FI69062B - NYA 16-METHOXY-16-METHYL-PROSTAGLANDIN-E1-DERIVATIVES AND METHODS FOR THE FRAMSTAELLNING OR DERAS ANVAENDNING SOM MAGEN SKYDDANDE AEMNEN - Google Patents

Description

NOTICE OF PUBLICATION 690 6 2

IKSTa LBJ UTLÄGGNI NGSSKRIFT

r »p- ·»>% -. »* · j t I.? 2 lft i n-> 5 • gg («) Γα-, Γ ^^ -, Γ .....

'V> ~ ^ (51) Kv.lk. * / Lnt.CI.4 C 07 C 177/00 ^ U0 | ^ || pl N L A N D (11) Patent application - PatentansBkning 802998 (22) Filing date - Ansökningsdag 24 09 80 (Fl) (23) Starting date —Glltighetsdag 24.09.8 0 (41) Published public - Blivit offentlig Q3 82

National Board of Patents and Registration / 44) Date of publication of the publication |

Patent-och registerstyrelsen '' Ansökan utlagd och utl.skriften publieerad 5U.UO.Ö1 »(32) (33) (31) Privilege claimed - Begärd priority (71) Gruppo Lepetit SpA, via Durando 38, 20158 Milan, I or ia -I taiien (IT) (72) Umberto Guzzi, Milan, Romeo Ciabatti, Novate Milanese (Mi lano), I tai ia-I ta 1 ien (IT) (74) Munsterhielm Ky Kb (54) New 16 -methoxy - 16-methyl-11-prostaglandin - E-j derivative, method for their preparation and their use as gastric protective agents -Nya 16 -methoxy-16-methyl-prostaglandin-Non-derivatives, methods for the preparation of derivatives and derivatives This invention relates to novel 16-methoxy-16-methyl-prostaglandin-E derivatives, to a process for their preparation and to their use as gastric protective agents, the term "use" referring to all industrially applicable aspects and measures of said use, including the development of new combining the compounds with pharmaceutical compositions thus lis are a particular object of the present invention.

The novel compounds which are primarily the subject of this invention are 16-methoxy-16-methyl-prostaglandin E4 derivatives having the following general formula

Il, '' CH2 \ 6 k CHp 2 C00R

? CH, ^ 5 ^ CH2 / 32 \ c2h / 1 4 °? CH3 18 20

NiXja ^ xi5 / Ki7 / CH ^ i9 / M, HO 'I CH3

OH

2,69062 wherein R represents a (C 1-4 alkyl group) or a non-toxic, pharmaceutically acceptable cation such as Na +, K +, ammonium cation and organic derivatives thereof.

In the above formula, a dashed line is used to mean that a particular substituent is below the level of the drawn molecule (cX configuration), while a thick solid line is used for a substituent above the level of the drawn molecule (^ A configuration).

The prostaglandin-type compounds of the above formula have two chiral centers in the lower side chain, i. at positions C-15 and C-16. Consequently, four different isomers of formula (I) can be prepared, which are described by the following combinations of configurational notations for positions C-15 and C-16: U5-R, 16-S), (15-S, 16-R), (15 -R, 16-R) and U5-S, 16-S).

The compounds of this invention have considerable anti-secretory activity, especially when administered orally, and have, even at very low oral doses, significant cell protective (cytoprotective) effects.

Prostaglandins form a number of natural substances that have been extensively studied because they have different pharmacological functions (interruptive, anti-secretory, hypotensive, bronchodilator) and also because they are involved in many biological methods (W. Lossert et al., Arzneim. Forsch. Drug Res., 2ί, No. 2, page 135, 1975).

As a result, there is a lot of literature in this field and there are also many patents and patent applications belonging to the classes of "synthetic" prostaglandins which differ from those naturally occurring in the cyclopentane ring structure and / or in one or both side chains (see for example GB patents 1 * + 09 8 ^ - 1, 1,506,816 and 13 * + 5 93 * +, BE patent 827,529 and U.S. patent 029,698).

The same prostaglandins of formula (I) which are the subject of the present invention, although completely new in themselves, are included in the general formula of BE patent 837 865 and GB patent 1 h-95 152. However, the above BE patent never describes 16-methyl-16-methoxy-prostaglandin E 2 derivatives having a saturated bond at the (^ position), whereas GB patent 1 ^ -95 152 produces only two 16 , 16-dimethyl-prostaglandin-E, in which, in addition, the methylene group in position 17 is replaced by an oxygen atom, which in turn is attached to a propyl or pentyl group, and in which a cis-5 double bond is always present.

3,69062 The compounds of this invention are prepared according to known methods commonly used in this field and extensively described in BE Patent 837,865. The starting material is a cyclopentane aldehyde of the formula 0R, r X 1

CH CH2 CH2 \ ^ ^ COOR

^ ch2 ^ ^ ch2 ^ ch2) - ((II) cho wherein R is as defined above and R1 ^ and R2 are, independently of one another, hydrogen or a hydroxy-protecting group, Preferably within the scope of this invention R1 is (C1-4) and an aliphatic acyl and R 2 is hydrogen or a tetrahydro-1H-pyran-2-yl radical.

The cyclopentane aldehyde used as starting material can be prepared by methods described in the literature (see, for example, BE patents 807-116 and 837,855).

The process for the preparation of the prostaglandin-type compounds of the present invention comprises, as a first step, the condensation of an aldehyde of the above formula (II) with a phosphonate reagent having the following general formula R 30. £ ch3 / P-CH0-CO-C-CH0-CH0-CHO-CHO 2 1 2 2 2 3 r3o ^ ch3 (III) wherein R3 is an alkyl group having 1 to 1 * carbon atoms, to give an intermediate of formula «1

i, CH CH2 ^ CH2 ^ / C00R

y — gh2 ^ ch2 ch2 / OCH3 CHo \ CH, /> CH2 ^ C ^ I ^ CH ^ 2 \ CH2 / or2 II ch3 (iv) 2 o 5 690 6 2 wherein R is as defined above and R2 is, independently of one another, hydrogens or hydroxy-functional protecting groups, and preferably R 1 is (C 2-1) aliphatic acyl and R 2 is hydrogen or a tetrahydro-1H-pyran-2-yl radical.

The condensation is carried out essentially under the same conditions as described in the chemical literature on prostaglandin syntheses, starting from cyclopentane aldehyde precursors and phosphorus reagents. In practice, the reaction is carried out in the presence of an inert organic solvent such as tetrahydrofuran, dimethoxyethane, benzene, dioxane and the like at a temperature in the range of 0 to 80 ° C.

To carry out the condensation, the phosphonate reactant must be converted into the corresponding anion and for this purpose about one equimolar part (calculated from the phosphonate of formula (III)) of alkali metal hydride is used. The phosphonate of formula (III) has a chiral center (indicated by an asterisk in formula (III) above) and may be used in optically active form or as a mixture of two possible isomers. Condensation between an aldehyde of formula (II) and two isomers of a phosphonate of formula (III) thus yields a mixture of two possible isomers of formula (IV) having the opposite absolute configuration (one R and one S) at the C-16 position. , while the use of a phosphonate of formula (III) in optically active form gives a compound of formula (IV) having the configuration given at the C-16 position (R or S). If a mixture of two possible isomers at the C-16 position is obtained, it can be separated into the two isomeric forms according to known methods, for example by chromatographic methods. In any case, although not absolutely necessary, it is preferable to carry out the separation into the individual isomers before the subsequent reactions of the intermediates of formula (IV). Thus, the second step of the reaction scheme involves the reduction of the 15-keto compound to the corresponding 15-hydroxy derivative with commonly used reducing agents such as sodium borohydride, zinc borohydride, diphenyltin hydride or lithium trialkylborohydrides.

Assuming that reduction of the oxo group at the C-15 position results in the formation of a second chiral center and that, as indicated above, it is more preferable to carry out the two possible isomers of formula (IV) separately, a mixture of each C-16 isomer is obtained. , having two products of formula (V), li 5 69062 having the same configuration at the C-16 position (R or S) and the opposite configuration (R and S) at the C-15 position.

^ ORj

i, CV iV / CH \ / COOR

\ _ / CH. The mixture of the two isomers of formula (V) thus obtained can be used as such in the following reaction steps or can be separated into two, single isomers, which are then subjected to the same reactions separately. Thus, in the former case, a mixture of the final products of formula (I) is obtained which, if desired, can be separated into its components, whereas in the latter case the use of a single isomer with given absolute configurations at positions C-15 and C-16 gives only one possible formula (I). ) isomers.

It has been found that when the reduction is carried out on a compound of formula (IV) wherein R 2 is hydrogen, and preferably the carbon atom at position 16 is one of the two possible absolute configurations, two C-15 isomers are obtained in very different amounts.

Sometimes one of the C-15 isomers, and usually the most polar, is obtained in very small amounts. Surprisingly, it has been found that if the reduction is carried out on a compound of formula (IV) in which R 1 is a hydroxy-functional protecting group and preferably a tetrahydro-1H-pyran-2-yl radical, the two isomers are obtained in approximately the same ratio. In this case, subsequent separation according to known methods, such as silica gel column chromatography or preparative thin layer chromatography using silica gel plates, gives two individual products of formula (V) in which the hydroxy group in position 11 is protected, preferably tetrahydro. H-pyran-2-yl-ether. However, depending on the configuration at position C-16, it may be necessary, before chromatographic separation of the mixture, to return the free hydroxy function to position 11.

According to a preferred embodiment of the present invention, a molar amount of a compound of formula (IV) wherein R 1 represents 6 69062 hydroxy-functional protecting groups, and preferably, a (C 2-1) aliphatic acyl is provided, and R 2 is hydrogen, given the absolute configuration at the C- 16, to react with about 2-3 equimolar amounts of 2,3-dihydrofuran in the presence of an anhydrous, inert organic solvent such as benzene and a catalytic amount of p-toluenesulfonic acid. The reaction takes place at room temperature and takes about 5 to about 20 minutes. There is thus obtained a compound of formula (IV) in which R is as defined above, R 1 is a hydroxy-functional protecting group and preferably a (C 2-1 +) aliphatic acyl group and R 2 is a tetrahydro-1H-pyran-2-yl radical.

Subsequent reduction of the 15-oxo group to the corresponding compound of formula (V) (as a mixture of two possible 15-position isomers) wherein R 2 is a tetrahydro-1H-pyran-2-yl radical. If desired, the mixture thus obtained can be separated into the individual C-15 isomers according to the methods described above. The mixture or individual isomers are then further reacted to give the final products of formula (I). The reaction steps starting from the compound of formula (V) to the final compound of formula (I) comprise protecting the hydroxy groups in positions 11 and 15 of the compounds of formula (V) above by reaction with a suitable protecting agent, preferably 3, 4-dihydro-2 with pyran, the resulting 11,15-protected compound of formula (V) is hydrolysed under mild conditions, for example with sodium or potassium carbonate if R 1 is an (C 2-1) aliphatic acyl group, to restore the free hydroxy group at position 9, then oxidizing said hydroxy group to the oxo group by conventional oxidation methods (e.g., Collins reagent, i.e., the pyridine / chromium oxide complex) and finally deprotecting at positions 11 and 15.

When the protecting groups of the hydroxy functions at positions 11 and 15 are tetrahydro-1H-pyran-2-yl radicals, their removal is preferably carried out by acid hydrolysis using a mixture of acetic acid water: tetrahydrofuran = 19: 11: 3 (v / v / v). at a temperature of LK) -1 + 5 ° C.

If these reactions are carried out with compounds of formula (V) having the same absolute configuration at position C16 and opposite configurations at position C-15, a mixture of two compounds of formula (I) which are isomers at position C-15 is obtained. If desired, said mixture can be separated into the individual isomers by the usual chromatographic methods described above.

The phosphorus reagents of formula (III) used as starting materials are 1 69062 prepared by condensing a lower alkyl ester of methylphosphonic acid of formula (R-, O) 0 3, 11, P-CH3 (VI) (R3or wherein R3 represents a (C1-4) alkyl group, X, -methyl-N-methoxy-hexanoic acid lower alkyl ester (or the corresponding acyl chloride) of formula (VII) OCHt ^ 3 xoc-c-ch2-ch2-ch2-ch3 (vii} ch3 wherein X can means -OR 3 or -Cl.

This process first involves the conversion of a methylphosphonate of formula (VI) to the corresponding anion by the addition of butyllithium at -78 ° C in tetrahydrofuran, followed by reaction with a compound of formula (VII) for about 1 hour at the same temperature. When it is desired to obtain an optically active form of a phosphonate of formula (III), the ε-methyl-β-methoxyhexanoic acid racemate is first separated into two antipodes by conventional methods, such as using an optically active base, e.g. ephedrine, atropine or amphetamine. which are separated by fractional crystallization. The separated antipodes are then converted to the corresponding optically active esters or acid chlorides of formula (VII), which in turn are condensed with a methylphosphonate of formula (VI).

The compounds of this invention are also potent inhibitors of gastric secretion when administered orally to laboratory animals. The existence of this biological activity could not be imagined at all by one skilled in the art, given that the corresponding compounds having a double bond at position 5 and described in BE patent 837,865 are only slightly active when administered per orale. In other words, it has been found that a small modification in the structure of these compounds has brought about considerable and advantageous changes in biological activity. The gastrointestinal inhibitory properties of these compounds, when administered orally, were evaluated for their efficacy in inhibiting histamine-induced acidity in dogs. Histamine, a potent stimulator of acid gastric secretion (see Bertaccini et al., Eur. Journ. Pharmacol., 28, 360, 1974), was administered intravenously by continuous infusion during the experiments.

A group of five mixed breed dogs was used in the experiment. Dogs underwent abdominal surgery according to the method of Bertaccini et al. (see above), to equip each animal with an innervated main stomach or gastric fistula (G, F.) and a denervated stomach or Haidenhain sac (H.P.). Gastric tube and Haidenhain bags were both cannulated to allow gravity to drain gastric fluids out. Subsequently, said gastric fluids were separately titrated with 0.1 N NaOH using an automatic titrator (Radiometer, Copenhagen). After a recovery period of 5 to 5 weeks, five dogs were first treated with a secretagogue alone (histamine doses were progressively increased every 30 minutes from a minimum of * + 0 to a maximum of 320 μg / kg / h) to stimulate acid gastric secretion and GF and HP. Every 30 minutes, the acidic product from both G.F. and H.P. was collected and titrated as described above. The values thus obtained (each as the average of five dogs) were considered "control values" or "controls". To evaluate the gastric secretory inhibitory activity of the compounds of the invention, they were administered by gavage to said dose, expressed in μg / kg / h, dissolved in 1 ml of physiological saline, 60 minutes before administration of the secretagogue. The gastric hyperacidity stimulant was administered intravenously by continuous infusion at the above doses, and every 30 minutes, gastric fluids from both G.F. and H.P. were collected and titrated. By doing so, it was possible to estimate, by simple calculations, the percentage inhibition of acid gastric secretion at the administered doses of histamine and active compound.

The results obtained with the compound of Example 1F at = -50.3 ° show that very low doses, 25-100 μg / kg / h, inhibit histamine at doses ranging from--0-160 μg / kg / h. induced gastric hyperacidity of about 95-35 (calculated relative to controls) in GF and about 60-30 in HP.

Under the same experimental conditions, the corresponding compounds having a C-5 double bond are almost inactive.

A second experiment performed under the same conditions as above, but with a fixed dose of histamine at 160 μg / kg / h instead of 9 69062 increasing doses, showed that the compound of Example 1F with 20 = -50.3 ° inhibited gastric acidosis. secretion by about $ 60, while the corresponding compounds having a double bond at the C-5 position are inactive. The compounds of this invention are also effective inhibitors of gastric hypersecretion when administered intravenously. This has been confirmed by considering the effects of histamine-induced gastric hypersecretion achieved by administering the compounds of this invention to rats anesthetized with simple intravenous doses. The experiments were performed mainly according to the method of Ghosh and Schild, Brit. J. Pharm. (1958), 13 »5 * + - 6l. According to this method, the rat is anesthetized with urethane and its stomach is rinsed with dilute sodium hydroxide solution (N / ^ + 000 NaOH, at a rate of about 1 ml / min) through the esophagus and the pH of the fluid from the cannula in the gastric port is continuously monitored by a glass electrode. connected directly to a readable pH meter and recorded from the device. As it passes through the abdomen, the rinsing agent collects sufficient buffer to act as a substantially linear buffer system in a suitable ratio so that the change in pH becomes a measure of acid secretion.

When the NAOOO NaOH solution is collected, after passing through the unstimulated abdomen, the initial value is about 6-6.5 ^ »ton stimulated by the stomach * ·

The secretory stimulant, in this case histamine, is then administered intravenously by continuous infusion at a dose of 1.5 mgAg / h. After a few minutes the pH begins to decrease and after about 10-20 minutes the secretory effect reaches its maximum and the pH is at its lowest value (pHhlstamllnllla stlmuioltu gastric). 3 ° · «Due to continuous infusion of histamine, remains constant Test compounds are then administered intravenously And pH is recorded continuously By taking the highest recorded pH that is evidence of the greatest inhibitory effect (pHM AE) achieved with the test compound using the following formula pHM.AE "pHH.SS χ 100 pHU.S. ~ pHH.SS

the percentage inhibition of gastric acid secretion can be easily calculated. A potency of 100 # means that the test compound, at the dose tested, returned the pH of the histamine-stimulated stomach to the original value of 10,69062 unstimulated stomach, while a potency of 0% means that the administration of the compound did not affect histamine-induced gastric secretion.

In representative experiments performed with the compound of Example 1F having a <1 = = 50.3 °, the following results were obtained:

Dose (μg / kg)% inhibition of acid gastric secretion 2.5 15 10 63 20 90 50 100 Nearest known compound The compound of Example 5 of US-4,201,865, which is the PGE 2 analog of the PGE 2 compounds of our application, with the difference of a double bond at the 5-position in the case of the PGE 2 analog.

To show that there is in fact a significant difference between the two compounds, which could not be inferred from the foregoing, we compared said compound with the compound of Example 1F of our application in a gastric secretion test and a diarrhea test.

Gastric secretion was assessed by the abdominal flow test 11 of the anesthetized rat described above, also presented by C. Scarpignato, G. Spina, G.C. Signorini and G. Bertaccini in Res.Commun.Chem. Pathol. Pharmacol. 1983, 3j}, 211.

Gastric hypersecretion was induced by continuous intravenous (i.v.) histamine infusion (1.5 mg / kg / hour) and the ability of test compounds to reduce this hypersecretion was evaluated.

The EDg values for the reference compound 1e and the compound of the present invention were 7.2 μg / kg and 4.5 μg / kg i.v., respectively. after dosing.

To demonstrate the superiority of the compounds of this invention, the diarrhea effect in mice was also evaluated. After all, diarrhea is known to be one of the most common, undesirable side effects of prostaglandins.

The diarrheal effect was evaluated by the method of Randall and Baruth (L.0. Randall and M. Baruth, Arch.Int.Pharmacodyn, 1976, 220, 94). Charles Rivers male CD ^ mice, weighing 20-22 g, were fasted for 24 hours before the test. Mice, 10 animals / dose / group, were orally administered logarithmically divided doses of the prostaglandin in question. Immediately after dosing

II

11,69062 mice were placed in individual cages with suction papers at the bottom for one hour. Diarrhea was assessed by the size of the moisture stains formed, using a rating table of 0-4, as reported by Randall and Baruth.

ED 2 g values were calculated by the method of Miller and Tainter (R. C. MiHler and M. L. Tainter, Proc.Soc.Exp.Biol.Med. 1944, 57, 261).

The ED 2 value for the reference compound was 750 V / kg, while the ED 2 value for the compound of the present invention was 1350 Y? Kg. Differences in activities and the occurrence of an undesirable side effect clearly indicate the superiority of the compound of this invention.

The ratio ED, -g (antisecretory) / ED5g (diarrhogenic), which is a significant therapeutic index, is clearly much better with the compound of this invention.

In view of the above, we consider that the compounds of this application are novel and justifiably significantly more potent than known, closely related prostaglandins.

Other experiments were performed which showed that the compounds of this invention also have considerable cell protective (cytoprotective) activity, which occurs at very low oral doses. In particular, the cytoprotective effect of the compounds of this invention was evaluated for their efficacy in rats in inhibiting the formation and reduction of gastric ulcers caused by high-dose 1- (p-chlorobenzoyl) -methoxy-2-methyl-2-indolyl-acetic acid (indomethacin) at oral doses are much lower than those doses that cause inhibition of gastric acid secretion. In these experiments, rats were not given food the day before the start of the experiments, but water was given at will. Test compounds were administered orally as a suspension in 0.5% aqueous methocell-1 solution (5 animals / dose), while indomethacin was administered intraperitoneally at 10,000 mg / kg in the same vehicle. The second group of rats (controls) received only uiogenic agent. The cell protective properties of the compounds of this invention were then expressed as "percentage inhibition of wounds compared to controls", which can be easily calculated by the following ratio: A * ^ (controls) "^ .UD (treated animals) --X 100 A * U * D * (controls) with AUD (| ζ0η ^ Γοΐ 1 it) is the mean gastric ulcer rate of the controls and the A.U.D. (kasUe1, yt animals) is the average degree of gastric ulceration 12 in animals receiving both indomethacin and the test compound. 69062 A.U.D.jt has been calculated according to the method of Thuillier et al. In Chim. Ther », 3, 53, 1968, by examining the wounds of the stomachs of laboratory animals And marking the results in groups by Orsta! + Age, depending on the number of wounds detected And the severity s 0 means no wounds in the gastric wall, * + means pierced by wounds. The simple degree of ulceration (S.U.D.) is then calculated for each individual stomach.

The sum of the S.U.D. values is divided by the number of animals to obtain the A.U.D. value of the stomachs of each group of animals.

‘In these experiments, the compound of Example 1 with a s -50.3 ° proved to be very active, even at very low doses. In fact, at a dose of 3 μg / kg (the lowest dose tested in these experiments), the percentage inhibition of wounds relative to controls was about * + 3, while the ED 2 q (i.e., the dose that inhibited wounds 50 μg relative to controls), calculated by extrapolation was 6 ug / kg.

It is clear, therefore, that the greater protective effect of these compounds on the abdominal mucosa is mediated by one or more mechanisms independent of inhibition of acid secretion because, as the results of this last experiment show, this compound protects cells at doses too low to inhibit acid secretion significantly. extent.

Due to the above results, the prostaglandin derivatives of this invention are useful in mammals for reducing and controlling excessive gastric acid secretion and also for use, even at very low doses, in the protective effect of the gastric mucosa, thereby reducing and preventing gastrointestinal wound formation. Thus, the present invention further encompasses pharmaceutical or veterinary compositions containing a prostaglandin derivative of formula (I) as an active ingredient.

In practicing the invention, the novel compounds are administered, preferably, orally in the form of capsules, coated tablets or syrups. If desired, parenteral dosage forms such as injectable ampoules may also be prepared. These pharmaceutical dosages are formulated in a known manner (see, e.g., Remington's Pharmaceutical Sciences, 13th Edition, Mack Publishing Co., Easton, Pennsylvania) and are prepared by conventional methods.

They may contain about 5-100 μg and preferably about 10-60} ug of active ingredient. In addition, therapeutic capsules and coated tablets may contain conventional pharmaceutically acceptable excipients such as inert diluents, lubricants and disintegrants. Syrups may contain conventional suspending, wetting and buffering agents, flavoring and preservative agents. The dosage regimen for the gastroprotective treatment of the prostaglandin compounds of this invention will depend on a variety of factors, including the type, age and weight of the mammal. However, good results can be obtained by administering the prostaglandin compounds of this invention in a daily dose of about 10 to 300, preferably in divided doses. However, it will be appreciated that a daily dose above the above limit may also be used, depending on the individual circumstances of the subject being treated.

The following examples further illustrate this invention.

Example 1 11?, 15-Dihydroxy-16-methoxy-16-methyl-9-oxo-Prosta-13 (E) -ene-1-acid methyl ester (15-R, 16-R) and (15-S, 16-R) or (15-R, 16-S) and (15-S, 16-S) A) To a mixture of 770 mg of a suspension of 8l, $ 8 in sodium hydride in mineral oil (0.026 mol) and 30 ml of anhydrous dimethoxyethane , a solution of 8 g (0.030 mol) of optically active dimethyl ester of 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid with = - + ^ + 1 ^ 2 ° (C = 1% in CHCl3) is added dropwise, * + In 0 ml of dimethoxyethane. The resulting mixture is allowed to stand at room temperature for 15 minutes, after which a solution of * + .08 g (0.013 mol) of 7-acetoxy-2H-formyl-3β-hydroxy-cyclopent-1H-yl is added gradually. ) heptanoic acid methyl ester in 50 mL of anhydrous dimethoxyethane. After standing at room temperature for 6 hours, the reaction mixture is poured into an aqueous solution saturated with NaH 2 O 2, which is then extracted with ethyl ether. The organic extract is dried over MgSO 4 and concentrated to dryness. The residue obtained is purified by column chromatography on silica gel, eluting with ethyl ether / petroleum ether 1: 1 (v / v). Yield 3.9 g of 9β-acetoxy-10β-hydroxy-16-methoxy-16-methyl-15-oxo-Prosta-13 (E) -ene-1-acid methyl ester having an absolute position at the C-16 position configuration R or S. 1 D = + 53.8 ° (O = 0.81% in CHCl 3). NMR absorption peaks in CDCl 3 (δ): 0.89; 1.1-2.1; 1.29; 2.08; 2.30; 2.1 + -2.6; 3.21, 3.68; + 1, 11; 5.23; 6.87.

B) A mixture of 5 g (0.0113 moles) of 9K-acetoxy-10 (hydroxy-16-methoxy-16-methyl-15-oxo-Prosta-13 (9 g) is prepared at a temperature of 5-10 ° C. E) -ene-1-acid methyl ester (prepared as described in A-14 69062 sa A) dissolved in 150 ml of anhydrous benzene, 2.6 ml (0.0285 moles) of 2,3-dihydropyran and 70 mg of p-toluenesulfone acid in 50 ml of anhydrous benzene, the mixture is then kept at room temperature for about 10 minutes. The reaction mixture is washed first with an aqueous solution saturated with sodium bicarbonate and then with water. Evaporation of the solvent gives a residue which is purified by silica gel column chromatography, eluting with petroleum ether / ethyl ether 7 * 3 (v / v). Yield 5 g of 9 ° {-acetoxy-16-methoxy-16-methyl-15-oxo-11β- (tetrahydro-1H-pyran-2-yl) oxy] -prosta-13 (E) -ene- 1-acid methyl ester in which the carbon atom at position 16 has the absolute configuration R or S. NMR absorption peaks in CDCl 3 (S): 0.885 l, 3.0-3? 1,255 2.06; 3,235 3,3-3ί 3,725 5,20; 6.8-7.1.

C) To a solution of 13.5 g of sodium borohydride in MDO per ml of methanol, cooled to -20 ° C, is added dropwise a solution of 5 g (0.0093 mol) of 9 ', - acetoxy-16-methoxy- 16-methyl-15-oxo-1H- [1- (tetrahydro-1H-pyran-2-yl) oxy] -prosta-13 (E) -ene-1-acid methyl ester (prepared as described in Section B). The resulting solution is kept at -20 ° C for about 2 hours, then poured into an aqueous solution saturated with NaH 2 PO 4, which is then extracted with ethyl ether. The organic extract is dried over Na 2 SO 4 and evaporated to dryness to give a residue 9 ° <acetoxy-15-hydroxy-16-methoxy-16-methyl-11H-tetrahydro-1H-pyran-2- a mixture of two possible isomers in the 15-position of the methyl ester of 1-yl) -oxy-13-(E) -ene-1-acid. Said isomers are first separated with Petro-ether: ethyl ether 8: 2 (v / v) to purify the crude mixture, and then eluted with petroleum ether: ethyl ether 6: 1 * (v / v).

The first eluted product (2.05 g of pure product, less polar isomer) has the following NMR spectrum: the main absorption peaks in CDCl 3 occur at the following frequencies, expressed in S units: o, 90; 1.13; 1.1 to 2.9; 2.07; 3,285 2.5 - * +, 3; 3.73; ^, 67; 5,205 5.7-5.9.

The second eluted product (2.1 g of pure product, more polar isomer) has the following NMR spectrum in CDCl 3 (ε * units): 0.93; 1.07; 1.1-2.9-, 2.07; 3.28; 3,2 - ^ 2; 3.72; »F, 675 5.20; 5.7 to 5.9.

The two products thus obtained have the same absolute configuration at the C-16 position (R or S) and the opposite configurations at the C-15 position. Thus, they represent a pair of isomers having the following absolute configurations at the C-15 and C-16 positions: (15-R, 16-R) and it 69062 15 (15-S, 16-R) or (15-R, 16-R) -S) and (15-S, 16-S).

Subsequent chemical modifications to give the final products of formula (I) do not alter the stereochemistry in the C-15 and C-16 weapons.

D) 2.1 g of 9β-acetoxy-15-hydroxy-16-methoxy-16-methyl-11β- [4- (tetrahydro-1H-pyran-2-yl) oxy] -prosta-13 (E) -ene-1 The more polar isomer of the methyl ester of -acid (prepared as described in section C) is dissolved in 150 any anhydrous benzene. After cooling, 1.3 ml (0.01-2 mol) of 2,3-dihydropyran are added and a solution of 75 mg of p-toluenesulphonic acid * in 0 ml of anhydrous benzene is added, after 15 minutes the solution is poured into aqueous sodium bicarbonate. The organic layer is separated, dried over Na 2 SO 4 and evaporated to dryness. The residue is purified by silica gel column chromatography, eluting with petroleum ether-ethyl ether = 7: 3 (v / v), to give 2.1 g of 9 ° -acetoxy-16-methoxy-16-methyl--11 ° (.15-bis- | (tetrahydro-1H-pyran-2-yl) oxy-1-prosta-13 (E) -ene-1-acid methyl ester having one of four possible absolute configuration combinations of C-15 and C-16 positions. spectrum (CDCl 3) s 0.92, 1.12, 1.15, 1.1-3.0, 2.07, 3.25, 3.32, 3.2-W, 2, 3.70; ^, 5-5.2, 5.3-5.6 (S units).

The compound thus obtained is dissolved in 200 ml of anhydrous methanol, and 2.1 g of anhydrous potassium carbonate is added to the resulting solution. After stirring at room temperature for 2b hours, the mixture is poured into an aqueous solution saturated with NaH 2 PO 4, which is then extracted with ethyl ether. The organic phase is separated, dried over Na 2 SO 4 and concentrated to dryness. 1.95 g of 9 ° (-hydroxy-16-methoxy-16-methyl-11β, 15-bis-tetrahydro-1H-pyran-2-yl) oxy-1-Prosta-13 (E) - ene-1-acid methyl ester (pure product). NMR spectrum in CDCl 3 (S): 0.92; 1.0 to 2.9; 1.10; 1.13; 3.25; 3.32; 3.2-V, **; M "5.0; 5.5 - 5.9.

E) A mixture of 6.38 g of celite, 7.25 g of Collins reagent (Py2.CrO3) and 1.95 g of 9 ° (-hydroxy-16-methoxy-16-methyl-1H-15-bis- Tetrahydro-1H-pyran-2-yl) oxy-4-prosta-13 (E) -ene-1-acid methyl ester in 180 ml of methylene chloride is stirred at room temperature for about 1 hour. The reaction mixture is poured into 1200 of any ethyl ether and filtered through celite. The filtrate is decolorized with activated carbon and concentrated to dryness. Yield: 1.77 g of 16-methoxy-16-methyl-9-oxo-10 (1,5-bis - [(terahydro-1H-pyran-2-yl) oxy] -prosta-13 (E) -ene 1-acid methyl ester NMR spectrum in CDCl 3 (S units): 16 69062 0.93, 1.0-2.9, 1.12, 1.15, 3.1, 3.25, 3, 32, 3.70, 5, M, 8.

F) The product thus obtained (1.77 δ) is suspended in 100 of any solution of acetic acid in anhydrous tetrahydrofuran in a ratio of 19 .mu.l (v / v / v), stirred at 50 DEG C. for two hours, after which the mixture is diluted with water and the pH is adjusted to 7. , 2 by adding sodium bicarbonate. The mixture is extracted with ethyl ether, which is then boiled off to give 1.19 g of crude product, which is purified by silica gel column chromatography, eluting with ethyl ether.

780 mg of pure 11 ° (1,15-dihydroxy-16-methoxy-16-methyl-9-oxo-Prosta-13 (E) -en-1-acid methyl ester are obtained in which the carbon atoms at positions 15 and 16 have one of the absolute values of the four a possible combination, i.e. (15-R, 16-R) or (15-R, 16-S) or (15-S, 16-R) or (15-S, 16-S) The compound has the following characteristics: [.alpha.] D @ 20 = -50 DEG C. = 0.96% (w / v) in CHCl3.

NMR in CDCl 3 (&): 0.92; 1.1-1.7; 1.11; 1.9 to 2.8; 2.29; 3.1 ^ 3.3; 3.2> +; 3.63; ^, 07; 12; 5.69.

The compound is a uniform product, determined by differential scanning calorimetry, and melts at * + 0-M} ° C.

G) Starting from 9-acetoxy-15-hydroxy-16-methoxy-16-methyl-11 - [(tetrahydro-1H-pyran-2-yl) oxy] -prosta-13 (E) -ene-1-acid methyl ester from the less polar isomer prepared as described in paragraph C) and working in exactly the same manner as described in paragraphs D), E) and F) gives 380 mg of 10 (15-dihydroxy-16-methoxy-16-raethyl-9-oxo- Prosta-13 (E) -ene-1-acid methyl ester having the same absolute configuration at position C-16 as the compound obtained in paragraph F), but the opposite, absolute configuration at position C-15. The compound has the following characteristics: = - 79.6 ° (C = 1 f OHOlj) NMS spectrum in CDCl 3 (S): 0.92) 1.1-1.7) 1.17) 1.9-2, 8) 2.29) 3.26) 3.69)> t, 10) S17) 5.75.

Example 2 11 C3 (, 15-Dihydroxy-16-methoxy-16-methyl-9-oxo-Prosta-13 (E) -ene-1-acid methyl ester (15-R, 16-S) and (15-S , 16-S) or (15-R, 16-R) and (15-S, 16-R) By working essentially as described in Example 1, but starting from the optical antipode of the phosphonate reagent used in Example 1, paragraph A), 0.3 ° (C = 1% in CHCl 3)

17 179062 Two other possible isomers of the 11β, 15-dihydroxy-16-methoxy-16-methyl-9-oxo-Prosta-13 (E) -ene-1-acid methyl ester of formula (I) are prepared. The two isomers have the same absolute configuration at position C-16, as opposed to the C-16 configuration of the two isomers of Example 1, and have opposite configurations at position C-15.

A) Condensing 5 g (0.0188 moles) of 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid dimethyl ester having = - * + 1.3 ° (C = 1% in CHCl 3), 2.5 g: with (0.0080 moles) 7- (5 ° (-acetoxy-2,3-formyl-3β-hydroxy-cyclopent-10-yl) -d-heptanoic acid methyl ester as described in Example 1, paragraph A) and working as described in paragraphs B) and C) of the same example, 9-acetoxy-15-hydroxy-16-methoxy-16-methyl-11β-tetrahydro-1H-pyran-2-yl) oxy-prosts-13 (E ) A mixture of the two C-15 isomers of the methylene ester of 1-ene-1-acid (2.65 g of crude product).

NMR spectrum in CDCl 3 (M: 0.91; 1.0-2.6; 1.06; 1.07; 1.13; 1.1 ^; 2.06; 2.29; 3.22; 3, 2 * +; 3,3-M; 3.68; M-, 5-6.6; 5.13; 5.5-5.7.

B) The mixture of the two C-15 isomers obtained above (2.65 g) is hydrolysed by treating 78 ml of a solution of acetic acid: water: tetrahydrofuran in a ratio of 19; 11; 3 (v / v / v). , At M-5 ° C for 90 minutes. The reaction mixture is neutralized with sodium bicarbonate and extracted with ether. Evaporation of the organic extract to dryness gives 2.55 g of crude product, which is 9 ° (-acetoxy-11 ° (1,5-dihydroxy-16-methoxy-16-methylethyl-Prosta-13 (E) -ene-1- a mixture of two C-15 isomers of the methyl ester of the acid The pure isomers are separated by silica gel column chromatography eluting with ethyl ether The first product eluted is the less polar isomer (860 mg) having the following characteristics: 1 ^ 20 = + 17.3 ° (C = 0 .95 1 CHCl 3) NMR spectrum in CDCl 3 (δ): 0.92, 1.05, 1.1-2.6, 2.07, 2.29, 3.23, 3.68, 3.93, M5 5.19, 5.63.

The second eluted product is the more polar isomer (yield 870 mg), has the following characteristics: W 2 O = + ^ 5.3 ° (C = ° '76 * in CHCl 3) NMR spectrum in CDCl 3 (<S): 0.91; 1.07 to 1.7; 1.13; 2.07; 2.2 to 3.0; 2.29; 3.25; 3.68; 3.89; »F, 15; 5.17? 5.53; 5.71.

C) A mixture of 870 mg (0.00191 moles) of the more polar isomer 18 69062, prepared as described in paragraph B) in 130 ml of anhydrous benzene, 30 mg of p-toluenesulfonic acid in 30 ml of anhydrous benzene and 2.5 ml (0.0273 mol) of 2,3-dihydropyran, is kept at 15 ° C for 15 minutes, then poured into an aqueous solution saturated with NaHCO 3 and the organic phase is separated. Wash with water, then dry the organic phase over Na 2 SO 4 and evaporate to dryness. The residue obtained is purified by chromatography on a column of silica gel and eluted with petroleum ether-ethyl ether 7: 3. Yield 1.09 g of 9 ° (-acetoxy-16-methoxy-16-methyl-10 (1,5-bis-γ (tetrahydro-1H-pyran-2-yl) oxy) -prosta-13 (E) -ene a methyl ester of 1-acid having the absolute configuration at position C-16, as opposed to the configuration of the product prepared in Example 1, paragraph E), and at position C-15 one of the two possible configurations.

NMR spectrum in CDCl 3 (δ): 0.92; 1.0-2.75 1.11? 1.1 ?; 2.05; 2.29; 3.22; 3.29; 3.3 - * +, 2; 3.68; > +, 6 - **, 9; 5.13; 5 + + - 5.8.

D) Working essentially as described in Example 1, paragraphs D) (last part), F) and G), but starting from the compound obtained in paragraph C) above, 250 mg of 11 ° <, 15-dihydroxy-16-raethoxy- 16-Methyl-9-oxo-Prosta-13 (E) -ene-1-acid methyl ester. This product has the following characteristics: = -51, * + ° (c = 0.52% in CHCl 3) NMR spectrum in CDCl 3 (&): 0.91; 1.1 to 3.2; l, l * f; 2.30; 3.25; 3.68; T + 07; **, l ° i 5.6-6.0.

E) Working as described in paragraphs C) and D) of this example, but starting from the less polar isomer (860 mg) obtained in paragraph B), 320 mg of 110β-dihydroxy-16-methoxy-16-methyl-9 -oxo-Prosta-13 (E) -ene-1-acid methyl ester. Said compound having the same absolute configuration at position C-16 as the corresponding isomer prepared in paragraph D) and the opposite configuration at position C-15 has the following characteristics: ΙτίΙβ0 = - 82.1 + ° (C = 0.95 # CHcy NMR- spectra: (CDCl 3) (S): 0.9 **; 1.1-1.8; 1.06; 2.0-2.9; 2.30; 3.2 **; 3.69; * *, 11; * +, 19; 5.6-5.9.

Claims (7)

1. I / -------- CH2 CH / CH2 \ / C "2 \ / C00R / CH2 CH2 ^ CH2 (II) / 'XHO or2 in which R represents the same as above and R 2 and R 2 , independently of one another, hydrogen or a protecting group of the hydroxy function, is reacted with a racemic phosphonate of formula (III) (R3 °) 'OCH3 yP-CH2-CO-C-CH2-CH2-CH2-CH3 (III) (R30r CH3 in which R3 is a (C1-6) alkyl group, or with one of the optical antibodies thereof, whereby a compound of formula (IV) is obtained. (IV, OR2 and O in which R, R 1 and R 2 are the same as above, b) the 15-oxo group is reduced to 15-hydroxy by treating the compound of formula (IV) with a mixed metal 1 hydride, which is sodium borohydride, zinc borohydride, diphenyltin hydride or lithium trialkyl borohydride, to give a compound of formula (V) OR1 V) or 'oh ch 3 in which R, R 1 and R 2 are the same as above; c) the hydroxy group in C-15 d) The hydroxy function in the C-9 position is released by removing the protecting group R 2, e) the hydroxy group in the C-9 position is oxidized to oxo, and the oxygen f) the hydroxy functions in C The -11 and the C-15 position are disturbed by a mild hydrolysis, for the said process it is further characteristic that when the mixture of isomers is obtained, it can optionally be separated into the individual isomers by conventional methods. 69062 24 A process for the preparation of pharmacologically active 16-methoxy-16-methyl-prostaglandin E1 derivatives of the general formula (I) 1.CH, X6 / 4 ^ CH / 'CH2 CH2 CH2 008 14 0CH3 18 2Q 13 ^ CH ^ Jjj _! '5c 17 / CH2 \ 19 ^ -CH> CH | | CH 2 / CH 2 / OH CH, Ht) 3 (I) in which R represents a (C 1-6 alkyl group or a non-toxic, pharmaceutically acceptable cation, characterized in that a) a cyclopentane aldehyde of formula (II) OR, Process according to claim 1, characterized in that an optically active 16-methoxy-16-methyl-prostaglandin-E1 derivative is prepared, wherein R represents a (C1-4) alkyl group or a non-toxic, pharmaceutically acceptable cation, and which compound chirality at the 16 position corresponds to the chirality at the C ^ position of the starting substance used according to formula (III), optically active 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid dimethyl ester whose stereoisomer = + 41.2 ° (c = 1% in CHCl 3), and which compound chirality at the C ^ g position corresponds to the chirality of the more polar stereoisomer of as intermediate of formula (V) obtained 9-acetoxy -15-Hydroxy-16-methoxy-16-methyl-10H-tetrahydro-1H-pyran-2-yl) oxyfrosta-13 (E) -ene-1-acid alkyl ester, which stereoisomer elutes as the other product , where the mixture of the stereoisomers is chromatographed on silica gel, as successive petroleum ether / ethyl ether, 8: 2 (voi./voi.) and petroleum ether / ethyl ether 6: 4 (voi./voi.). Process according to Claim 1, characterized in that 11 ° <1,5-dihydroxy-1,6-methoxy-16-methyl-9-oxo-prosta-13 (e) -en-1-acid acid is prepared. methyl ester, whose chirality in the Cställ position corresponds to the chirality in the C3 position of the starting substance used, according to formula (III) being 3-methoxy-3-methyl-2-oxo-heptylphosphonic acid dimethyl ester stereoisomer, the = + 41.2 ° (c = 1%, CHCl 3), and whose chirality in the C 2 position corresponds to the chirality of the more polar stereoisomer of as intermediate of formula (V) obtained 9-acetoxy-15-hydroxy -16-methoxy-16-methyl-11β- (tetrahydro-1H-pyran-2-yl) oxy-prosta-13 (E) -ene-1-acid methyl ester, which stereoisomer elutes as the second product in which the mixture of the stereoisomers is chromatographed on silica gel, with as the eluant successive petroleum ether / ethyl ether, 8: 2 (voi. / voi.) and petroleum ether / ethyl ether, 6: 4 (voi. 4. Process according to claim 1, characterized in that 15R, 16R-11 <*, 15-dihydroxy-16-methoxy-16-methyl-9-oxo-prosta-13 (E) -en-1-acid are prepared. methyl ester. The process according to claim 1, wherein R 2 is preferably a (C 2 -C 4) aliphatic acyl and R 2 is hydrogen or tetrahydro-1 H -pyran-2-yl radical. A process according to claim 1, wherein the reduction of the 15-oxo group to 15-hydroxy is carried out on the compound of formula (V),