CH637949A5 - Process for the preparation of novel sodium salts of prostaglandin derivatives - Google Patents

Abstract

Sodium salts of prostaglandin derivatives of the formula I <IMAGE> are prepared by hydrolysing a corresponding methyl ester with an equivalent amount of sodium hydroxide. The corresponding methyl esters are obtainable by reaction of an iodo compound of the formula V <IMAGE> with a dehydroiodinating reagent. In the sodium salts of the formula I and the iodo compounds of the formula V, the substituents have the meaning given in Patent Claim 1. The sodium salts of the formula I frequently have a longer activity and higher selectivity than previously known prostaglandin derivatives. On account of their good solubility, they are also particularly suitable for the formulation of pharmaceutical preparations which can be administered orally.

Description

The present invention relates to new sodium salts of prostaglandin derivatives which, because of their solubility, are particularly suitable for administration.

The prostaglandins and their analogs are organic compounds described in the literature, which are derivatives of prostanoic acid.

The prostanoic acid has the following formula, in which the numbering of the carbon atoms is also given:

C00H

is

L is a radical of the formula io (1) - (CH2) d-C (R2) 2-

(2) -CH2-0-CH2-Y- or

(3) -CH2CH = CH-, in which d is 0 or an integer from 1 to 5, the radicals R2 15 are identical or different from one another and are hydrogen atoms, methyl groups or fluorine atoms, provided that the one radical R2 must not have the meaning of a methyl group if the other radical R2 is a fluorine atom,

20 Y is a direct bond or a group of the formula - (CH2) k-, where k is 1 or 2,

Q one of the following groupings

The formulas appearing in the present description represent the special optically active isomer which has the same absolute configuration as PGEX from mammalian tissues. In the formulas, dashed lines to the cyclopentane ring or to the side chain denote substituents in the a configuration, that is to say below the plane of the ring or the side chain. Boldly marked bond lines denote substituents in the β configuration, that is to say above the plane.

For background information see e.g. Bergstrom et al., Pharmacol. Rev. 20.1 (1968) and Pace-Asciak et al., Biochem. 10.3657 (1971).

The aim of the present invention was to provide new sodium salts of prostaglandin derivatives which show the pharmacological effects typical of prostaglandins and are particularly suitable for administration because of their good solubility.

The present invention therefore relates to a process for the preparation of sodium salts of prostaglandin derivatives of the formula I.

L - COONa

O-OCH

25th

O,

A

H H

/ \

'\

Rg OH or R8 OH

is what

Rg represents a hydrogen atom or an alkyl radical with 1-4 carbon atoms,

30 R4 means one of the following groupings: (1) a group of the formula

Rs

35 -C -CgH2g-CH3

Rs in which the grouping CgH2g denotes an alkylene radical with 1-9 40 carbon atoms, which has 1-5 carbon atoms in the chain which is between the group of the formula -CR5R6- and the terminal methyl group, R5 and R6 are the same as or are different from one another and denote hydrogen atoms, alkyl radicals having 1-4 carbon atoms or 45 fluorine atoms, provided that one of the radicals R5 and Rg is only a fluorine atom if the other of these two radicals is a hydrogen atom or also a fluorine atom,

(2) a grouping of the formula

(I)

55

i

-C-Z

i

re

■ Q-

(T).

in which

D: a grouping of the formulas

\> ■ \ s \ /

oh in which the radicals T are identical to or different from one another and are alkyl radicals with 1-4 carbon atoms, 60 fluorine atoms, chlorine atoms, trifluoromethyl radicals or radicals of the formula -OR7, in which R7 is a hydrogen atom or an alkyl radical with 1-4 carbon atoms,

s = 0 or an integer in the range 1-3, provided that, however, no more than two of the radicals T have a meaning other than that of alkyl groups, Z is a direct bond, an oxa group of the formula -O or represents an alkylene radical of the formula CjH2j which has 1-9 carbon atoms, but with 1-6 carbon atoms

637 949

6

must be present in the chain between the grouping of the formula CR5R6 and the phenyl ring, and

R5 and R6 have the same meanings that were mentioned under (1), provided that, however, neither of the two radicals R5 and R6 may be a fluorine atom if Z is an oxygen atom; or

(3) the grouping of the formula

-ch2x .ch2ch3> c = c <(

H nH

V represents a direct bond or a radical of the formula -CH2-,

W is a radical of the formula -CH2- or -CH2-CH2-, and X has one of the following meanings

(1) trans-CH = CH-

(2) cis-CH = CH—

(3) -C = C- or

(4) -ch2ch2—,

having.

The process according to the invention for the preparation of the sodium salts of the formula I is characterized in that an appropriate methyl ester of the formula II

CH2-CH2-CH2-C00CH5 £ »CH

o \

r \

(IV)

H

! Q «= C 'OH H <- ^ C- (CH2) ^ - CH3

S0H

L - COÛCH-

, 0-C = CH

(Ii)

having.

The sodium salts of the formula I or the preferred sodium salts of the formula III are preferably prepared in the form of a free-flowing powder.

20 The saponification of the methyl ester of the formula II with the sodium hydroxide is preferably carried out in a solvent, for example in an alcoholic aqueous solution. After this saponification, the solvent and the water can then be removed from the sodium salt formed, preferably by subjecting the product to lyophilization.

The unsaturated methyl esters of the formula II required as starting material for carrying out the process according to the invention can be obtained by splitting off hydrogen iodide from the corresponding monoiodo-substituted saturated methyl esters.

Another object of the present invention is therefore a process for the preparation of the sodium salts of prostaglandin derivatives of the formula I, which is characterized in that an iodine compound of the formula V

^ 0-C-CH-L-COOCH ^

in which

Di L, Q, V, W, X, and R4 have the same meaning as in formula I, saponified with an equivalent amount of sodium hydroxide.

A preferred sodium salt of the formula I prepared by the process according to the invention has the following formula III

9 ^

CH2-CH2-CH2-C00Na CH •

(V)

55

(in)

X-C-R «

in which

Di L, Q, V, W, X, and R4 have the same meaning as in formula I with a dehydroiodination reagent and the methyl ester of formula II obtained

L COOCH,

c = c

H

OH H '

C- (CHa) ^ - CHa ys

H, S0H

, and this can be obtained by using as the methyl ester of formula II one which has the following formula IV

; 0-C = CH

(II)

X-C-R *

7

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in which

Dj, L, QfV, W, X, and R4 have the same meaning as in formula I, saponified with an equivalent amount of sodium hydroxide to give the sodium salts of formula I.

In this production process, a tertiary amine, preferably 1,5-diazabicylo (4,3,0) nonen-5-, 1,4-dia-zabicyclo (2,2,2) octane or l. Can be used as dehydroiodination reagent in the first 5 process step , 5-Diazabicyclo (5,4,0) -undecen-5, or sodium or potassium peroxide, sodium or potassium carbonate, sodium or potassium hydride, sodium or potassium 10 benzoate, sodium or potassium acetate, sodium or Use potassium trifluoroacetet, sodium or potassium bicarbonate, silver acetate or tetraalkylammonium peroxides of the formula (Rn ^ NC ^, in which R12 denotes an alkyl radical with 1-4 carbon atoms. 15

To produce the preferred sodium salts of the formula III given above, a compound of the following formula VI

20th

J

1

o J ^ CH-CH2-CH2-CH2-C00CH3

(VI)

/ c®c

OH. H 'N> (CHa) 4-CHa H OH

used and this with a dehydroiodination reagent to the methyl ester of formula IV

30th

CH2-CH2-CH2-C00CH3

0 ^ H

, c = c

OH H '^ C- (CHa) 4-CHa

/ \ _., H OH

4S

(a) PGFa connections when DL 1

means

(b) IIß-PGFa compounds when Di means

(c) 11-Deoxy-ll-keto-PGFa compounds when Dj \

means

(d) 11-Deoxy-ll-methylene PGFa compounds when Dj \

means

(e) 11-Deoxy-PGFa compounds when Dt \

\ /

means

(IV)

(f) 1 l-Deoxy-10, ll-didehydro-PGFa compounds when Di

\

means and

(g) 11-Deoxy-l 1-hydroxymethyl-PGFa compounds, 53 ifÜ!

means.

implemented and then saponified to form the sodium salt of formula III.

In this production process, the reaction with the dehydroiodination reagent is preferably carried out in an inert organic medium, for example in dimethylformamide m. For example, the reaction with the dehydroiodination reagent can be carried out at a temperature of 25-50 ° C. and when isolating the methyl ester of the formula V it is advantageous to maintain basic conditions.

6s The preparation of the preferred sodium salts of the formula III as the sodium salts of the formula I in the two-stage process according to the invention for the preparation of the preferred sodium salts of the formula I are prostaglandin derivatives, namely starting material required iodine compounds of the formula VI, they have the following structure

CHs0H

8th

are accordingly referred to as 9-deoxy-6,9-epoxy-A5-PGFla.

The sodium salts of the formula, or the preferred sodium salts 5 of the formula III, produced by the process according to the invention are extremely effective in causing various biological reactions. For this reason, these compounds are suitable for pharmacological VI purposes. Some of the biological reactions are: inhibition of platelet aggregation, stimulation of smooth muscles, systematic lowering of blood pressure, inhibition of gastric secretion and reduction of undesirable gastrointestinal effects by systemic administration of prostaglandin synthase inhibitors.

Because of their biological effects, the known ones; 15 prostaglandins useful for examination, prevention, are therefore a methyl ester of the PGFla, namely the connection, control or relief of numerous diseases and the physiological desirable as the methyl ester of 9-deoxy-6,9-epoxy-5-iodine-PGFla Conditions in mammals and can be drawn. This iodine compound of the formula VI falls under humans, agricultural animals, domestic animals and the general formula of the iodine compounds of the formula zoological species as well as laboratory animals such as e.g. Mäu-V, namely when> iodine compounds of the formula V 20 sen> rats, rabbits and monkeys.

D: the group of the formula These compounds are useful for inhibiting the

Platelet aggregation, to reduce the adhesive properties of the platelets and to eliminate or prevent thrombi in mammals including humans, rabbits and rats. For example, the compounds are useful for the treatment and prevention of myocardial infarction, for the treatment and prevention of post-operative thrombosis, for keeping implanted vessels open, and for the treatment of conditions such as atherosclerosis, arterioskle-30 rose, blood clotting through lipemia and other clinical conditions. where the underlying etiology is one, L- (CH2) 3-means, QH is OH, R5 is the n-pentyl residue lipid imbalance or hyperlipidemia, V is a single bond, W the rest - CH2- and other applications in vivo are Xtrans-CH = CH- in geriatric patients. the prevention of cerebral ischemic failures and the

In the used in the one-step process according to the invention as 35 long-term prophylaxis after myocardial infarction and stroke material and in the two-step method. For these purposes, the compounds are administered systemically according to methods according to the method formed as an intermediate, for example. intravenously, subcutaneously, intramuscularly or in thylesters of the formula n, the grouping of the formula form sterile implants for prolonged action. For quick

Effect, especially in emergency situations, intravenous -L-COOCH3 40 administration is preferred. Doses of approximately 0.01 are used

up to about 10 mg / kg body weight per day, the exact amount being present in trans configuration, based on the W-C bond, of the age, weight and condition of the patient or patient. In the esters of the formula II and also in the sodium salts res, which depends on the frequency and type of administration, the formula I is W in the C-8 position, V in the C-9 position and X in When these compounds are added, whole blood is obtained

C-12 position bound to the cyclopentane ring. 45 to applications in vitro, such as in the storage of

The methyl esters of formula II and also the sodium salts of whole blood for use in heart / lung machines. That of formula I are enol ethers and they are called PGF2a derivatives blood containing these compounds can also be named by organs, regardless of the modifications in one or e.g. Heart and kidney, which have been taken from a donor on the other side chain, by V and W in the heterocyclic ring and are ready for transplantation. They or the cyclopentane ring system Dj corresponding to those in FIG. 50 are also useful for the production of conventions known and customary in platelet rei-prostaglandin chemistry. Chen concentrates for use in thrombocytopenia, the preferred chemotherapy and radiation therapy according to the inventive method. In vitro applications use 0.001-1.0 [ig / ml whole blood.

These compounds are extremely effective stimulators of the 55 smooth muscles, and they are also highly active in strengthening other known stimulators of the smooth muscles, for example oxytocin agents such as oxytocin and the various mother comalkaloids, including their derivatives and analogs. They are therefore useful instead of or together (III) 60 men less than the usual amounts of these known

Stimulators, e.g. to relieve the symptoms of paralytic ileus or to fight or prevent atonic uterine bleeding after miscarriage or childbirth, to reject the placenta as well as during the puerperium. For the latter 65 purposes, the compound is administered by intravenous infusion immediately after miscarriage or childbirth at a dose of about 0.01 to about 50 µg / kg body weight per minute until the desired effect is achieved. Following

637 949

CH-CH- (CH2) 3-C00CH ^

9 \ 3

/H

/ ^

HO H C-C5H11

/ \

H OH

prepared sodium salts of formula III

CH2-CH2-CH2-COONa C = CH ■

9 \

c = c

OH Hy ^ C- (CH2) 4-CHs

/\H

637 949

Doses are injected or infused intravenously, subcutaneously or intramuscularly during the puerperium in an amount of 0.01 to 2 mg / kg body weight per day, the exact dose depending on the age, weight and condition of the patient.

These compounds are also useful as hypotensive agents for lowering blood pressure in mammals, including humans. For this purpose, administration is by intravenous infusion in an amount of about 0.01 to about 50 Hg / kg body weight per minute, or in one or more doses of about 25 to 500 (ig / kg body weight per day.

These prostaglandin derivatives are also useful in mammals including humans and certain farm animals, e.g. Dogs and pigs, to reduce and control excessive gastric juice secretion, thereby reducing or avoiding the formation of gastric / intestinal ulcers and accelerating the healing of such existing ulcers. For this purpose, the compounds are injected or infused intravenously, subcutaneously or intramuscularly, at an infusion dose of about 0.1 to about 20 μg / kg body weight per minute, or at a total dose per day by injection or infusion of about 0.01 to about 10 mg / kg body weight administered per day, the exact dose depending on the age, weight and condition of the patient or animal, the frequency and type of administration.

These compounds are also useful for reducing the undesirable gastrointestinal effects resulting from the systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are given for this purpose by co-administering the prostaglandin together with the anti-inflammatory prostaglandin synthetase inhibitor. U.S. Patent No. 3,781,429 discloses that the ulcerogenic effects of certain,

Non-steroidal anti-inflammatory agents in rats by simultaneous oral administration of certain prostaglandins of the E and A series including PGE ^ PGE2, PGE3,13,14-dihydro-PGE! and the corresponding 11-deoxy-PGE and PGA compounds are inhibited. For example, the prostaglandins are useful for reducing the undesirable gastric and intestinal effects resulting from the systemic administration of indomethacin, phenylbutazone and aspirin. These substances are mentioned in US Pat. No. 3,781,429 as non-steroidal anti-inflammatories. They are also known as prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, e.g. Indomethacin, aspirin or phenylbutazone is administered in a known manner to relieve an inflammatory condition, for example in any known dosage regimen for systemic administration.

The prostaglandin is administered together with the anti-inflammatory prostaglandin synthetase inhibitor either in the same or a different way. If, for example, the anti-inflammatory substance is administered orally, the prostaglandin can also be administered orally or rectally in the form of supositories or, in women, vaginally in the form of suppositories or a vaginal device for slow delivery (see, for example, US Pat. No. 3,545,439) . However, if the anti-inflammatory substance is administered rectally, the prostaglandin derivative is also administered rectally. However, the prostaglandin derivative can also be given orally or vaginally in women. If the route of administration for anti-inflammatory substance and prostaglandin is the same, it is advisable to combine both substances in a single dosage form.

The dosage regimen for prostaglandin in this treatment depends on various factors including the type, age, weight, gender and medical condition of the patient, the dosage regimen of the anti-inflammatory synthetase inhibitor and the patient's sensitivity to the synthetase inhibitor with regard to gastrointestinal effects. For example, Not every patient who needs an anti-inflammatory substance has the same unpleasant gastrointestinal effects. Rather, these often change in type and extent. It is therefore within the veterinarian's experience to determine whether the administration of the anti-inflammatory substance produces undesirable gaio strointestinal effects in humans or animals and to prescribe the effective amount of prostaglandin with which these effects can be substantially eliminated.

These compounds are also useful for the treatment of asthma. For example, they are useful as bronchial dilators or as inhibitors of mediators such as SRS-A and histamine released from cells activated by an antigen / antibody complex. The compounds therefore fight cramps and make breathing easier in diseases such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes the compounds are administered in various dosage forms, e.g. orally in the form of tablets, capsules or liquids, rectally in the form of suppositories, parenterally, subcutaneously or intramuscularly, intravenous administration in emergency situations being preferred, by inhalation in the form of aerosols or solutions for nebulizers or by sniffing in the form of powders . Doses of 0.01 to 5 mg / kg body weight are used one to four times a day, the exact amount depending on the age, weight and condition of the patient 30 and the frequency and mode of administration. For the above purposes, these prostaglandins are expediently combined with other antiasthmatics, for example sympathomimetics (isoproterenol, phenylephrine, ephedrine and the like), xanthine derivatives (theophylline and aminophylline) 35 and corticosteroids (ACTH and prednisolone).

Effective administration in humans is by oral inhalation or aerosol inhalation.

For administration by oral inhalation with conventional nebulizers or by means of oxygen aerosols, it is advisable to provide the active ingredient in dilute solution, preferably in concentrations of about 1 part of the active ingredient, to prepare about 100 to 200 parts by weight of solution. Common additives for stabilizing these solutions or for producing isotonic media can be used, e.g. Na-45 trium chloride, sodium citrate, citric acid, sodium bisulfite and the like.

For administration in a dosage unit for inhalation containing a propellant, the preparation in question can contain the active ingredient suspended in an inert propellant (e.g. mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) and a co-solvent such as ethanol, fragrances and stabilizers. Instead of a co-solvent, a dispersant such as e.g. Use oleyl alcohol. Suitable agents for inhalation therapy are e.g. in U.S. 55 PS 2,868,691.

These compounds are also suitable for swelling of the nose and are used for this purpose in an amount of about 10 Hg to about 10 mg / ml of a pharmacologically suitable liquid carrier or as an aerosol spray for topical use 60.

The compounds are also suitable for the treatment of peripheral vascular diseases in humans. Peripheral vascular diseases are understood to mean diseases of the blood vessels outside the heart and diseases of the lymphatic vessels, 65 e.g. Frostbite, ischemic cerebrovascular diseases, artheriovenous fistulas, ischemic leg ulcers, phlebitis, venous disorders, gangrene, the hepatorenal syndrome, ductus arteriosus, non-obstructive mesenteric ischemia, arteritis,

637 949 10

Lymphangitis and the like. The prostaglandin derivative is only used locally or systemically.

Examples of peripheral vascular diseases. With these diseases.

The compounds according to the invention are administered orally. The prostaglandin derivative is administered, for example, orally or vaginally.

parenterally by injection or infusion directly into a vein in doses of approximately 5 to 50 mg / treatment to an adult

or artery, with intravenous or intra-arterial woman, with 1 to 5 treatments within 24 hours,

le injection is preferred. The doses range from administered. The connection can also be intramuscular or

0.01-1.0 mg given subcutaneously by infusion per hour or by injection 1 in amounts of about 1 to 25 mg / treatment to 4 times a day, the exact amount being given by. The exact amount for these purposes depends on age,

Age, weight and condition of the patient and the frequency weight and condition of the patient or animal.

and route of administration depends. Treatment will be 1 to 10 days. The compounds are also useful in farm animals that are continued for 5 days, although 3 days are usually used to ensure abortion (especially if heifers have a long-term therapeutic effect, heifers), as a means of determining the heat and if systemic or side effects are observed, the regulation or synchronization of the oestrus. The amount of livestock reduced below the value at which these side effects include horses, cattle, sheep and pigs. The rules occur. 15 Heat synchronization or synchronization allows more effective. These compounds are therefore useful for treating conception and contractions and allow peripheral vascular diseases in the extremities in patient herd owners that all female animals in short prayer with circulatory disorders of the extremities, taking the correct periods of time give birth. This leads to a higher treatment for pain relief and beginning healing percentage of live births than with natural drainage of ulcers. 20 The prostaglandin is injected or administered in the feed in a detailed discussion of the course of the disease and the doses of 0.1 to 100 mg / animal and can be combined with other clinical observations in peripheral vascular diseases such as steroids. The dosage schemes and the previously known treatment methods deliver the gene from the respective animal species. For example, ZA-PS 74/0149, Derwent Farmdoc No. 58.400V. s. a. Elliott, Mares the prostaglandin derivative 5 to 8 days after Ovulation et al., Lancet, 1975, pp. 140-142. 25 and return to the heat. Cattle are regular

These compounds can be used in place of oxytocin intervals treated within a 3 week period so that, like all animals, the onset of labor in pregnant females becomes festering at the same time.

Cows, sheep and pigs, as well as in humans, in or These compounds also increase blood flow near the time of birth, or in pregnant animals in intestine kidney, causing urine volume and electrolyte content to cause fetal death about 20 weeks before Birth 30 may be increased. For this reason, the time of connection is suitable. For this purpose, the compound is used intravenously in genes for the treatment of kidney disfunction, in particular at an amount of 0.01 to 50 [xg / kg body weight per minute blocking the renal vascular layer. E.g. the connections are infused until or almost until the end of the second stage of labor, can be used to relieve and correct edema, i.e. the expulsion of the fetus. The connections, for example from large surface burnings, are particularly useful when one or more 35 are sulting and for the treatment of shocks. For these purposes, weeks after the birth of the natural contractions, the compounds are preferably initially not used intravenously yet, or 12 to 60 hours after being injected at a dose of 10 to 1000 jx / kg body weight, or tearing the membrane when the natural contractions not infused intravenously in an amount of 0.1 to 20 [xg / kg body weight. Oral administration is also possible. This perweight per minute until the desired effect is achieved. Compounds are also useful for controlling emp- 40 Later doses are given intravenously, intramuscularly or subcutaneously in the prison cycle in menstruating female mammals. Those injected or infused in an amount of 0.05 to 2 mg / kg of the menstruating female mammals become such body weights per day.

who already have the maturity required for menstruation. These prostaglandin derivatives are also useful for

have, but are not yet so old that regular treatment of proliferating skin diseases in humans and struation has ceased. For this purpose, the prostagland 45 pets such as psoriasis, atopic dermatitis, non-specific inderivat systemic in a dose of 0.01 to about 20 mg / kg dermatitis, primary irritant contact dermatitis, allergic

Body weight administered, expediently during the time contact dermatitis, cell carcinoma of the skin, lamellar ichthyosis,

space that begins around the time of ovulation and epidermolytic hyperkeratosis, pre-malignant, caused by the sun

ends at about the time of the menses or shortly before. Also induced keratosis, non-malignant keratosis, acne and seborrhea

intravaginal and intrauterine administration are possible. Dermatitis in humans and atopic dermatitis are also seen, and by similar administration the expulsion of mange in domestic animals becomes. These connections facilitate the sym

Embryo or fetus during the first or second third of ptome of proliferative skin diseases. For example, the normal gestation period or pregnancy is caused. the psoriasis improved when a psoriasis-free lesion

These compounds are also useful for producing sion which has noticeably lost thickness or is visible, but

a cervical dilation in bearing and non-bearing 55 is completely or completely cleaned.

female mammals for gynecological and obstetricians. For these purposes, the compounds are topically in a

purposes. In the case of a suitable pharmaceutical carrier containing the compounds caused by these compounds

Labor induction and clinical abortion are also used, e.g. cervical enlargement observed as ointment, lotion, paste, gel, spray. In cases of fruit or aerosol, where carriers such as petrolatum, lanolin, po-

Ability the cervical ethylene glycols or alcohols caused by these compounds is used. These connections

KAL enlargement to facilitate sperm movement to make gene as an active ingredient from about 0.1 to about 15 wt .-% and

Uterus. The cervical caused by prostaglandins preferably makes up about 0.5 to about 2% of the preparation. Except

Extension is also useful in surgical gynecology as topical administration can be injected, e.g. intra-

e.g. for D and C (cervical enlargement and uterine curettage), dermal, intra- or perilösional or subcutaneously, whereby one

where a mechanical extension uses a perforation of the uterus, 65 speaking sterile saline solutions.

Can cause cervical strains or infections. The compounds are also useful as inflammation - also advantageous in diagnostic procedures in which inhibitors to prevent chronic inflammation in mammals -

Tissue examination is required. In these cases including swelling and other uncomfortable

11

637 949

Effects, whereby the methods and amounts of treatment according to US Pat. No. 3,885,041 can be used.

The sodium salts of the formula I, or the preferred sodium salts of the formula III, prepared by the processes according to the invention cause numerous of the biological reactions known for the older prostaglandin compounds. For example, they are surprisingly more specific and have a much longer duration of biological action. They have the further advantage that they can be successfully administered orally, sublingually, intravaginally, buccally or rectally, in addition to the other methods. Each of these new analogs is therefore suitable instead of the known prostaglan din-Fa compounds for at least one of the pharmacological purposes known for these compounds and is surprisingly more useful because it has a different and narrower spectrum of biological action than the known prostaglandin. It is therefore more specific in its action and causes fewer and less undesirable side effects like the well-known prostaglandin. Furthermore, because of the prolonged action, fewer and smaller doses of the new compounds can often be used to achieve the desired result.

In the one-step process according to the invention, the methyl ester of the formula II is saponified to form the sodium salt of the formula I. In the two-stage process according to the invention, the methyl ester of the formula II is prepared in the first stage by the iodine compound of the formula V

H J

C00CH-

(v)

in which

Dj L, Q, V, W, X, and R4 have the same meaning as in formula I subject to hydrogen iodine elimination by reacting this iodine compound of formula V with a dehydroiodination reagent.

The iodine compound of the formula V required as a starting material can be prepared by using a compound of the following formula XIII

ho

1 \ w-ch = ch-l- C00CŒL

XIII

c-r4

in which

Db L, Q, V, W, X and R4 have the same meaning as in formula I, iodinated and cyclized to form the iodine compound of formula V.

The starting materials of the formula XIII required in this process are either already known compounds or they can easily be prepared by known working processes. Please refer to the following publications:

For PGF2 <x, see U.S. Patent 3,706,789, for 15-methyl and 15-ethyl-PGF2o, U.S. Patent 3,728,382, for 16,16-dimethyl-PGF2a, see U.S. Patent 3,903,131; for 16,16-difluoro-PGF2a compounds, U.S. Patents 3,962,293 and 3,969,380; for 16-phenoxy-17,18,19,20-tetranor-PGF2a see Derwent Farmdoc No. 73279U; for 17-phenyl-18,19,20-trinor-PGF2a see Derwent Farmdoc No. 31279T; Regarding ll-deoxy-PGF2a, see Derwent Farmdoc No. 10695V; for PGD2, see U.S. 15 PS 3,767,813; with regard to 2a, 2b-Dihomo-PGF2ct s. Derwent Farmdoc No. 61412S and U.S. Patents 3,852,316 and 3,974,195; for 3-oxa-PGF2a, U.S. Patent 3,923,861; with respect to 3-oxa-17-phenyl-18,19,20-trinor-PGF2a, U.S. Patent 931,289; for substituted phenacyl esters see. Derwent Farmdoc No. 2016828X; for substituted phenyl esters see. U.S. Patent 3,890,372; with regard to C-1 alcohols, that is 2-decarboxy-2-hydroxymethyl compounds s. U.S. Patent 3,636,120; for C-2 tetrazoyl derivatives see. U.S. PSS 3,883,513 and 3,932,389; regarding A2-PGF2a compare Derwent Farmdoc No. 25 46497W and DOS 2 460 285; with respect to 5,6-eis -PGF2a s. U.S. Patent 3,759,978; 2,2-Dimethyl-PGF2ct analogs see. Derwent Farmdoc No. 59.033T and DOS 2 209 039; for 9-deoxy-9-hydroxymethyl-PGF2a s. U.S. Patent 3,950,363; for 11 ß-PGF2a compounds see. U.S. Patent 3,890,371; regarding liso deoxy-PGF2a s. Derwent Farmdoc No. 10695V; regarding 11-deoxy-ll-hydroxymethyl-PGF2as. U.S. PSS 3,931,282 and 3,950,363; for 16-methylene PGF2a s. Derwent Farmdoc No. 19594W and DOS 2 440 919; for 17,18-didehydro-PGF2ct compounds see. U.S. Patent 3,920,726; for 3- (or 35 4-) oxa-17,18-didehydro-PGF2a compounds see. U.S. Patent 3,920,723; regarding 15-oxo-PGF2as. U.S. Patent 3,728,382; for 15-deoxy-PGF2a, see. Derwent Farmdoc No. 9239W; for 13,14-cis compounds see. U.S. Patent 3,932,479; regarding ll-deoxy-15-deoxy-PGF2os. Derwent Farmdoc No. 5694U; 40 for œ-homo-PGF2a connections see p. Derwent Farmdoc No. 4728W; and for 2,2-difluoro-PGF2a compounds see. Derwent Farmdoc No. 67438R.

The starting material of formula XIII is then subjected to a jodation and cyclization in order to obtain the starting product of formula V. Either an aqueous system containing iodine, potassium iodide and an alkali carbonate or bicarbonate, or an organic solvent system such as methylene chloride containing iodine in the presence of an alkali metal carbonate can be used to carry out the iodination and cyclization. The reaction can be carried out at temperatures below 25 ° C and preferably at about 0 to 5 ° C for 10 to 20 hours. Then the reaction is expediently stopped with sodium sulfite and sodium carbonate and the compound of the formula V is isolated from the reaction mixture.

With regard to the substituents which can occur in the starting materials of the formulas XIII, V and II and also with regard to the substituents which can be found in the sodium salts of the formula I, the following examples are given: 60 The radical R8 can include the meaning of a Have alkyl radicals with 1-4 carbon atoms and in groups of the formula r5 I

65 -C-CgH2g-CH3

R6

637 949

or the formula

12

Scheme i

-c-z i

re

<3

- (T).

The radicals R5 and Rg can also be alkyl radicals with 1-4 carbon atoms and also substituents T in the phenyl nucleus of the last-mentioned structure can have the meaning of alkyl radicals with 1-4 carbon atoms or alkoxy radicals with 1-4 carbon atoms. The following may be mentioned as examples of such alkyl radicals or the alkyl part of the alkoxy group:

Methyl residues, ethyl residues, propyl residues and butyl residues.

As already mentioned above, in the last-mentioned structure the phenyl radical has 0, 1, 2 or 3 substituents T, these being identical or different from one another and alkyl radicals having 1-4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl radicals or radicals of the formula -OR7, in which R7 is a hydrogen or an alkyl radical with 1-4 carbon atoms, but no more than 25 of 2 of the radicals T may have a different meaning than that of alkyl groups with 1-4 carbon atoms. Examples of such substituted phenyl radicals are the following:

an unsubstituted phenyl radical, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, p-tolyl, m-to-lyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and 2,4-dichloro-3-methylphenyl.

The methyl esters of the formula XIII, V or II can be prepared from the corresponding free acids by known methods. For example, the corresponding free acids can be converted into the corresponding methyl esters by reaction with diazomethane. The esterification with diazo methane is advantageously carried out by reacting a solution of the diazomethanes in a suitable inert solvent, preferably in diethyl ether, with the acid, which is expediently present in the same or another inert diluent. After the esterification has ended, the solvent can be evaporated off and the ester can be purified in a conventional manner, preferably by chromatography. The contact of the acid with the diazomethane should preferably not be longer than is necessary to effect the esterification, in particular about 1 to 10 minutes, in order to avoid undesired changes in the molecular structure.

Another method of esterifying the carboxyl group to form the corresponding methyl ester is to convert the free acid to the silver salt, followed by reaction of this salt with methyl iodide. The silver salts can be prepared by conventional methods, e.g. by dissolving the acid in cold dilute aqueous ammonia, evaporating excess ammonia under reduced pressure and then adding the stoichiometric amount of silver nitrate.

W-CB = CH-L-Rx

XIII

3 '

i

V-O-CH-CH-L-Ri l i W

v

V- (b)

V-0-C = CH-L-Ri

II

The reaction scheme below explains the preparation of the starting materials of the formula II required in the process according to the invention. In this reaction scheme, Rx means the grouping -COOCH3.

In the previous reaction scheme, the sybons Db L, Q, R4, V, W and X have the same meaning as in the sodium salts of formula I.

In step (a) of the preceding reaction scheme, the compounds of the formula XIII are subjected to iodination and cyclization, the iodine compounds of the formula V being obtained. Preferred working methods and materials for carrying out this iodination and cyclization have already been explained above.

In step (b) of the reaction scheme, the iodine compound of the formula V is then reacted with a dehy-

13

637 949

drojodierungs reagent transferred into the enol ether of formula II. Appropriate reagents are e.g. from Fieser and Fieser, "Reagents for Organic Synthesis", p. 1308, John Wiley and Sons, Inc., New York, N.Y. (1967). In stage (b), preference is given to tertiary amines and the following reagents: sodium or potassium peroxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium or potassium trifluoroacetate, sodium or potassium bicarbonate , Silver acetate and tetraalkylammonium peroxides of the formula (Ri2) 4N02, in which R12 denotes an alkyl radical having 1 to 4 carbon atoms.

Preferred tertiary amines are 1,5-diazabicyclo [4.3.0] nonen-5 - (“DBN”),

1,4-diazabicyclo [2.2.2] octane («DABCO»), and

1.5-diazabicyclo [5.4.0] undecen-5 ("DBU").

Other preferred reagents are sodium or potassium peroxide and tetramethylammonium peroxide. Further information on the peroxides can be found in Johnson and Nidy, J. Org. Chem. 40, 1680 (1975). For larger batches, electrochemical generation of the peroxide is recommended, see Dietz et al., J. Chem. Soc. (B), 1970, pp. 816-820.

The dehydroiodination step is expediently carried out in an inert organic medium such as dimethylformamide and followed by thin layer chromatography until the starting material disappears. The reaction takes place at 25 ° C and can be accelerated at 40 to 50 ° C.

When working up the reaction mixture, it is advisable to maintain basic conditions, e.g. with triethylamine to avoid acidic decomposition or structural change of the product. The purification can be carried out by crystallization and separation of the impurities and starting materials remaining in the mother liquor, or by column chromatography. For the chromatographic separation, a column filled with magnesium silicate (Florisil) is preferred over silica gel. The decomposition of the product is avoided if the column is pretreated with triethylamine.

In step (b), the starting material of the formula II is formed in the form of the corresponding trans compound, i.e. in this starting material of formula II is the group of formula -L-R1; in which Rx means the group -COOCH3, in the trans position to the bond W-C. Accordingly, after the saponification of these methyl esters of the formula II has been carried out, the sodium salts of the formula I are also present as transisomers.

If optically active methyl esters of the formula II are desired, then optically active starting materials or intermediates are used, or separation processes known in prostaglandin chemistry are carried out when using racemic starting materials or intermediates.

The products formed at each reaction stage are often mixtures which, as is known to the person skilled in the art, can be used as such in a subsequent stage or, if appropriate, can be separated in a conventional manner by fractionation, column chromatography, liquid / liquid extraction or the like before further processing.

The methyl esters of the formula II obtained in accordance with the preceding reaction scheme are then saponified using the process according to the invention to form the sodium salts of the formula I. As already mentioned, this saponification is carried out with an equivalent amount of sodium hydroxide, preferably in an aqueous alcoholic solution, and the mixture obtained is then expediently subjected to lyophilization, and the sodium salt of the formula I can thus be prepared in the form of a free-flowing powder.

With a view to an optimal combination of biological properties, specific activity, activity level and activity duration, certain sodium salts of the formula I are preferably prepared.

For example, those sodium salts of the formula I in which Q is the grouping of the formula are preferred

/ \

Rg OH,

10th

where R8 represents a hydrogen atom or an alkyl radical having 1-4 carbon atoms. A preferred meaning for the radical Rs is a hydrogen atom or the methyl radical. Sodium salts of the formula I are also preferred, in which a residue of the formulas or

25 is.

In the sodium salts of the formula I prepared by the process according to the invention, the radical R4 is furthermore preferably the n-pentyl, 1,1-dimethylpentyl or 1,1-difluoropentyl radical, or the radical of the formula

30th

35

• ch:

-S «

or

~ c:

40 Furthermore, in the sodium salts of the formula IL prepared by the process according to the invention, preferably one of the following radicals means - (CH2) 3-, - (CH2) 4- or - (CH2) 5-, the group - (CH2) 3- is particularly preferred.

45 A particularly preferred sodium salt of the formula I prepared by the process according to the invention thus has the following formula III, as already mentioned above

50 CH2-CH2-CH2-COONa

55

60

<X »

(in)

OH H'C C NMCHah-CHe

Y /, SOH

on.

6S The invention will now be explained in more detail by means of examples.

These examples describe the preparation of methyl esters of the formula II, which are carried out when the invented

637 949

Process according to the invention are required as starting materials and the saponification of these methyl esters of the formula II by the process according to the invention with formation of the desired sodium salts of the formula I is also explained.

In these examples, the infrared absorption spectra were recorded with a Perkin-Elmer Model 421 spectrophotometer. Unless otherwise specified, undiluted samples were used. The NMR spectra were recorded with a Varian A-60, A-60D or T-60 spectrophotometer in deutorochloroform solutions with tetramethylsilane as the internal standard. The mass spectra were recorded with a double-focusing high-resolution mass spectrometer Varian model MAT CH7 or CEC model 110B or a gas chromatograph / mass spectrometer LCB model 9000 (ionization voltage 22 or 70 ev).

“Skellysolve B” means a mixture of isomeric hexanes. "Florisil" is a magnesium silicate for chromatographic purposes, manufacturer Floridin Co; s. Fieser et al., "Reagents for Organic Synthesis" p. 393 John Wiley and Sons, Inc., New York, N.Y. (1967).

The term silica gel chromatography is understood to mean elution, collecting the fractions and combining those fractions which, according to the thin-layer chromatogram, contain the desired product free of starting material and impurities. “Concentration” is also understood to mean concentrating under reduced pressure, preferably less than 50 mm, and at a temperature below 35 ° C.

example 1

Preparation of ll-deoxy-10, ll-didehydro-PGF2a-methyl ester and its 9β-epimer; and ll-deoxy-10, ll-didehy-dro-PGF2a and its 9β-epimer. The preparation of a starting material of the formula XIII of the preceding reaction scheme is explained using this example:

A mixture of 1.74 g of PGA2 methyl ester and 12 ml of tetrahydrofuran is treated at -78 ° C. with 24 ml of a 10% diisobutylaluminum hydride solution in toluene. After stirring for one hour at -78 ° C, 100 ml of a 1: 1 mixture of tetrahydrofuran and saturated aqueous ammonium chloride solution are added and the mixture is heated to about 25 ° C. The mixture is acidified with sodium bisulfate and extracted with ethyl acetate. The organic phase is washed with sodium bisulfate solution, sodium carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated to give 1.8 g of product. This crude product is subjected to column chromatography, the title compounds being obtained in the following order: 11-deoxy-10.1 l-didehydro-9 β-

ll-deoxy-10, ll-didehydro-PGF2a methyl ester, PGF2a methyl ester,

ll-deoxy-10, ll-didehydro-PGF2a and 11-deoxy-10,11 -didehydro-9β-PGF2a.

Example 2

Preparation of the 9-deoxy-6,9-epoxy-5-iodine-PGFla-methyl ester.

The compound mentioned in the title corresponds to the iodine compound of the formula V which is used as the starting material in the two-stage process according to the invention and in this connection reference is also made to the compound of the corresponding formula V in the reaction scheme given above.

In this formula V, as already mentioned, Rx is a grouping of the formula -COOCH3 and the further substituents have the following meaning:

14

L = - (CH2) 3 - R4 = n-pentyl V = valence bond W = -CH2-5 X = trans-CH = CH, D1 =

10th

Q =

/ \)

H OH

The iodination and cyclization described in this example is stage (a) of the reaction scheme given earlier.

A suspension of 2.0 g of the corresponding PGF2a-Me-20 ethyl ester, which falls under the formula X3II of the preceding reaction scheme, is treated in the form of the 11,15-bis-tetrahydropyranyl ether in 23 ml of water with 0.7 g of sodium bicarbonate and cooled in an ice bath. 1.93 potassium iodide and 2.82 g iodine are added to the resulting solution and the mixture is stirred at about 0 ° C. for 16 hours. A solution of 1.66 g of sodium sulfite and 0.76 g of sodium carbonate in 10 ml of water is then added. After a few minutes the mixture is extracted with chloroform. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give mainly the bis-tetra-hydropyranyl ether of the title compound in the form of an oil (2.2 g). Hydrolysis of this ether in a mixture of acetic acid / water / tetrahydrofuran (20: 10: 3) mainly gives the title compound, which is further purified by silica gel chromatography 35; Rf 0.20 (thin layer chromatogram on silica gel in acetone / methylene chloride 30:70). The peaks in the mass spectrum for the compound v (trimethylsilyl derivative) are 638,623,607,567,548,511 and 477.

If the procedure of Example 2 is repeated, but with the replacement of the starting material of the formula XIII by the following compounds XIII or their C-1 1 ether, the corresponding iodine compounds I are obtained:

15-methyl-PGF2a 15-ethyl-PGF2o 4516.16-dimethyl-PGF2a 16.16-difluoro-PGF2a 16-phenoxy-17.18,19,20-tetranor-PGF2a 17 -phenyl-18,19,20-trinor -PGF2a 1 l-deoxy-PGF2c [

50 2a, 2b-dihomo-PGF2a 3-oxa-PGF2a

3-öxa-17-phenyl-17,19,20-trinor-PGF2a.

55 Example 3

Preparation of the 9-deoxy-6,9-A5-PGFla methyl ester. The compound mentioned in the title represents a methyl ester which can be used as a starting material in the one-step process according to the invention, or a methyl ester of the formula II prepared in the first step in the two-step process according to the invention.

The dehydroiodination process described here represents step (b) of the previous reaction scheme, wherein in the product of the formula II Rx is the grouping of the For-65 mei COöCH3. The further meaning of the symbols is the following:

L = - (CH2) 3—

R4 = n-pentyl

15

637 949

V = valence bond W = -CH2-X = trans-CH = CH,

Di =

q =

A)

H OH

A mixture of 0.25 g of the iodine compound of the formula V prepared by the process according to Example 2, 0.25 ml of 1,5-diazobicyclo [4.3.0] -nonen-5 and 15 ml of benzene at 72 ° C. for 72 hours let stand and then heated to 45 ° C for 4 hours. The resulting mixture is cooled and mixed with ice water and a little diethyl ether, the phases are separated. The organic phase is dried over magnesium sulfate and concentrated to give the title compound as an oil (0.20 g). Crystallization from cold (-10 ° C) hexane gives 0.14 g of product which softens at about 25 ° C;

R £ 0.51 (thin layer chromatogram on silica gel in ethyl acetate); NMR peaks at 5.5.4.57.3.8-4.3.3.62.3.53 and 0.9ô; IR absorptions at 1755 and 1720 cm \ peaks in the mass spectrum (trimethylsilyl derivative) at 495,479,439, 423,2724,349,199 and 173.

The procedure of the above example is repeated, but with the replacement of 1,5-diazabicyclo- [4.3.0] nonen-5 by 1,5-diazabicyclo [5.4.0] undecene-5, using 0.75 ml l, 5-diazabicyclo [5.4.0] undecene-5 per 0.5 g of the iodine compound, 0.44 g of product is obtained.

Example 4

Preparation of the 9-deoxy-6,9-epoxy-A5-PFGla-methyl ester.

The compound mentioned in the title is identical to the methyl ester prepared according to Example 3.

Another example of dehydroiodination of the corresponding starting material of the formula V is described on the basis of this example.

A mixture of 1.0 g of the iodine compound of the formula V, which was obtained by the process according to Example 2, and of 1.0 ml of 1.5 diazabicylo [4.3.0] nonen-5 and 60 ml of benzene is approximately 20 hours Heated to 42 ° C. Then 0.5 ml of l, 5-diazabicyclo [4.3.0] nonen-5 are added and the mixture is heated for a further 6 hours. The mixture is left at about 25 ° C for 60 hours and then reheated to 40 to 50 ° C. Then the reaction mixture is cooled, washed with ice water mixed with a few drops of triethylamine and dried over magnesium sulfate, whereby 0.9 g of the title compound is obtained in the form of an oil. The product is dissolved in 8 ml of diethyl ether and crystallized from cold (-10 ° C) hexane containing a trace of triethylamine to give 0.46 g of crystals which become mushy at 25 ° C. Further crystal fractions (0.33 g) are combined and chromatographically purified on a Florisil column pretreated with triethylamine using hexane / ethyl acetate / triethylamine (75: 25: 0.5), with ethyl acetate containing 0.25% of triethylamine (50-75%) - hexane is eluted. This gives 0.21 g of the title compound, which crystallizes on cooling.

Example 5

Preparation of the 9-deoxy-6,9-epoxy-A5-PGFla-methyl ester.

The methyl ester mentioned in the title is again identical to the methyl ester prepared according to Example 3.

This example is used to explain a further embodiment of step (b) described in the reaction scheme, that is to say the dehydroiodination of the corresponding starting material of the formula V to form the ester of the formula II.

A mixture of 0.213 g of the 9-deoxy-6,9-epoxy-5-iodine-PGFla-methyl methyl ester of the formula V prepared by the process according to Example 2 in 3 ml of dimethylformamide is mixed with a fresh solution of 0.45 g of potassium peroxide treated in 10 ml of Dime-io thylformamide, which contains 0.75 g of dicyclohexyl-18-crown-6, in an ice bath. After about 30 minutes, the reaction mixture is poured into ice water and extracted with diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to give the title compound which gives the same Rf in the thin layer chromatogram as the product of Example 3.

The above product is subjected to column chromatography on Florisil pretreated with triethylamine (5%) - methylene chloride. The product is eluted with ethyl acetate / hexane / tri-20 ethylamine (50: 50: 0.1) to give 0.076 g of the title compound of R £ 0.45 (thin layer chromatogram on silica gel in ethyl acetate / methylene chloride 3: 7 using plates pretreated with triethylamine (5%) - methylene chloride).

25 Repeating the procedure of Example 5, but substituting the potassium peroxide with sodium peroxide, tetramethylammonium peroxide, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, sodium trifluoroacetate, potassium 30-trifluoroacetate, potassium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, the title compound is also obtained in this way.

Example 6

35 Preparation of the 9-deoxy-6,9-epoxy-A5-PGFla sodium salt.

The saponification process according to the invention is explained in more detail using this example, specifically the saponification of the methyl ester of the formula II prepared by the process according to example 3 was carried out to form the desired end product of the formula I.

A mixture of 0.30 g of 9-deoxy-6,9-epoxy-A5-PGFla methyl ester and 5 ml of methanol is treated with 9 ml of 0.01N sodium hydroxide solution and stirred at about 25 ° C. for 72 hours . The solution is then diluted with 5 ml of water, frozen to about -75 ° C and lyophilized overnight. The title compound is obtained as a white free-flowing powder.

The above procedure is repeated with larger amounts. 0.150 g of the title compound is thus obtained as white free-flowing powder from 0.150 g of the enol ether methyl ester. A sample dissolved in methanol / water shows practically no mobility in the thin layer chromatogram on silica gel plates in acetone-methylene chloride (3: 7), compared with the starting material from Rf 0.45 (thin layer chromatogram on 55 silica gel in acetone / methylene chloride 3: 7 with triethylamine- (5%) - methylene chloride pretreated plates).

If the process according to Examples 2, 3 and 5 is repeated, but using other starting materials of the formula XIII, further methyl esters of the formula 60 V or methyl esters of the formula II are obtained. The corresponding 9-deoxy-6.9 is thus obtained -epoxy-5-iodine-PGFla, 9-deoxy-6,9-epoxy-A5-PGFla compounds, with the following characteristics:

16-methyl,

65 16,16-DimethyI-,

16-fluorine,

16,16-difluoro,

17-phenyl-18,19,20-trinor-,

637 949

16

17- (m-trifhiormethylphenyl) -18,19,20-trinor-, 17- (m-chlorophenyl) -18,19,20-trinor-, 17- (p-fluorophenyl) -18,19,20-trinor- ,

16-methyl-17-pheny 1-18,19,20-trinor-,

16,16-dimethyl-17, phenyl-18,19,20-trinor-, 16-fluoro-17-phenyl-18,19,20-trinor-, 16,16-difluoro-17-phenyl-18,19, 20-trinor-, 16-phenoxy-17,18,19,20-tetranor-, 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-, 16- (m-chlorophenoxy) -17,18 , 19,20-tetranor-, 16- (p-fluorophenoxy) -17,18,19,20-tetranor-, 16-phenoxy-18,19,20-trinor-, 16-methyl-16-phenoxy-18, 19.20-trinor-,

13,14-didehydro-, 16-methyl-13,14-didehydro-, 16,16-dimethyl-13,14-didehydro-,

16-fluoro-13,14-didehydro-,

16,16-difluoro-13,14-didehydro-,

17-phenyl-18,19,20-trinor-l 3,14-didehydro-, 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-didehydro-,

17- (m-chlorophenyl) -18,19,20-trinor-13,14-didehydro-, 17- (p-fluorophenyl) -l 8,19,20-trinor-13,14-didehydro-, 16-methyl -17-phenyl-18,19,20-trinor-13,14-didehydro-, 16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-, 16-fluoro-17 -phenyl-18,19,20-trinor-13,14-didehydro-, 16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-, 16-phenoxy-17,18 , 19,20-tetranor-13,14-didehydro-, 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-didehydro,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro, 16-phenoxy-18,19-20-trinor-13,14-didehydro-, 16-methyl-16-phenoxy -l 8,19,20-trinor-13,14-didehydro-, 13,14-dihydro-,

16-methyl-13,14-dihydro-,

16,16-dimethyl-13,14-dihydro-,

16-fluoro-13,14-dihydro-,

16,16-difluoro-13,14-dihydro-,

17-phenyl-18,19,20-trinor-13,14-dihydro-, 17- (m-trifhiormethylphenyl) -18,19,20-trinor-13,14-dihydro-, 17- (m-chlorophenyl) - 18,19,20-trinor-13,14-dihydro-, 17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro-, 16-methyl-17-phenyl-18,19, 20-trinor-13,14-dihydro-,

16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16, 16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 16-phenoxy-17,18,19,20-tetranor-l 3,14-dihydro-, 16- (m- Trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-di-hydro-,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

16-phenoxy-18,19,20-trinor-13,14-dihydro-,

16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-,

2,2-difluoro,

2,2-difluoro-16-methyl-,

2,2-di £ luor-16,16-dimethyl-,

2,2-difluoro-16-fluorine,

2,2-difluoro-16,16-difluoro-,

2,2-difluoro-17-phenyl-18,19,20-trinor-,

2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-,

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-,

2,2-difhior-17- (p-fluorophenyl) -18,19,20-trinor-,

2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-,

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-,

2,2-difluoro-l 6-fluoro-17-phenyl-18,19,20-trinor-,

2,2-difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-,

2,2-difluoro-l 6-phenoxy-17,18,19,20-tetranor-,

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,2ö-tetra-

nor-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-, 2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-, 2,2-difluoro-l 6-phenoxy-18,19,20-trinor-, 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-, s 2,2-difluoro- 16-methyl-16-phenoxy-18,19,20-trinor-, 2,2-difluoro-16-methyl-13,14-didehydro-, 2,2-difIuor-16,16-dimethyl-13,14- didehydro-, 2,2-difluoro-16-fluoro-13,14-didehydro-, 2,2-difluoro-16,16-difluoro-13,14-didehydro-, io 2,2-difluoro-17-phenyl- 18,19,20-trinor-13,14-didehydro-, 2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-didehydro-,

2,2-difIuor-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dide-hydro-,

15 2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-didehydro-,

2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-didehydro-,

2,2-difluoro-16,16-dimethyl-17-phenyL-18,19,20-trinor-13,14-20 didehydro-,

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-, 2,2,16,16-tetrafluoro-17-phenyl-.18,19,20-trinor- 13,14-didehydro-,

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-didehy-25 dro-,

2,2-difluoro-16- (m-trifluonomethylphenoxy) -17,18,19,20-tetranor-13,14-didehydro-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14 didehydro-,

30 2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-didehydro-, 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13, 14-didehydro-,

2,2-difluoro-13,14-dihydro-, 2,2-difluoro-16-methyl-13,14-dihydro-, 35 2,2-difluoro-16,16-dimethyl-13,14-dihydro-, 2,2,16-trifluoro-13,14-dihydro-, 2,2,16,16-tetrafluoro-13,14-dihydro-, 2,2-difluoro-17-phenyl-18,19,20-trinor- 13,14-dihydro-, 2,2-difluor-17- (m-trifIuormethylphenyl) -18,19,20-trinor-40 13,14-dihydro-, 2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-,

2,2-difiuor-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihy-dro-,

45 2,2-difluoro-16-methyl-17-phenyl-l 8,19,20-trinor-l 3,14-dihydro-,

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-,

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 50 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor- 13,14-dihy-dro-,

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-, 2,2-difluoro-16- (m-trifluorinethylphenoxy) -17,18,19,20-tetra -nor-13,14-dihydro-, 55 2,2-difluoro-16- (itt-chlorophenoxy) -17,18,19,20-tetranor-13,14 dihydro-,

2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

2,2-difluoro-16-phenoxy-18,19,20-trinor-13,14-dihydro-, 60 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13, 14-dihydro,

16-methyl-cis-13,

16,16-dimethyl-cis-13-,

16-fluoro-cis-13-,

6516,16-difluoro-cis-13-,

17-phenyl-18,19,20-trinor-cis-13-, 17- (m-trifhiormethylphenyl) -18,19,20-trinor-cis-13-, 17- (m-chlorophenyl) -18.19, 20-trinor-cis-13-,

17th

637 949

17- (p-fuorphenyl) -18,19,20-trinor-cis-13-,

16-methyl-17-phenyl-lg, 19,20-trinor-cis-13-,

16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-,

16-fluoro-17-phenyl-18,19,20-trinor-cis-13-,

16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-,

16-phenoxy-17,18,19,20-tetranor-cis-13-,

16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-cis-13-,

16- (m-chlorophenoxy) -17,18,19,20-tetranor-cis-13-,

16- (p-fluorophenoxy) -17,18,19,20-tetranor-cis-13 -,

16-phenoxy-18,19,20-trinor-cis-13-,

16-methyl-16-phenoxy-18,19,20-trinor-cis-13-,

2,2-difluoro-cis-13-,

2,2-difluoro-16-methyl-cis-13-,

2,2, -difluoro-16,16-dimethyl-cis-13-,

2,2-difluoro-16-fluorocis-13-,

2,2-difluoro-16,16-difIuor-cis-13-,

2,2-difluoro-17-phenyl-18,19,20-trinor-cis-l 3-,

2,2-difluoro-17- (m-trifluoromethylphenyl) -18,19,20-trinor-cis-

13-,

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-cis-13-,

2,2, -difluoro-17- (p-fluorophenyl) -18,19,20-trinor-cis-13,

2,2, -difluoro-16-methyl-17-phenyl-18,19,20-trinor ~ cis-13-,

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-,

2,2-difluoro-16-fior-17-phenyl-18,19,20-trinor-cis-13-,

2,2-difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-,

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-cis-13-,

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetra-

nor-cis-13-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-cis-13-,

2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-cis-13-,

2,2-difluoro-16-phenoxy-18,19,20-trinor-cis-13-,

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-,

2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-,

3-oxa-,

3-oxa-16-methyl-,

3-oxa-16,16-dimethyl-,

3-oxa-16-fluorine,

3-oxa-16,16-difluoro-,

3-oxa-17-phenyl-18,19,20-trinor-, 3-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-, 3-oxa-17- (m-chlorophenyl) - 18,19,20-trinor-, 3-oxa-17- (p-fluorophenyl) -18,19,20-trinor-, 3-oxa-16-methyl-17-phenyI-18,19,20-trinor- , 3-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-, 3-oxa-16-fluoro-17-phenyl-18,19,20-trinor-, 3-oxa-16 , 16-diiîuor-17-phenyl-18,19,20-trinor-, 3-oxa-16-phenoxy-17,18,19,20-tetranor-, 3-oxa-16- (m-trifluoromethylphenoxy) -17 , 18,19,20-tetranor-, 3-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-, 3-oxa-16- (p-fluorophenoxy) -17,18,19 , 20-tetranor-, 3-oxa-16-phenoxy-18,19,20-trinor-, 3-oxa-16-methyl-16-phenoxy-18,19,20-trinor-, 3-oxa-13, 14-didehydro-,

3-oxa-16-methyl-13,14-didehydro-, 3-oxa-16,16-dimethyl-13,14-didehydro-, 3-oxa-16-fluoro-13,14-didehydro-,

3-oxa-l 6,16-difluoro-13,14-didehydro-, 3-oxa-17-phenyl-18,19,20-trinor-13,14-didehydro-, 3-oxa-17- (m- trifluoromethylphenyl) -18,19,20-trinor-13,14-didehydro-,

3-oxa-17- (m-chlorophenyl) -18,19,20-trinor-13,14-didehydro-, 3-oxa-17- (p-fluorophenyl) -18,19,20-trinor-13,14 -didehydro-, 3-oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-didehy-dro-,

3-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-didehydro-,

3-oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-,

3-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-didehydro-,

3-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-, 3-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14 -didehydro-,

3-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro-,

3-oxa-16-phenoxy-18,19,20-trinor-13,14-didehydro-, 3-oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-didehydro-,

3 -oxa-13,14-dihydro-,

3-oxa-16-methyl-13,14-dihydro-,

3-oxa-16,16-dimethyl-13,14-dihydro-,

3-oxa-16-fluoro-13,14-dihydro-,

3 -oxa-16,16-difluoro-13,14-dihydro-,

3-oxa- 17-phenyl-18,19,20-trinor-13,14-dihydro-,

3-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-di-

hydro,

3-oxa-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-, 3-oxa-17- (p-fluorophenyl) -18,19,20-trinor-13,14 -dihydro-, 3-oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-, 3-oxa-16,16-dimethyl-17-phenyl-18,19,20 -trinor-13,14-dihydro-,

3-oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-,

3-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihy-

dro-,

3-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-, 3-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14 -dihydro-,

3-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

3-oxa-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihy-dro-,

3-oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-,

3-oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-,

3-oxa-cis-13-,

3-oxa-16-methyl-cis-13 -,

3-oxa-16,16-dimethyl-cis-13-,

3-oxa-16-fluorocis-13-,

3-oxa-16,16-difluoro-cis-13-,

3-oxa-17-phenyl-18,19,20-trinor-cis-13-,

3-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-cis-13-,

3-oxa-17- (m-chlorophenyl) -18,19,20-trinor-cis-13-,

3-oxa-17- (p-fluorophenyl) -18,19,20-trinor-cis-13-,

3-oxa-16-methyl-17-phenyl-18,19,20-trinor-cis-13-,

3-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-cis-13-,

3-oxa-16-fluoro-17-phenyl-18,19,20-trinor-cis-13-,

3-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-cis-13-,

3-oxa-16-phenoxy-17,18,19,20-tetranor-cis-13-,

3-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-

cis-13-,

3-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-cis-13-,

3-oxa- (p-fluorophenoxy) -17,18,19,20-tetranor-cis-13-,

3-oxa-16-phenoxy-18,19,20-trinor-cis-13-,

3-oxa-16-methyl-16-phenoxy-18,19,20-trinor-cis-13-,

3-oxa-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16-methyl-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16,16-dimethyl-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16-fluoro-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16,16-difluoro-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-

didehydro,

3-oxa-17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-di-hydro-trans-14,15 -didehydro-,

3-oxa-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro-trans-14,15 -didehydro-,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

637 949

18th

Called 9-deoxy-6,9-epoxy-A5-PGFlo compounds. 2,3-didehydro-

2,2-dimethyl,

2a, 2b-dihomo,

5 4-oxa-4a-homo-,

7a homo,

1 l-deoxy-10,11-didehydro-,

llß-,

11-keto,

io 11-deoxy,

11-deoxy-l 1-methylene,

11-deoxy-l 1-hydroxymethyl,

15ß-,

15-keto,

15 15-deoxy,

15-methyl-15 (S) -,

15-methyl-15 (R) - and 17,18-didehydro-,

3-oxa-16-methyl-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihy-dro-trans-14,15 -didehydro-,

3-oxa-16-fluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16,16-difluoro-17-phenyl-18,19,20-trinor-13,14-dihy-dro-trans-14,15-didehydro-,

3-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-

13.14-dihydro-trans-14.15-dihydro-,

3-oxa-16- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-dihy-dro-trans-14,15-didehydro-,

3-oxa-16- (p-fluorophenoxy) -17,18,19,20-tetranor-13,14-dihy-dro-trans-14,15-didehydro-,

3-oxa-16-phenoxy-18,19,20-trinor-13,14-dihydro-trans-

14.15-didehydro-,

3-oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dihydro-trans-14,15 -didehydro-,

The following 9-deoxy-6,9-epoxy-5-iodine-PGFlct compounds and are examples of further methyl esters of the formula V or of the formula II

20 The saponification of the corresponding methyl esters of the formula II by the process of Example 6 then gives the corresponding sodium salts of the formula I.

C.

Claims (10)

637 949 (1) trans-CH = CH— (1) a group of the formula 40 45 Rs I. -C-CgH2g-CH3 re L - COONa i • O-OCH (i) in which the grouping CgH2g denotes an alkylene radical with 1-9 carbon atoms, which has 1-5 carbon atoms in the chain, which is located between the group of the formula -CR5R6- and the terminal methyl group, R5 and thus R6 are the same or different from one another are different and represent hydrogen atoms, alkyl radicals with 1-4 carbon atoms or fluorine atoms, provided that one of the radicals R5 and R6 is only a fluorine atom if the other of these two radicals is a hydrogen atom or also a 55 fluorine atom, (1) - (CH2) d-C (R2) 2- (1) a group of formula R5 I. -C-CgH2g-CH3 R6 in which the grouping CgH2g denotes an alkylene radical with 1-9 carbon atoms, the 1-5 carbon atoms in the (ii) in which Di L, Q, V, W, X, and R4 have the same meaning (1) - (CH2) d-C (R2) 2- (2) cis-CH = CH- (2) a grouping of the formula 60 Rf -c-z (T). in which the radicals T are identical to or different from one another and alkyl radicals with 1-4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl radicals or radicals of 637 949 (2) -CH2-0-CH2-Y- or 20 (3) -CH2CH = CH- means in which d is 0 or an integer from 1 to 5, the radicals R2 are identical or different from one another and are hydrogen atoms, methyl groups or fluorine atoms, provided that the one radical R2 then does not have the meaning of a methyl group if the other radical R2 is a fluorine atom, Y is a direct bond or a group of the formula - (CH2) k -, where k is 1 or 2, 30 Q one of the following groupings H A / \ / \ O, H H Rg OH or R8 OH 35 is what R8 represents a hydrogen atom or an alkyl radical with 1-4 carbon atoms, R4 means one of the following groupings: 2. The method according to claim 1, characterized in that a sodium salt of the following formula III CH2-CH2-CH2-COONa ? \ = CH <X H (in) i C = C 'OH C- (CHß) 4-CHS H . SQH prepared by using a methyl ester of formula IV ÇH -CH -CH -C00CH, £ = CH (2) cis-CH = CH- (2) a grouping of the formula io . f-CT "' Re in which the radicals T are identical to or different from one another and denote alkyl radicals with 1-4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl radicals or radicals of the formula -OR7, in which R7 is a hydrogen atom or an alkyl radical with 1-4 carbon atoms, s = 0 or an integer in the range 1-3, provided, however, that no more than two of the radicals T have a meaning other than that of alkyl groups, 25 Z is a direct bond, an oxa group of the formula —O- or an alkylene radical of the formula CjH2j which has 1-9 carbon atoms, but where 1-6 carbon atoms must be present in the chain between the grouping of the formula CR5R6 and the phenyl ring, and Rs and R6 have the same meanings as mentioned under (1), provided that, however, neither of the two radicals R5 and R6 may be a fluorine atom if Z is an oxygen atom; or (2) -CH2-0-CH2-Y- or 2nd PATENT CLAIMS 1. Process for the production of sodium salts of prosaglandin derivatives of the formula I. L - co on a 0-C = CH (I) in which Dj a grouping of the formulas / or is, L is a residue of the formula (3) -C = C- or (3) the grouping of the formula -CH2v yCH2CH3 > = C \ H H V represents a direct bond or a radical of the formula -CH2-, W is a radical of the formula -CH2- or -CH2-CH2-, and X has one of the following meanings 3. The method according to claim 1 or 2, characterized in that the sodium salt is produced in the form of a free-flowing powder. 3rd 637 949 as in Formula I, saponified with an equivalent amount of sodium hydroxide. (3) —C = C— or (3) the grouping of the formula -CH2X, CH2CH3 / C = C \ H H 40 V represents a direct bond or a radical of the formula -CH2-, W is a radical of the formula -CH2- or -CH2-CH2-, and X has one of the following meanings 45 (1) trans-CH = CH— (3) -CH2CH = CH-, in which d is 0 or an integer from 1 to 5, the radicals R2 are identical to or different from one another and denote hydrogen atoms, methyl groups or fluorine atoms, provided that the one radical R2 then must not have the meaning of a methyl group if the other radical R2 is a fluorine atom, Y is a direct bond or a group of the formula - (CH2) k—, where k is 1 or 2, Q one of the following groupings Chain which is located between the group of the formula -CR5R6- and the terminal methyl group, R5 and R6 are the same or different from one another and represent hydrogen atoms, alkyl radicals having 1-4 carbon atoms or 5 fluorine atoms, provided that one of the Radicals R5 and is only a fluorine atom if the other of these two radicals represents a hydrogen atom or also a fluorine atom, (4) -CH2CH2-, has, characterized in that an iodine compound of formula V net that in the first stage of the process as a dehydroiodination reagent, a tertiary amine, preferably 1,5-diazabicyclo (4,3,0) nonen-5-, 1,4-diazabicyclo (2,2,2) octane or 1 , 5-Diazabicyclo (5i4,0) -undecen-5, or sodium or potassium 5 peroxide, sodium or potassium carbonate, sodium or potassium hydroxide, sodium or potassium benzoate, sodium or potassium acetate, sodium or potassium trifluoroacetet, sodium or potassium bicarbonate , Silver acetate or tetraalkylammonium peroxides of the formula (Ri2) 4N02, in which R12 is an alkyl radical io with 1-4 carbon atoms. 4th Formula -OR7, in which R7 is a hydrogen atom or an alkyl radical having 1-4 carbon atoms, s = 0 or an integer in the range 1-3, provided that, however, no more than two of the radicals T have a meaning other than that of alkyl groups, Z represents a direct bond, an oxa group of the formula -O- or an alkylene radical of the formula CjH2j, which has 1-9 carbon atoms, but 1-6 carbon atoms must be present in the chain between the grouping of the formula CR5R6 and the phenyl ring, and Rs and R6 have the same meanings that were mentioned under (1), provided that, however, neither of the two radicals Rs and R6 may be a fluorine atom if Z is an oxygen atom; or 4. The method according to any one of claims 1-3, characterized in that one carries out the saponification of the methyl ester with the sodium hydroxide in a solvent, preferably an alcoholic-aqueous solution. (4) -CH2CH2-, has, characterized in that a corresponding-5o the methyl ester of formula II O, / \ / \ / \ H H Rg OH or Rg OH L - CQ0CH- is what Rg represents a hydrogen atom or an alkyl radical with 1-4 carbon atoms, R4 means one of the following groupings: 5 637 949 dierungsreagens in an inert organic medium, preferably in dimethylformamide. 5. The method according to any one of claims 1-4, characterized in that after the saponification, solvent and water are removed from the sodium salt formed, preferably by subjecting the material to lyophilization. 6. Process for the preparation of sodium salts of prostaglandin derivatives of the formula I. L is a residue of the formula 7. The method according to claim 6, characterized in that the reaction with the dehydrojo 8. The method according to claim 6 or 7, characterized in that a sodium salt of the following formula III CH „-CH -CH -COONa 15 | 2 2 2 = CH (III) H c — c * "ÜH H /" "^ - (CHa ^ -CHa h" OH prepared by using a compound of the following formula VI as the iodine compound of the formula V .0-C-CH- L-COOCH- d i 35 ^ -CH-CH2-CH2-Ch2-C00CH5 (V) 40 H (VI) in which D t L, Q, V, W, X, and R4 have the same meaning as in formula I, reacted with a dehydroiodination reagent and the methyl ester of formula II obtained L - COOCH-r , 0 -C = CH 45 0 * OH. H '^ C-lCHa) 4-CHa \ / S0H used and this with a dehydroiodination reagent to the methyl ester of formula IV ch2-ch2-ch2-cooch3 9 a (IV) /H c-c OH H '^ C-CCHaJ ^ CHs H ^ N0H in softer Dx L, Q, V, W, X, and R4 have the same meaning 65 and then convert them to form the sodium salt as in formula I, saponified with an equivalent amount of sodium hydrogen of the formula III. saponified hydroxide to the sodium salts of formula I. 9. The method according to any one of claims 6-8, dadjirch 9 \ (IV) H X-C-R, in which a grouping of formulas CH; or is ch2oh, C = C ' Hy VxC- (CHa) ^ - CHa N0H. saponified. 10. The method according to any one of claims 6-9, characterized in that one carries out the reaction with the dehydroiodination reagent at a temperature of 25-50 ° C and basic conditions are maintained in the isolation of the methyl ester of the formula V. / or chsoh