.p. 40-48 ° C, was checked by differential calorimetry.

G) 9a-Acetoxy-15-hydroxy-16-methoxy-16-methyl-11a - [(tetrahydro-1H -) - obtained in each of the steps described in steps D), E) and F) above and as described in step C). starting from the less polar isomer of pyran-2-yl) oxy] prost-13 (E) -en-1-acid methyl ester 380 mg of 11a, 15-dihydroxy-16-methoxy-16-methyl-9-oxo -prost-13 (E) -en-1-acid methyl ester is ka-6184 831 where the absolute configuration of the carbon atom 16 is the same as the carbon configuration of the product obtained in step F), but The absolute configuration of the carbon atom is contrary to the absolute configuration of the carbon atom of said compound.

Product features:

[Α] D = -79.6 ³ (C = 1%, chloroform).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.92, 1.1-1.7, 1.17, 1.9-2.8,

2.29, 3.26, 3,69,4,10,4,17,5,75.

Example 2a, 15-Dihydroxy-16-methoxyl-6-methyl-9-oxo-prost-13 (E) ene, - acid methyl ester (15-R, 16-S) and (15-S) , 16-S) or (15-R, 16-R) and (15-S, 16-R).

By proceeding essentially as described in Example 1, but using the phosphonate reagent described in Step A of the first Example, an optical antipode drug is used. m.p. = - 41.3 ° (c = 1%, chloroform), 11a, 15-dihydroxy-16-methoxy-16-methyl-9-oxo-prost-13 (E) -en of formula I The other two isomers of the acid retryl ester are obtained. The absolute configuration of the carbon 16 in these two isomers is the same as and opposite to the configuration of the carbon 16 of the two isomers obtained as described in Example 1 and the absolute configuration of the carbon 15 in these two isomers is opposite.

a) In each of the procedures described in Example 1, Step A, 5 g (0.0188 mole) of 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid dimethyl ester [a] ² j = -41, 3 ° (c-1%, chloroform) was condensed with methyl (7- (5a-acetoxy-2,3-formyl-3a-hydroxycyclopent-1-yl) -heptanoic acid) (2.5 g, 0.0080 mol) and then followed by the same procedure as in Example 1, steps B and C, to give 2.65 g of crude product, which is 9? -acetoxy-15-hydroxy-16-methoxy-16-methyl-11? - [(tetrahydro-111-pyran-2) - yl) oxy] prost - 13 (E) -en-1-acid methyl ester is a mixture of two isomers of carbon 15.

Nuclear Magnetic Resonance Spectrum (CDCl _a ): 0.91, 1.0-2.6, 1.06, 1.07, 1.13.1, 14.2.06, 2.29, 3.22, 3, 24, 3.3-4.2, 3.68, 4,54,6,5,13,5,5-5,7.

b) A mixture of two isomers of carbon 15 (2.65 g) is hydrolyzed as follows: Acetic acid: water: tetrahydrofuran (19: 11: 3, 78 ml) is heated at 45 ° C for 1.5 hours. . The mixture was then neutralized with sodium bicarbonate and extracted with diethyl ether. The diethyl ether is distilled off to give 2.55 g of crude product of 9a-acetoxy-11,15-dihydroxy-16-methoxy-16-diethyl-prost-13 (E) -en-1-acid acid ethyl ester. a mixture of two isomers of carbon 15. The pure isomers were obtained by chromatography on a silica gel column eluting with diethyl ether. The less polar isomer was first eluted (860 mg) having:

[.alpha.] D @ 20 = + 17.3 DEG (c = 0.95%, chloroform).

Nuclear Magnetic Resonance Spectrum (CDC13): 0.92, 1.05. 1.1-2.6, 2.07,

2.29, 3.23, 3.68, 3,93,4,15, 5,19, 5,63.

Second, the more polar isomer is eluted (yield: 8 Ό mg), which has the following characteristics:

[α] D + 45.3 ° (c = 0.76%, chloroform).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): 0.91, 1.0-1.7, 1.13, 2.07, 2.2-3.0, 2.29, 3.25, 3.68, 3.89, 4.15, 5.17, 5.53, 5.7i.

c) To a solution of the more polar isomer (870 mg, 0.00191 mol) prepared in step b) above in 130 ml of anhydrous benzene is added a solution of 30 mg of p-toluenesulfonic acid in 30 ml of anhydrous benzene and 2.5 ml of (2,373 mol) of 2,3-dihydropyran and the mixture was heated at 15 ° C for a quarter hour. It is then poured into a saturated aqueous solution of sodium bicarbonate and the benzene portion is separated off. The benzene portion was washed with water, dried over sodium sulfate and the solvent was distilled off.

The residue was purified by silica gel column chromatography (eluent: petroleum ether / diethyl ether 7: 3). There were thus obtained 1.09 g of 9a-acetoxy-16-yl-ethoxy-16-methyl-11,15-bis [(tetrahydro-1H-pyran-2-yl) oxy] prost-13 (E) -r-n-1. The ssv-methyl ester is obtained in which the absolute configuration of the carbon 16 omega is opposite to the absolute configuration of the carbon 16 of the product obtained in Example 1 (E) and the configuration of carbon 15 is either R or S.

Nuclear Magnetic Resonance Spectrum (CDC13): 0.92, 1.0-2.7, 1.11, 1.15, 2.05, 2.29, 3.22, 3.29. 3.3-4.2, 3.68, 4.6-4.9, 5.13, 5.4-5.8.

d) By essentially the same procedure as described in Example 1, Step D, Part Two, Example 1, Steps F and G, starting from the female compound described in Example 2, step c) above, 250 mg of 11a, 15-dihydroxy Methyl 16-methoxy-16-methyl-9-oxo-prost-13 (E) -en-1-acid is obtained.

This product features:

(m.p. = -51.4 ° (c = 0.52%, chloroform).

Nuclear Magnetic Resonance Spectrum (CDC13): 0.91, 1.1-3.2, 1.14, 2.30, 3.25, 3,68,4, 07,4,10,5,6,6,6 .

e) In each of the procedures described in steps c) and d) above and starting from the less polar isomer (860 mg) prepared in step b) of this example, 320 mg of 11a, 15-dihydroxy-16-methoxy-16- methyl 9-oxo-prost-13 (E) ene-1-acid methyl ester is obtained.

The carbon 16 configuration of this compound is the same as the absolute configuration of the carbon 16 of the compound obtained in step d) above, but the configuration of the carbon 15 is contrary to the configuration of the carbon 15 of said compound.

features:

[Α] D = -82.4 ° (C = 0.95%, chloroform).

Nuclear Magnetic Resonance Spectrum (CDC13): 0.94, 1.1-1.8, 1.06, 2.0-2.9,

2.30, 3.24, 3.69, 4,11,4,19, 5,6-5,9.

-7184 831

Example 3

A capsule is filled with a mixture of the following ingredients:

1x, 15-Dihydroxy-16-methoxy-16-methyl-9-oxo-prost-13 (E) -en-1-acid methyl ester 40 µm talc 3 mg lactose 3 mg cathoxymethylcellulose sodium salt gives 3 mg of starch 90 mg.

Example 4

A dragee contains the following ingredients:

1α, 15-Dihydroxy-16-inethoxy-16β-methyl-9-oxoprost-13- (E) -yl-1-acid methyl ester 60 µg carboxymethylcellulose sodium salt 4 mg magnesium stearate 4 mg gelatin 7 mg starch 7 shirts sucrose 20 mg plus gum arabic, lactose, titanium dioxide, shellac. The dragee is prepared by conventional methods.

Claims (6)

Patent claims A process for the preparation of 16-methoxy-16-methyl-prostaglandin E1 derivatives of the formula I wherein R is an alkyl group containing from 1 to 4 carbon atoms, characterized in that a cyclopentane aldehyde of formula III wherein R is as defined above and R! and R ₂ is a hydroxyl protecting group with a racemic or optically active form of a phosphonate of formula III wherein R 1 is C 1 -C 4 alkyl, and the resulting 15-oxo group of the resulting compound of formula IV, wherein R, R 1 and R ₂ are as defined above, is reacted with a complex metal hydride such as sodium borohydride, zinc borohydride, diphenyl tin hydride or a lithium trialkylborohydride with a 15-hydroxy group, the hydroxy group at position 15 of the compound of formula V thus obtained, wherein R, R 1 and R ₂ are as defined above, is protected with a suitable hydroxyl protecting group and removing the hydroxy group at position 9, oxidizing the hydroxy group at position 9 to the oxo group, and finally deprotecting the hydroxyl groups at positions 11 and 15 under mild conditions, when obtained by the above process, a mixture of isomers, if desired, is pure isolating the isotherms. Process for the preparation of optically active 16-methoxy-16-methyl-prostaglandin E1 derivatives of the formula I according to claim 1, wherein R is a C 1 -C 4 alkyl group having a carbon at the 16-position having a chirality equal to the stereoisomer of the 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid dimethyl ester ([α] D = + 41.2 °, c = 1, chloroform) at the 3-position carbon atom, and the 15-position carbon atom of which has the same chirality as 9-acetoxy-15-hydroxy-16-methoxy-16-methyl-11a - [(tetrahydro-1 H - pyran-2-yl) oxy] · prostate-13 (E) -ene-1-acid methyl ester chirality of the more polar stereoisomer, which was separated on a silica gel column with 8: 2 petroleum ether / ethyl ether followed by 6: Eluting with 4% petroleum ether / ethyl ether, the second product eluting with a cyclopentane aldehyde of formula II wherein R is as defined above and R 1 and R ₂ are hydroxy protecting groups - reacted with an optically active phosphonate of general formula III having an optical rotation of? 0 = + 41.2 °, in which R _{3 is a C} 1-4 alkyl group. 15 oxo groups of the compound of formula ( _II) wherein R 1 and R _{2 are} as defined above are reduced to a 15-hydroxy compound of a complex metal hydride such as sodium borohydride, zinc borohydride, diphenyltin hydride or a lithium trialkyl borohydride. The more polar isomer of R, R, and R _{2 having} the meaning given above, by chromatography on silica gel, eluting first with petroleum ether / ether (8: 2) and then petroleum ether / ethyl ether (6: 4). The hydroxy group at position 15 is selected from a suitable h the hydroxy group at position 9 is liberated, the hydroxy group at position 9 is oxidized to the oxo group and finally the protecting groups are removed from the hydroxyl groups at positions 11 and 15 under mild conditions. 3. A process according to claim 2 for the preparation of ali, 15-dihydroxy-16-methoxy-16-methyl-9-oxo-prost-13 (E) -ene 1-acid methyl ester having a carbon at the 16-position having a chirality. which is identical to the chiral carbon at the 3-position of the dimethyl ester of 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid [(ajθ = + 41.2 °, Cl, chloroform) and has a chiral carbon of 15 which is the same as 9-acetoxy-15-hydroxy-16-methoxy-16-methyl-11a - [(tetrahydro-1H-pyran-2-yl) oxy] prost-13 (E) -en-1-acid with the chirality of the more polar stereoisomer of the methyl ester, which is eluted as the second product after elution with 8: 2 petroleum ether / ether and then 6: 4 petroleum ether / ethyl ether as the stereoisomer separates the stereoisomers. cyclopentane aldehyde wherein R is methyl The process of claim 1, wherein the starting material is of formula II -8,184 831 using compound Almi R _(aliphatic acyl group is 2-4 carbon atoms, R ₂ is tetrahydro-lH-pyran-2-yl; powder and R are as defined in claim 1 meanings. 5. A process according to claim 1 wherein the starting material is a compound of formula 11 wherein R ₂ is tetrahydro-1H-pyran-2-yl and R and R ₁ are hydrogen. the. Having the meaning given in claim 1. 6. A process for the preparation of a pharmaceutical composition for the protection of the gastric mucosa of a mammal, comprising the preparation of a compound of formula I according to claim 1, wherein R is as defined in claim 1, as a carrier and / or medicament. or together with other excipients to form a pharmaceutical composition.