CH632245A5 - Process for preparing novel prostaglandin derivatives possessing a 9-deoxy-6,9-epoxy functionality - Google Patents

Description

The aim of the present invention was to develop processes for the preparation of new prostaglandin derivatives which either have a pharmacological effect themselves or which can be used as intermediates in the production of other corresponding materials.

The present invention relates to a process for the preparation of iodine compounds of the formula I.

10th

15

20th

I.

V-O-C-CH-L-Ri '/

(I)

2s in which D is a radical of the formula

The present invention relates to a process for the preparation of new prostaglandin derivatives with 9-deoxy-6,9-epoxy function.

According to the process according to the invention, the corresponding new iodine compounds are first prepared by iodination and cyclization of corresponding starting materials which have a hydroxyl group and a double bond. These can then be converted into corresponding enol ethers by reaction with a dehydroiodination reagent, or converted into a mixture of a corresponding keto compound with the hemiketal by dehalogenation and hydrolysis.

The prostaglandins and their analogs are known organic compounds which are derivatives of prostanoic acid.

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

CH;

or

CH2OR ia is what

R13 is a hydrogen atom, the tetrahydropyranyl radical, the tetrahydrofuranyl radical, the 1-ethoxyethyl ester, or one

COOH

50 grouping of the formula

H

55

The formulas appearing in the present description represent the special optically active isomer which has the same absolute configuration as PGEi 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 level 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).

R14 -0 -C •

I.

R

15

• C -R ir

I.

R ie is in which

60 Ru is an alkyl radical with 1-18 carbon atoms, a cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 carbon atoms, the phenyl radical or a phenyl radical which is substituted with 1,2 or 3 alkyl radicals with 1-3 carbon atoms, represents

65 R15 and R16 are identical to or different from one another and denote hydrogen atoms, alkyl radicals with 1-4 carbon atoms, phenyl radicals or phenyl radicals substituted with 1,2 or 3 alkyl radicals with 1-4 carbon atoms, or

9

632245

Ris and Ri6 together form a grouping of the formula - (CKh) a- or - (CH2) b-0- (CH2) c-, in which a = 3, 4 or 5, B = 1,2 or 3, and c = 1, 2 or 3, provided that b + c = 2, 3 or 4 and R 7 represents a hydrogen atom or the phenyl radical, L represents a radical of the formula

NH

Zt or

(1) - (CH2) d-C (R2) 2-

(2) -CH2-O-CH2-Y- or

(3) -CH2CH = CH-

means in which d is 0 or an integer from 1 to 5,

the residues R2

are identical to or different from one another and denote hydrogen atoms, methyl groups or fluorine atoms, provided that the one radical R2 may 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 = 1 or 2,

Q one of the following groupings

II / \

O, H H,

Rg ÔH

or

Rs OH

10th

15

is, or a group of formula

0

II

-CH-C-R10

20 I

R

11

is what

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

Ri represents one of the following:

(1) a grouping of the formula -COOR3,

in which

R3 is a hydrogen atom, a pharmacologically acceptable cation, an alkyl radical with 1-12 carbon atoms, a cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 carbon atoms, the phenyl radical, a phenyl radical with 1,2 or 3 chlorine atoms or alkyl groups with 1 -4 carbon atoms is substituted, a grouping of the following formulas:

0

means what

Rio is a phenyl, p-bromophenyl, p-biphenyl, p-nitro-25 phenyl, p-benzamidophenyl or a 2-naphthyl radical, and

Rn is a hydrogen atom or a benzoyl radical,

(2) the group of the formula -CH2OH;

30th

NH-C-CH3,

(3) a group of the formula -CH2N (Rs) 2,

where the residues

Ro are identical to or different from one another and denote hydrogen atoms or alkyl radicals having 1-4 carbon-35 atoms; or

(4) the group of the formula

/ NH-N

- <II

N-N

R4 means one of the following groupings: 45 (1) a group of the formula

r £

50

55

"CgH2g ~ CH3

re

»

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 60 -CR5R6- and the terminal methyl group, R5 and Rs are identical or different from one another and hydrogen atoms, alkyl radicals with 1-4 carbon atoms or fluorine atoms, provided that one of the radicals Rs and Rs is only a fluorine atom, 65 if the other of these two radicals is a hydrogen atom or also a fluorine atom,

(2) a grouping of the formula

632245

r'-QT

(T).

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

s = 0 or an integer in the range from 1 to 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 CjHbj, which has 1-9 carbon atoms, but 1-6 carbon atoms must be present in the chain between the grouping of the formula CRsRö and the phenyl ring , and Rs and Ró have the same meanings as mentioned under (1), provided that, however, neither Rs and Re may be a fluorine atom if Z is an oxygen atom; or

(3) the grouping of the formula

-ch2. xh2ch3 "c = c -.

W H

10th

In another preferred embodiment of the present invention, the iodination and cyclization are carried out in an organic solvent system which contains iodine in the presence of an alkali metal carbonate.

s As can be seen from the publication in the Journal of the American Chemical Society, 99.4182 (1977), the starting materials of the formula XIII are preferably used in the form of their cis compounds.

According to a preferred embodiment of the present invention, the corresponding cis compound of the formula is therefore used as the starting material of the formula XIII

15

20th

25th

HI

C.

\

L - R,

x-c-r4

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

W is a radical of the formula -CHh- 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-.

The process according to the invention for the preparation of these iodine compounds of the formula I is characterized in that a compound of the formula XIII

used.

The present invention further relates to a process for the preparation of anol ethers of the formula II in which

Di a grouping of the formulas

R "

35

, 0-c = ch

, w-ch = ch-l-ri

(XIII)

(II)

55

in which

D, L, Q, Ri, R4, V, W and X have the same meaning as in formula I,

subject to iodination and cyclization to form the iodine compound of the formula I.

According to a preferred embodiment of the present invention, the iodination and cyclization of the starting materials of the formula XIII is carried out in an aqueous medium which contains iodine, potassium iodide and an alkali metal carbonate or bicarbonate. According to one or cfHsOH

® is, and

L, Q, V, W, X, Ri and R4 have the same meaning as in formula I.

The process for the preparation of the new compounds of the formula II is characterized in that, starting from a corresponding starting material of the formula XIII, the corresponding iodine compound of the formula Ia is firstly obtained by iodination and cyclization by the process described above

11

632 245

^ -O-C-CH-L-Ri JA

(la)

X-C-R4 '

q m which

Di, L, Q, V, W, X and Ri and R4 have the same meaning as in formula II,

produces, and this compound is reacted with a dehydroiodination reagent and converted into the enol ether of the formula II.

The preferred dehydroiodination reagents used in this process in the second reaction stage are tertiary amines, preferably 1,5-diazabicyclo (4,3,0) non-5,1,4-diazabicyclo (2,2,2) octane or 1, 5-diazabi-cyclo- (5,4,0) undecene-5. Further preferred dehydroiodination reagents are 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 or tetra-alkylammonium peroxides of the formula (Ri2> 4N02, in which R12 denotes an alkyl radical with 1-4 carbon atoms.

A preferred enol ether of the formula II produced by this last-mentioned process is a corresponding acid of the following structure VI

(fH2 "CH2" CH2 ~ COOH

(VI)

H

c = c '

H '^ C- (CH2) 4-CH3

/ N

H S0H

or the sodium salt of this acid or the methyl ester of this acid. If the sodium salt of the acid of the formula VI is prepared, it is preferably produced in the form of a free-flowing powder.

Another object of the present invention is a method for producing a mixture of the keto compound of formula IV

OH

W-C-CH ^ L-Ri

(IV)

with the corresponding hemiketal of formula III

OH

10th

15

20th

40

45

C-CHa-L-Ri

(III)

being in these formulas

D, L, Q, V, W, X, Ri and R4 have the same meaning as in the compounds of formula I.

The process for the preparation of the mixture of the keto compound of the formula IV with the corresponding hemiketal of the formula III is characterized in that a starting material of the formula XIII according to the process described above by iodination and cyclization into an iodine compound of the formula I

3rd

25th

30th

35

V-O-C-CH-L-Ri

7 /

(I)

transferred in which

D and the substituents have the same meaning as in formula IV or III,

and subjecting this iodine compound to dehalogenation and hydrolysis to form a mixture of the keto compound of Formula IV with the hemiketal of Formula III.

According to a preferred embodiment of this process, the deiodination of the compound of the formula I is carried out by reaction with silver carbonate and perchloric acid in an inert organic medium, preferably tetrahydrofuran, preferably in the absence of light, and thus a mixture receives, which contains the keto compound of formula IV as the main component.

According to a further embodiment of this process, the mixture containing the keto compound of ss formula IV as the main component can be dissolved in an organic solvent, preferably acetone or methylene chloride, after a few days the balance between the keto compound of formula IV and the hemiketal of formula III sets.

According to a further preferred embodiment of this two-stage process described above, the deiodination of the compounds of the formula I is carried out in alcoholic solution, preferably methanol, by treatment with an alkali metal hydroxide, preferably potassium hydroxide, after which the mixture of the keto compound is acidified of the formula IV and the hemiketal compound of the formula III which contains the acid form of the compound of the formula I as an impurity.

632245

The prostaglandin derivatives of the formula I or II or III or IV which can be prepared by the processes according to the invention include the following classes of compounds:

(a) PGFa compounds if

12

if

D

(b) IIß-PGFa compounds if

D

io means.

The following formula V has a preferred iodine compound of the formula I which is prepared by the one-stage process according to the invention

IS

means

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

20th

25th

CH-CH- (CHa) s-C00H? \

M

30th

means

and this compound is a derivative of PGFia and can accordingly be referred to as 9-deoxy-6,9-epoxy-5-iodine PGFia.

D This acid of the formula V falls under the general formula 35 of the iodine compound of the formula I, namely if in the iodine compounds of the formula ID the group of the formula

40

ch2oh means

(e) ll-deoxy PGFa compounds when J ^)

45

is L- (CH2) 3- means Q ÒH

50

Ri is -COOH, Rs is the n-pentyl radical, V is a single bond, W is -CH2- and X is trans-CH = CH-.

According to the two-stage process 55 according to the invention, enol ethers of the formula II

(f) 11-Deoxy-10,11 -idehydro-PGFa compounds when TN

V V x l —- r,

means and

(g) 11-deoxy-11-hydroxymethyl PGFa compounds,

(II)

13

632245

Formula III hemiketals

OH

v-a f)

^ 'C-CH2 "L-Rì

-V-w

(III)

and keto compounds of formula IV

•OH

W-C-CHj-L-Ri

(IV)

income. The 6-hydroxy compounds (hemi-ketals) of formula III and the 6-keto compounds of formula IV are named as derivatives of PGFia.

Preferred compounds of the formulas II, III and IV prepared by the two-stage process according to the invention are those in which the substituents have the same meaning as in the preferred acids of the formula I prepared by the one-stage process according to the invention and of the formula I top structure V. The preferred enol ethers of formula II thus have the following structure VI

CH2-CH2-CH2-C00H

a = ch

15

9 \

VI

20th

25th

/ C = c

OH Hy N> (CH2K-CH3

/ \ -., H OH

produced.

In these compounds the symbols D, L, Q, Ri, R4, V, W and X have the same meaning as in formula I and in the enol ethers of formula II, Di has the meaning given above. Appropriately, however, in the enol ethers of the formula II Ri there is no carboxyl group if Di is a group of the formula, i.e. H. they are compounds that can be referred to as 9-deoxy-6,9-epoxy-A5-PGFia.

In the same way, preferred hemiketals of formula III are those acids which have the following structure VII

OH

ch- (ch2) 4-cooh 0 \

35

vi

\

H OH,

L - (CH2) 3-, R4 n-pentyl, V is a valence bond, W is the radical -CH2- and X is trans-CH = CH-.

In the enol ethers of the formula II, the group of the formula -L-Ri must also be in a trans configuration, based on the W-C bond, as can also be seen from the spelling of this formula.

In the compounds of the formulas I, II, III and IV prepared by the processes according to the invention, W is bonded to the cyclopentane ring in the C-8 position, V in the C-9 position and X in the C-12 position. In the compounds of formula III, the wavy line denotes the binding of the hydroxyl group in the a or β configuration.

The enol ethers of the formula II are named as PGF2a derivatives, regardless of the modifications in one or the other side chain, of V and W in the heterocyclic ring or the cyclopentane ring system J) i, corresponding to the conventional 45 known in prostaglandin chemistry

have and which can be referred to as 9-deoxy-6,9-epoxy-6-hydroxy-PGFia.

In the same way, preferred keto compounds of formula IV are those acids which VIII VIII

55

60

on. y

'CH2 - C - (CH2) 4-COOH

/ \

vi i i

C = 0L H C-C5H11

Oh

H

OH

and these compounds can be referred to as 6-keto-PGFia.

65 The compounds of the formulas I, II, III and IV which can be prepared by the processes according to the invention are extremely effective in causing various biological reactions. For this reason, these

632245

14

bindings for pharmacological purposes. Some of the biological responses are: inhibition of platelet aggregation, stimulation of smooth muscles, systemic lowering of blood pressure, inhibition of gastric secretion and reduction of undesirable gastrointestinal effects by systemic administration of prostaglandin synthetase inhibitors.

Because of their biological effects, the known prostaglandins are useful for the investigation, prevention, control or alleviation of numerous diseases and undesirable physiological conditions in mammals and humans, agricultural animals, domestic animals and zoological species, and laboratory animals such as, for example, B mice, rats, rabbits and monkeys.

These compounds are useful for inhibiting platelet aggregation, reducing platelet adhesion properties, and eliminating or preventing 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, arteriosclerosis, blood clotting due to lipemia and other clinical conditions in which the underlying etiology is linked to lipid imbalance or hyperlipidemia. Further applications in vivo in geriatric patients are the prevention of cerebral ischemic failures and long-term prophylaxis after myocardial infarctions and strokes. For these purposes the compounds are administered systemically, e.g. B. intravenously, subcutaneously, intramuscularly or in the form of sterile implants for prolonged action. For rapid action, especially in emergency situations, intravenous administration is preferred. Doses of from about 0.01 to about 10 mg / kg of body weight per day are used, the exact amount depending on the age, weight and condition of the patient or animal, the frequency and mode of administration.

The addition of these compounds to whole blood leads to applications in vitro, such as. B. in the storage of whole blood for use in heart / lung machines. The blood containing these compounds can also by organs, for. B. heart and kidney, which have been taken from a donor and are ready for transplantation. They are also useful for the production of platelet-rich concentrates for use in thrombocytopenia, chemotherapy, and radiation therapy. In vitro applications use 0.001-1.0 p, g / ml whole blood.

These compounds are extremely effective smooth muscle stimulators, and they are also highly active in enhancing other known smooth muscle stimulators, for example oxytocin agents such as oxytocin and the various ergot alkaloids including their derivatives and analogs. They are therefore useful instead of or together with less than the usual amounts of these known stimulators, e.g. B. to relieve the symptoms of paralytic ileus or to combat or prevent atonic uterine bleeding after miscarriage or delivery, to reject the placenta as well as during the puerperium. For the latter purposes, the compound is administered by intravenous infusion immediately after the miscarriage or childbirth at a dose of about 0.01 to about 50 Hg / kg body weight per minute until the desired effect is achieved. Subsequent 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 (xg / kg body weight per minute, or in one or more doses of about 25 to 500 p.g / kg body weight per day.

These prostaglandin derivatives are also useful in mammals including humans and certain farm animals, e.g. B. dogs and pigs, to reduce and control excessive gastric juice secretion, whereby the formation of gastric / intestinal ulcers can be reduced or avoided and the healing of such existing ulcers can be accelerated. For this purpose, the compounds are injected or infused intravenously, subcutaneously or intramuscularly, with an infusion dose 20 of about 0.1 to about 20 µg / kg body weight per minute, or with a total dose per day by injection or infusion of about 0.01 up to about 10 mg / kg of body weight 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 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 with the anti-inflammatory prostaglandin synthetase inhibitor. US Pat. No. 3,781,429 discloses that the ulcerogenic effect of certain non-steroidal anti-inflammatory 35 inhibitors in rats by oral administration of certain E and A series prostaglandins including PGEi, PGE2, PGE3,13, 14-Dihydro-PGEi and the corresponding 11-deoxy-PGE and PGA compounds is inhibited. The prostaglandins are, for example, useful for reducing the undesirable effects on the stomach and intestines that result 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 45. They are also known as prostaglandin synthetase inhibitors.

The anti-inflammatory synthetase inhibitor, e.g. B. indomethacin, aspirin or phenylbutazone, is administered in a known manner to facilitate an inflammatory so 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 suppositories or, in women, vaginally in the form of supositories or a vaginal device for slow delivery (see, for example, US Pat. No. 3 545 439) can be given. If, on the other hand, 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 expedient to combine the two substances in a single dosage form.

The dosing schedule for prostaglandin is included

15

632 245

This treatment of various factors including the type, age, weight, gender and medical condition of the patient, the dosing schedule of the anti-inflammatory synthetase inhibitor and the patient's sensitivity to the synthetase inhibitor with regard to gastrointestinal effects. For example, B. 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 experience of the doctor or veterinarian to determine whether the administration of the anti-inflammatory substance produces undesirable gastrointestinal 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 dialers or as inhibitors of mediators such as. B. SRS-A and histamine, which are released from cells activated by an antigen / antibody complex. The compounds therefore fight cramps and make breathing easier in conditions such as bronchial asthma, bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, the compounds are administered in various dosage forms, e.g. B. orally in the form of tablets, capsules or liquids, rectally in the form of suppositories, parenterally, subcutaneously or intramuscularly, intravenous administration being preferred in emergency situations, 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 and the frequency and type of administration. For the above purposes, these prostaglandins are suitably combined with other anti-asthmatics, for example sympathomimetics (isoproterenol, phenylephrine, ephedrine and the like), xanthine derivatives (theophylline and aminophylline) and corticosteroids (ACTH and prednisolone).

The effective administration in humans takes place by oral inhalation or by 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 such as. As sodium chloride, sodium citrate, citric acid, sodium bisulfite and the like.

For administration in a dose unit for inhalation containing a propellant, the preparation in question can contain the active ingredient 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. B. use oleyl alcohol. Suitable agents for inhalation therapy are e.g. B. described in U.S. Patent 2,868,691.

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

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, e.g. B. frostbite, ischemic cerebrovascular diseases, artheriovenous fistulas, ischemic leg ulcers, phlebitis, venous disorders, gangrene, the hepatorenal syndrome, ductus arteriosus, non-obstructive mesenteric ischemia, arteritis, lymphangitis and the like. These are just examples of peripheral vascular diseases. In these diseases, the compounds according to the invention are administered orally or parenterally by injection or infusion directly into a vein or artery, intravenous or intra-arterial injection being preferred. The doses range from 0.01-1.0 μg given per hour for infusion or 1 to 4 times per day for injection, the exact amount depending on the age, weight and condition of the patient and the frequency and type depends on the administration. Treatment is continued for 1 to 5 days, although 3 days is usually sufficient to ensure a sustained therapeutic effect. If systemic or side effects are observed, the amount is reduced below the value at which these side effects occur.

These compounds are therefore useful for the treatment of peripheral vascular diseases in the extremities in patients with limb circulatory disorders, the treatment leading to pain relief and the onset of ulcer healing.

ZA-PS 74/0149, Derwent Farmdoc No. provides a detailed discussion of the course of the disease and the clinical observations in peripheral vascular diseases and the previously known treatment methods. 58.400V. s. a. Elliott, et al., Lancet, 1975, pp. 140-142.

These compounds can be used in place of oxytocin to induce labor in pregnant females such as cows, sheep and pigs, as well as in humans at or near the time of birth, or in pregnant animals when the fetus dies intrauterine about 20 weeks before the birth. For this purpose, the compound is infused intravenously in an amount of 0.01 to 50 ng / kg body weight per minute up to or almost until the end of the second stage of labor, i.e. the expulsion of the fetus. The compounds are particularly useful if the natural contractions have not started one or more weeks after the time of birth, or 12 to 60 hours after the membrane has torn if the natural contractions have not started. Oral administration is also possible.

These compounds are also useful for controlling the conception cycle in menstruating female mammals. Menstruating female mammals are understood to mean those that are already mature enough to menstruate, but are not yet as old,

that regular menstruation has stopped. For this purpose, the prostaglandin derivative is systemically administered in a dose of from 0.01 to about 20 mg / kg of body weight, expediently during the period that begins approximately at the time of ovulation and ends approximately at the time of menses or shortly before. Intravaginal and intrauterine administration are also possible. Furthermore, similar administration causes the embryo or fetus to be ejected during the first or second third of normal gestation or pregnancy.

These compounds are also useful for producing cervical dilatation in pregnant and non-pregnant female mammals for gynecological and obstetric purposes. Cervical enlargement is also observed in the induction of labor caused by these connections and in clinical abortion. In cases of infertility, the cervical enlargement caused by these compounds serves as a relief

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

632 245 16

the sperm movement to the uterus. The cervical enlargement caused by prostaglandins containing a suitable pharmaceutical carrier is also useful in the preparations, e.g. B. as an ointment, lotion, paste, gel,

operative gynecology such as B. D and C (cervical spray or aerosol, using carriers such as petrolatum,

enlargement and uterine curettage) where mechanical lanolin, polyethylene glycols or alcohols are used. These

Enlargement of a perforation of the uterus, cervical strains s connections make as an active ingredient about 0.1 to about 15

or can cause infections. It is also advantageously% by weight and preferably about 0.5 to about 2% of the preparation

in diagnostic procedures in which extensions are made. In addition to topical administration,

Tissue examination is required. In these cases it will be decorated, e.g. B. intradermally, intra- or perilösional or the prostaglandin derivative applied locally or systemically. subcutaneously, using appropriate sterile saline solutions

The prostaglandin derivative is used, for example, orally or io.

vaginally in doses of about 5 to 50 mg / treatment to one. The compounds are also useful as an inflammation adult woman, with 1 to 5 treatments administered within 24 inhibitors to prevent chronic inflammation during acid hours. Also, the compound can intramuscularly include swelling and other unanagularly or subcutaneously in amounts of about 1 to 25 mg / day, taking the treatment methods given. The exact amount for these is and amounts according to US Pat. No. 3,885,041 can apply. Purposes depends on the age, weight and condition of the patient. The 6-keto, iodine ether, or animal that can be produced according to the invention. Enol ether and hemiketal compounds cause numerous

The compounds are also useful in farm animals as rich ones in the older prostaglandin compounds

Abortion agents (especially in the case of biological reactions known for slaughter. They are, for example, heifers), surprisingly more specific as aids for determining the oestrus 20 and have an essential one and for regulating or synchronizing the oestrus. The biological effect is too long. They possess the horses, cattle, sheep and other advantage that they can be successfully administered orally, sublingually, intravenously.

Pigs. The regulation or synchronization of the ginal, buccal or rectal can be administered

Heat allows more effective influencing of Emp in addition to the other methods. Each of these new conception and contractions and enables the herd owner that 25 yoga is therefore suitable instead of the known prostaglandin-all female animals in short predetermined time periods Fa-connections for at least one of these conjunctiva. This leads to a higher percentage of fertilizing known pharmacological purposes and is over-live births than with natural processes. The prostate is surprisingly more usable because it has a different and narrower glandin injected or administered in the feed in doses with a spectrum of biological effects than the known one from 0.1 to 100 mg / animal and can be used with other agents such as 30 prostaglandin. It is therefore more specific in its effects to combine steroids. The dosage regimen and causes fewer and less undesirable side slopes depending on the animal species. For example, we get effects like the well-known prostaglandin. Furthermore, wise mares can take the prostaglandin derivative 5 to 8 days after the ovulation, which is often less and less due to the prolonged action, and return to the heat. Cattle will apply 35 desired results in doses of the new compounds to achieve regular intervals within a 3 week period.

treated so that all the animals are at the same time in heat if you according to the one-step Ver-become. drive iodine compounds of formula I, then these compounds can also increase the blood flow in which they also have protective groups in the rest D, d. H. in the rest of the mammalian kidney, which means that the volume and electrolyte content of the D13, R13 must have another of the meanings given for urine. For this reason, the references are suitable as that of a hydrogen atom. This protection, which comes from bonds for the treatment of kidney dysfunction, in particular the starting material of the formula XIII, in particular when the layer of kidney vessels is blocked. For example, groups can be used after the implementation of the one-step, the compounds useful for facilitating and resolving the process according to the invention, edema, which results, for example, from large surfaces, which then results in corresponding iodine compounds of the burns, and for the treatment of 45 formula I. , in which the group R13 in the rest D is a shock. For these purposes, the compounds are pre-hydrogen atom. In this case, the initially intravenously injected in a dose of 10 residues D corresponds to the group Di as defined in connection with up to 1000 jig / kg body weight, or intravenously infused in the compounds of the formula II.

an amount of 0.1 to 20 jig / kg body weight per minute produced by the process according to the invention until the desired effect is achieved. Subsequent doses of compounds which still have protective groups are injected intravenously, intramuscularly or subcutaneously, generally as starting materials for carrying out white or infused in an amount of 0.05 to 2 mg / kg of more physical reactions, while the corresponding weight per day. Corresponding, deprotected compounds. These prostaglandin derivatives can also be used for the treatment of proliferating skin diseases in humans directly as active ingredients in pharmaceutical products.

and pets such as psoriasis, atopic dermatitis, non- In the two-step process according to the invention for specific dermatitis, primary irritant contact dermatitis, production of the enol ethers of the formula II, as already mentioned allergic contact dermatitis, cell carcinoma of the skin, lamel-, the iodine compounds initially obtained are shown Ichthyosis, epidermolytic hyperkeratosis, pre-Formula I subjected to dehydroiodination. This malignant, sun-induced keratosis, non-malignant dehydroiodination is preferred with one of the further

Keratosis, acne and seborrhea dermatitis in people mentioned dehydroiodination reagents mentioned above

and atopic dermatitis and mange in pets. This leads.

Compounds alleviate the symptoms of proliferative. Reaction Scheme A below shows that

Skin diseases. For example, the psoriasis is improved, the one-step process according to the invention for the preparation of the iodine compounds of the formula I and the two-step invented when a psoriasis-free lesion is noticeably less thick.

lost or visible, but incomplete or perfect process for the production of hemiketals that is constantly cleaned. Formula III and the keto compounds of formula IV closer

For these purposes, the connections are explained topically in:

17th

632245

Scheme A

W-CH = CH-L-Ri

In scheme A, the radical D has the meanings given above, and after protective groups R13 have been split off, this radical D can be converted into the radical Di with a free hydroxyl group on the carbon atom 11.

The other substituents in reaction scheme A have the following meaning:

XII i

10th

1

(a)

V-0-CH-ÒH-L-Ri

L means

(1) - (CH2) d-C (R2) 2-

(2) -CH2-O-CH2-Y- or

(3) -CH2CH = CH-

15 where d is a number from 0 to 5, the radicals R2, which may be the same or different, hydrogen, methyl or fluorine, with the proviso that one radical R2 is not methyl when the other is fluorine, and Y is a valence bond or a radical - (CH2) k-, where k is the number 1 or 2, 20.

Q means

II / \

O, H H, R8 ÒH, or Rs OH

25th

OH

wherein Rs represents hydrogen or an alkyl radical having 1 to 4 carbon atoms.

Ri means

30th

35

(1) -COOR3

(2) -CH2OH

(3) -CH2N (R9> or

(4)

-c

/

NH-N

-N

xW-C-CHa-L-Ri

IV

■ R.

IÎ

(c)

1

(d)

wherein R3 (a) is an alkyl radical with 1 to 12 carbon atoms, 40 (b) cycloalkyl radical with 3 to 10 carbon atoms, (c) aralkyl radical with 7 to 12 carbon atoms, (d) the phenyl radical or (e) one with 1, 2 or 3 Chlorine atoms or alkyl radicals with 1 to 4 carbon atoms substituted phenyl radical,

0

II

NH-C NH-C-CH3,

50

■ R:

I 1 I

60 (h)

ff W

65

NH-C

O

II

-NH-C-CH3,

0

II

- (^ "" ^ - NH-C-NHs

632245

or n> -CH-C-R10

I.

Ri i wherein Rio is the phenyl, p-bromophenyl, p-biphenyl, p-nitrophenyl, p-benzamidophenyl or 2-naphthyl radical and Rn is hydrogen or the benzoyl radical, (m j is hydrogen or

(n) denotes a pharmacologically acceptable cation and the radicals R9, which may be the same or different, are hydrogen or alkyl radicals having 1 to 4 carbon atoms.

R.- means

I.

0)

"CgH2,

, -CH,

R «R«

r

(2)

-c-z <3r

re

(T) <

or

(3)

-CH2 ^ .CH2CH3 c = c H H

wherein CgM2g is an alkylene radical with 1 to 9 carbon atoms, with 1 to 5 carbon atoms in the chain between -CRsRs- and the terminal methyl group, Rs and R &, which may be the same or different, is hydrogen, alkyl radicals with 1 to 4 carbon atoms or fluorine, below with the proviso that one of the radicals Rs and Rö is fluorine only if the other is hydrogen or fluorine, and with the further proviso that neither Rs nor R "is fluorine if Z represents the oxa group (-0-), Z a Oxa atom (-0-) or a radical Cjl hj which is a valence bond or an alkylene radical having 1 to 9 carbon atoms, having 1 to 6 carbon atoms between CRsR <.- and the phenyl ring, T is an alkyl radical having 1 to 4 carbon atoms, Fluorine, chlorine, triluormethyl or a radical of the formula -OR7-, in which R7 is hydrogen or an alkyl radical having 1 to 4 carbon atoms, and s is the number 0, 1, 2 or 3, with the proviso that no more than 2 radicals T are different from alkyl and that, if s is the number 2 or 3, the radicals T may be the same or different.

V means a valence bond or a residue -CH2-, W

a residue - (CHîJh-, where h is 1 or 2, and X is one of the residues

(1) trans-CH = CH-s (2) cis-CH-CH-

(3) -C = C-or

(4) -CH2CH2-.

Examples of alkyl radicals having 1 to 12 carbon atoms 10 are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl radical and their isomeric forms. Examples of cycloallcyl radicals having 3 to 10 carbon atoms, including alkyl-substituted cycloallcyl radicals, are cyclopropyl, 2-methylcyclo-isopropyl, 2,2-bimethylcyclopropyl, 2,3-ethylcyclopropyl,

2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl,

3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl,

2® 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cyclo-heptyl, cyclooctyl, cyclononyl and cyclodecyl.

Examples of aralkyl radicals with 7 to 12 carbon atoms are benzyl, phenethyl, 1-phenylethyl, 2-phenyl-propyl, 4-phenylbutyl, 3-phenylbutyl, 2- (l-naphthyl-25-ethyl) - and l- (2-naphthylmethyl) rest.

Examples of phenyl radicals substituted by 1 to 3 chlorine atoms or alkyl radicals having 1 to 4 carbon atoms are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-di-chlorophenyl, 2,4,6-trichlorophenyl -, p-tolyl, m-tolyl-, 3® o-tolyl-, p-ethylphenyl-, p-tert-butylphenyl-, 2,5-dimethyl-phenyl-, 4-chloro-2-methylphenyl- and 2, 4-dichloro-3-methylphenyl radical.

The starting materials of formula XIII from Scheme A are known or can be easily prepared by known methods. Regarding PGF2 "compare US Pat. No. 3,706,789, with regard to 15-methyl- and 15-ethyl-PGF2", US Pat. No. 3,728,382, with respect to 16,16-dimethyl-PGF2a compare US Pat. No. 3,903,131; for 16,16-difluoro-PGF2a compounds, U.S. Patents 3,962,293 and 3,969,380; for 16-phenoxy-4 »17,18,19,20-tetranor-PGF2a see Derwent Farmdoc No. 73279U; for 17-phenyl-IS, 19,20-trinor-PGF2a see Derwent Farmdoc No 31279T; for 11-deoxy-PGF2a see Derwent Farmdoc No. 10695V; for PGB2, see U.S. Patent 3,767,813; with respect to 2a, 2b-4s Dihomo-PGF2a s. Derwent Farmdoc No. 61412S and U.S. Patents 3,852,316 and 3,974,195; for 3-oxa-PGF2, U.S. Patent 3,923,861; U.S. Patent 3,931,289 to 3-oxa-17-phenyl-18,19,20-trinor-PGF2a; for substituted phenacyl esters see. Derwent Farmdoc No. 16828X; for substituted Phe-s® nyl ester s. U.S. Patent 3,890,372; for C-1 alcohols, that is 2-becarboxy-2-hydroxymethyl compounds, see. U.S. Patent 3,636,120; for C-2 tetrazoyl derivatives see.

U.S. PSS 3,883,513 and 3,932,389; regarding Ä2-PGF2 <x compare Derwent Farmdoc No. 46497W and DOS 2 460 285; ss regarding 5,6-cis-PGF2a s. U.S. Patent 3,759,978; for 2,2-dimethyl-PGF2 "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 1 lß-PGF2a compounds see. U.S. Patent 3,890,371; for 6® 11-deoxy-PGF2a see. Derwent Farmdoc No. 10695V; regarding ll-deoxy-ll-hydroxymethyl-PGF2as. U.S. PSS3,931,282 and 3,950,363; for 16-methylene PGF2a s. Derwent Farmdoc No. 19594W and DOS 2 440 919; for 17,18-dide-hydro-PGF2a compounds see. U.S. Patent 3,920,726; for es 3- (or 4-) oxa-17,1 o-didehydro-PGF2a compounds s. U.S. Patent 3,920,723; for 15-oxo-PGF2a see. U.S. Patent 3,728,382; for 15-deoxy-PGF2a, see. Derwent Farmdoc No. 9239W; for 13,14-cis compounds see. U.S. PS

19th

632 245

3,932,479; regarding 11-deoxy-15-deoxy-PGF2 «s. Derwent Farmdoc No. 5694U; for co-homo-PGF2 "compounds see. Derwent Farmdoc No. 4728W; and for 2,2-difluoro-PGF2a compounds see. Derwent Farmdoc No. 67438R.

With regard to the 2-decarboxy-2-amino-PGF2a compounds, reference is made to the addendum to the present description.

In step (a) according to Scheme A, the starting material of the formula XIII is subjected to iodination and cyclization to form the iodine compounds of the formula I. Either an aqueous system which contains iodine, potassium iodide and an alkali metal carbonate or bicarbonate is used for this purpose, or an organic solvent system such as methylene chloride that contains iodine in the presence of an alkali metal carbonate. The reaction is carried out at temperatures below 25 ° C and preferably at about 0 to 5 ° C for 10 to 20 hours. Then the reaction is stopped with sodium sulfite and sodium carbonate and the compound of formula I is isolated from the reaction mixture.

In step (b) of Scheme A, the iodine compound of formula I is converted to the 6-keto compound with silver carbonate and perchloric acid. The reaction takes place in an inert organic medium such as tetrahydrofuran and is followed by thin-layer chromatography; it normally takes 15 to 24 hours at about 25 ° C. The reaction is preferably carried out in the absence of light.

In step (c) according to Scheme A, the 6-keto compound of the formula IV is converted into a balance from the compounds III and IV in solution. This is done by simply using a solution of compound IV in an organic solvent such as. B. produces acetone or methylene chloride and this can stand for several days. The resulting mixture is then concentrated and broken down, for example by silica gel chromatography, to give the hemiketal of Formula III.

Step (d) according to scheme A provides a further process for the preparation of hemiketal III. The iodine compound of formula I in alcoholic solution, for. B. in methanol, with aqueous alkali metal hydroxide, e.g. As potassium hydroxide, treated at a temperature in the range of 0 to 30 ° C for several hours. After acidification, a mixture of the acid form of compound I and hemiketal III is obtained together with some compound IV, which are separated from one another, e.g. B. by silica gel chromatography or by fractional crystallization.

The new compounds of formulas I, III and IV, wherein Ri is not a carboxyl group, e.g. B. the esters in which R3 from -COOR3 is an alkyl radical with 1 to 12 carbon atoms, cycloalkyl radical with 3 to 10 carbon atoms, aralkyl radical with 7 to 12 carbon atoms, a phenyl or one with 1 to 3 chlorine atoms or alkyl radicals with 1 to 4 carbon atoms substituted phenyl radical, are prepared from the acids of the formulas I, III and IV in question, that is to say compounds in which Ri = —COOH, by known methods. For example, the alkyl, cycloalkyl and aralkyl esters are prepared by reacting the acids with the relevant diazo hydrocarbon. For example, the methyl esters are obtained with diazomethane. Analog are with diazoethane, diazobutane, l-diazo-2-ethylhexane, diazocyclohexane and phenyldiazomethane z. B. formed the ethyl, butyl, 2-ethylhexyl, cyclohexyl and benzyl esters. The methyl esters are preferred.

The esterification with diazo hydrocarbons is carried out by reacting a solution of the diazo hydrocarbon 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 is evaporated off and the ester is purified in a conventional manner, preferably by chromatography. The contact of the acid with the diazo hydrocarbon should preferably not be longer than is necessary to effect the esterification, in particular about 1 to 10 minutes, in order to avoid undesired molecular changes. Diazocarbons are known or can be prepared by known 10 methods, see e.g. B. Organic Reactions, John Wiley & Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

Another method for esterifying the carboxyl group of the new compounds of formulas I, III and IV 15 is to convert the free acid to the silver salt, followed by reacting this salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phen-20 ethyl iodide and the like. The silver salts are produced by conventional methods, e.g. B. by dissolving the acid in cold dilute aqueous ammonia, evaporating excess ammonia under reduced pressure and then adding the stoichiometric amount of silver nitrate 25.

The phenyl and substituted phenyl esters of the compounds of the formulas I, III and IV are prepared by silylating the acid in order to protect the hydroxyl groups, for example by replacing each hydroxyl group with the 30 radical -0-Si- (CH3) 3. The carboxyl group can also be converted into a residue -COO-Si- (CH3) 3. The -COO-Si- (CH3) 3 group is converted back into the carboxyl group by briefly treating the silylated compound with water. Methods for carrying out this silyation are known and are described below. The subsequent treatment of the silylated compound with oxalyl chloride leads to the acid chloride which is reacted with phenol or the substituted phenol to form a silylated phenyl or substituted phenyl ester. Then the silyl groups, e.g. B. the formula -0-Si- (CH3) 3, converted back into hydroxyl groups by treatment with dilute acetic acid. Methods of performing this conversion are known.

The 45 two-stage process according to the invention for the preparation of the enol ethers of the formula II is explained using the following reaction scheme B.

Scheme B

50

60

65

w-ch = ch-l-rx xi i

632245

Scheme B (continued)

L - R.

I 1

In Scheme B, the symbols xJ, L, Q, Ri, R4, V, W and X have the meanings given in connection with Scheme A.

In step (a) of scheme B, as in scheme A, the starting materials of the formula XIII are subjected to iodination and cyclization to form the iodine compounds of the formula I.

In step (b) according to scheme B, the iodine compound I is converted into the enol ether of the formula II by reaction with a dehydroiodination reagent. Appropriate reagents are e.g. B. 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 tetra -alkylammonium 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,

20th

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 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 recommended to maintain basic conditions, e.g. B. with triethylamine to avoid acidic decomposition or structural change of the product. The purification is 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.

20 ester groups, the p-phenylphenacyl residue on the Cl-carboxyl group or the 4-bromobenzoate residue on the hydroxyl groups on Cl 1 and C-15 remain unchanged in the conversions according to scheme B and are present in the product of formula II if they are in the starting material XIII 25 were present. The preferred method for producing end products II in the form of esters is based on iodine compounds of the formula I, which are the esters in question.

The 30 sodium salts are particularly favorable for administration because of their presence as free-flowing powder and their solubility.

The iodine compounds of the formula I prepared by the processes according to the invention, the enol ethers of the formula II, the hemiketals of the formula III and also the keto compounds of the formula IV can, if R 1 is a carboxyl group and Q is the grouping of the formula

H ÔH

40 mean to be used to produce the corresponding 1,15-Lac-tone. For example, the compounds produced by the process according to the invention for producing the

45 9-Deoxy-6,9-epoxy-5-iodine-PGFia-l, 15-lactones and the 9-deoxy-6,9-epoxa-A5-PGFia-1,15-lactones. The preparation of these lactones using the compounds prepared by the process according to the invention is explained in more detail at the end of the description with reference to reaction scheme C.

Although the diagrams show a special configuration for 55 starting materials and products, the process steps are also and not only suitable for application to the other optically active isomers and geometric cis-trans isomers, but also to mixtures including racemic mixtures and mixtures of enantiomeric forms. 60 If optically active products are desired, optically active starting materials or intermediates are used, or, if racemic starting materials or intermediates are used, separation processes known in prostaglandin chemistry.

65 The products formed at each reaction stage are often mixtures which, as is known to the person skilled in the art, are used as such in a subsequent stage or, if appropriate, in a conventional manner by fractionation, column chromatography

21st

632 245

topography, liquid / liquid extraction or the like can be separated before further processing.

With regard to an optimal combination of biological properties, specific activity, activity level and duration of activity, certain compounds in the formulas I to IV are preferred. So Q is preferably the grouping y \

Rs OH,

Rs being particularly preferably hydrogen or methyl.

A further preference for the compounds of the formulas I, III and IV with respect to Ri is that R3 in the radical -COOR3 consists either of hydrogen or an alkyl radical having 1 to 12 carbon atoms. Furthermore, R3 is preferably an alkyl radical with 1 to 4 carbon atoms, in particular the methyl or ethyl radical, because of the optimal absorption after administration. In the compounds of the formula II, R3 is preferably not hydrogen, but rather an alkyl ester or a salt of a pharmacologically acceptable cation.

For reasons of long-term stability, R3 is furthermore preferably an amido-substituted phenyl radical or substituted phenacyl radical.

The ring 3> is preferably a residue or

R4 is preferably the n-pentyl, 1,1-dimethylpentyl or 1,1-difluoropentyl radical, the rest of those fractions understood which contain the desired product free of starting material and impurities according to the thin-layer chromatogram. “Concentration” means concentration at reduced pressure, preferably less than 50 mm, and at a temperature below 35 ° C.

Preparation 1

11-deoxy-10.1 l-didehydro-PGF2a methyl ester and its 10 9β-epimer; and 11-deoxy-10,11-didehydro-PGF2ci and its 9β-epimer.

A mixture of 1.74 g of PGAî 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 at -78 ° C. for 1 hour, 100 ml of a 1: 1 mixture are treated from 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 20 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 25 being obtained in the following order:

11-deoxy-10.1 l-didehydro-PGF2a-methyl ester, 11-deoxy-10.11 -didehydro-9ß-PGF2a-methyl ester,

11-Deoxy-10,11 -didehydro-PGF2a and 30 11 -deoxy-10,11 -didehydro-9ß-PGF2a.

example 1

9-deoxy-6,9-epoxy-5-iodine PGFia methyl ester (formula I: L = - (CH2) 3-, R. = -COOCH3, R4 = n-pentyl, V - valence-35 bond, W = -CH2-, X = trans-CH = CH-,

-CHa

-C2H4

- »■ © <G>

40

or

L preferably consists of one of the residues - (CH2) 3-, - (CH2) 4- or - (CH2) s-, in particular of - (CH2) 3-.

In the following 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 tetramethyl-silane 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 LKB 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).

Under the expression silica gel chromatography is the elution, collecting the fractions and pooling

4SQ = H OH).

Compare scheme A, step (a). A suspension of 2.0 g of PGF2a methyl ester XIII in the form of the 11,15-bis-tetrahydro-pyranyl ether in 23 ml of water is treated with 0.7 g of sodium bicar-50 bonate and cooled in an ice bath. 1.93 g of potassium iodide and 2.82 g of iodine are added to the resulting solution and the mixture is stirred at about 0 ° C. for 16 hours.

Then a solution of 1.66 g of sodium sulfite and 0.76 g of sodium carbonate in 10 ml of water is added. After a few ss 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-tetrahydropyranyl ether of the title compound in the form of an oil (2.2 g). The 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; Rf 0.20 (thin layer chromatogram on silica gel in acetone / methylene chloride 30:70). The peaks in the 65 mass spectrum for compound I (trimethylsilyl derivative) are 638,623,607,567,548,511 and 477.

If the procedure of Example 1 is repeated, but with the replacement of the starting material of the formula XIII by the following

632245

22

Compounds XIII or their C-1 1 ether, the corresponding iodine compounds I are obtained:

15-methyl-PGF2a

15-ethyl-PGF2a

16,16-dimethyl-PGF2a 16,16-difluoro-PGF2 «

16-phenoxy-17,18,19,20-tetranor-PGF2a

17-phenyl-l 8,19,20-trinor-PGF2a ll-deoxy-PGF2a 2a, 2b-dihomo-PGF2o 3-oxa-PGF2a

3-oxa-l 7-phenyl-17,19,20-trinor-PGF2a.

10th

15

Example 2

6-Keto-PGFict methyl ester (formula IV: D, L, Q, Ri, Ra, V, W and X as in Example 1).

Compare scheme A, step (b). A solution of 0.45 g of the methyl ester of the iodine compound from Example 1 in 20 ml of tetrahydrofuran is treated with 0.250 g of silver carbonate and 0.10 ml of 20% 90% perchloric acid and stirred at about 25 ° C. for 24 hours. Then the mixture is diluted with 25 ml of ethyl acetate and the organic phase is washed with saturated sodium carbonate solution and saturated sodium chloride solution, dried and concentrated to an oil 25 (0.41 g). Silica gel chromatography eluting with ethyl acetate / Skellysolve B (3: 1) gives the title compound of formula IV as the more polar material compared to starting material I. The product consists of an oil (0.32 g) of Rf 0, 38 (thin layer chromatogram 30 on silica gel in acetone / methylene chloride 1: 1). Infrared absorption at 1740 cm-1 for the carbonyl group, NMR peaks at 5.5.3.2-4.8.3.7.2.1-2.78.

Example 3 35

9-Deoxy-6,9-epoxy-6-hydroxy-PGFia methyl ester

(Formula III: J), L, Q, Ri, R4, V, W and X as in Example 1, ~

means bond in a or ß configuration.

Compare scheme A, step (c). A solution of 0.2 g of the 40 6-keto compound IV according to Example 2 in 10 ml of acetone is left to stand at about 25 ° C. for 2 days. The solution is then concentrated and subjected to silica gel chromatography, giving the title compound III with Rf 0.50 (thin layer chromatogram on silica gel in acetone / methylene chloride 45 1: 1).

Example 4

9-deoxy-6,9-epoxy-5-iodine-PGFia (formula I) and 9-deoxy-6,9-epoxy-6-hydroxy-PGFio (formula III: J), L, Q, Ri, R4, V, W and X as in Example 1). so

Compare scheme A, step (d). A solution of 1.0 g of the iodine compound I according to Example I in 30 ml of methanol is treated with 20 ml of 3N aqueous potassium hydroxide solution at about 0 ° C. for about 5 minutes and then at about 25 ° C. for 2 hours. The mixture is acidified to pH 1.0 with 25 ml of 2N potassium bisulfate solution and 50 ml of water, saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to an oil (1.3 g). The oil is subjected to silica gel chromatography eluting with acetone / methylene chloride (30:70 to 50:50). This gives compound I first and later compound III as a more polar fraction.

The compound of formula I is an oil (0.33 g), Rf 0.33 (thin layer chromatogram on silica gel in acetone / methylene chloride (1: 1) + 2% acetic acid); Infrared absorption at 3360,2920,2860,2640,1730,1710,1455,1410,1380, 1235, 1185, 1075, 1050, 1015,970 and 730 cm- '. Peaks in

60

65

Mass spectrum (trimethylsilyl derivative) at 681,625,606, 569,535,479 and 173.

The compound of formula III is a solid (0.113 g) with a melting point of 93 to 98 ° C., which after recrystallization from acetone / Skellysolve B is 95 to 105.2 ° C. It contains no iodine, Rf 0.13 (thin layer chromatogram on silica gel in acetone / methylene chloride (1: 1) + 2% acetic acid); Mass spectrum peaks (trimethylsilyl derivative) at 587,568,553, 497,485,478,407,395,388 and 173.

The compound of formula III is methylated with diazomethane to give the methyl ester, which has the same properties as the product of Example 3.

If the processes of Examples 2 and 4 are repeated, but with the iodine compound I replaced by the iodine compounds described in connection with Example I, the compounds of the formulas IV and III in question are obtained. If the procedure of Example 3 is repeated, but with the compounds IV thus obtained, the compounds III in question are also obtained.

Example 5

9-Deoxy-6,9-epoxy-A5-PGFia methyl ester (formula II: L = - (CH2) 3-, Q =

A

H OH,

Ri = COCH3, R4 = n-pentyl, X - trans-CH = CH-,

V = valence bond, W = methylene).

Compare Scheme B. A mixture of 0.25 g of the iodine compound I (see Example I), 0.25 ml of 1,5-diazobicyclo [4.3.0] non-5 and 15 ml of benzene is at 72 ° C. for 72 hours allowed to 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; Rf 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 0.9 8; IR absorptions at 1755 and 1720 cm-1, 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 l, 5-diazabicyclo- [4.3.0] nonen-5 by l, 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 6

9-Deoxy-6,9-epoxy-A5-PGFia methyl ester (formula II: L = - (CH2) 3-, Q =

A

H OH,

Ri = -COOCH3, R4 = n-pentyl, X = trans-CH = CH-,

V = valence bond, W = methylene).

Compare Scheme B. A mixture of 1.0 g of the iodine compound I according to Example 1.1.0 ml of 1,5-diazabi-cyclo [4.3.0] nonen-5 and 60 ml of benzene is heated to about 42 ° C. for 20 hours . Then 0.5 ml of 1,5-diazabi-cyclo [4.3.0] nonen-5 is added and the mixture is heated for a further 6 hours. The mixture is left to stand at about 25 ° C for 60 hours and then reheated to 40 to 50 ° C. Then the reaction mixture is cooled, with ice water mixed with a few drops of triethylamine

23

632245

washed and dried over magnesium sulfate to give 0.9 g of the title compound as an oil. The product is dissolved in 8 ml of diethyl ether and crystallized from cold (-10 ° C.) hexane, which contains 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), ethyl acetate containing 0.25% triethylamine (50 -75%) - Hexane is eluted. This gives 0.21 g of the title compound, which crystallizes on cooling.

Example 7

9-deoxy-6,9-epoxy-A5-PGFia methyl ester (formula II). is

Compare Scheme B. A mixture of 0.213 g of 9-deoxy-6,9-epoxy-5-iodine-PGFia methyl ester of the formula I (see Example 1) in 3 ml of dimethylformamide is mixed with a fresh solution of 0.45 g of potassium peroxide in 10 ml of dimethylformamide, which contains 0.75 g of dicyclohexyl-18-crown-6, were treated in an M 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 thin layer chromatogram as the product of Example 5.

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

The procedure of Example 7 is repeated, but with the replacement of potassium peroxide by sodium peroxide, tetra-methylammonium peroxide, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, sodium umtrifluoroacetate, potassium trifluoroacetate, sodium 40 Potassium bicarbonate and silver acetate, the title compound is also obtained.

Example 8

9-deoxy-6,9-epoxy-5-iodine-PGFia-p-phenylphenacyl ester 45 (formula I) and

9-Deoxy-6,9-epoxy-PGF2a-p-phenylphenacyl ester (Formula II).

A. A mixture of 0.20 g of the iodine compound of the formula

I according to Example 4 (acid), 0.50 g of p-phenylphenacyl bromide, 0.4 ml of diisopropylethylamine and 10 ml of acetonitrile are stirred at about 25 ° C. for 40 minutes. It is then mixed with dilute aqueous citric acid and saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is dried and concentrated. The residue ss is subjected to silica gel choreography while eluting with ethyl acetate (25-100%) - SkellysoIve B, whereby 0.20 g of the 5-iodine compound according to the title is obtained as a colorless oil.

B. 0.20 g of the product according to Part A are treated with 0.4 ml of 60 l, 5-diazabicyclo [4.3.0] nonen-5 in 15 ml of benzene at 42 ° C. for 22 hours. The reaction mixture is cooled, washed with ice water containing sodium chloride,

dried over magnesium sulfate and concentrated to give 0.12 g of the second title compound as an oil. The oil is crystallized from benzene / hexane. All fractions are combined and chromatographically separated on a Florisil column pretreated with hexane / ethyl acetate / triethylamine (80: 20: 0.5) while eluting with ethyl acetate to give compound II as an oil. Crystallization from ether / hexane gives 0.016 g of crystals with a melting point of 71-72 ° C (sintering at 65 to 67 ° C).

Example 9

9-deoxy-6,9-epoxy-5-iodine-PGFia methyl ester-11,15-bis (4-bromobenzoate) and

9-Deoxy-6,9-epoxy-A5-PGFia methyl ester-1,15-bis (4-bromobenzoate).

A. A mixture of 0.4494 g of the iodine compound I according to Example 1 in 5 ml of pyridine, which is cooled in an ice bath, is treated with 0.657 g of 4-bromobenzoychloride with stirring. Then the mixture is left to stand for 16 hours and then poured into cold 10% sulfuric acid, whereupon it is extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated. The residue is subjected to silica gel chromatography, giving 0.70 g of the 5-iodine compound as the title as a colorless oil; NMR peaks at 7.3-8.0.5.65.3.8-5.5, 3.65 and 0.9 ô.

B. 0.20 g of the product according to Part A are treated with 0.4 ml of l, 5-diazabicyclo [4.3.0] nonen-5 in 15 ml of benzene at 42 ° C. for 22 hours. The reaction mixture is cooled, washed with ice water, dried and concentrated to give 0.18 g of the second title compound as an oil.

The preparation is repeated with 0.50 g of the iodine compound, 1 ml of 1, 5-diazabicyclo [4.3.0] nonen-5 and 25 ml of benzene.

The combined products are chromatographically separated on a Florisil column pretreated with hexane / ethyl acetate / triethylenamine (90: 10: 1) while eluting with hexane / ethyl acetate / triethylamine (90: 10: 0.25), giving 0.37 g of the times title compound as a colorless oil; NMR peaks at 7.2-7.8.5.6.4.9-5.4.6.4.0.3.6 and 0.9 Ô.

Example 10

Preparation of 9-deoxy-6,9-epoxy-A5-PGFia, sodium salt.

The compound mentioned in the title is the sodium salt of the acid of structure VI below

£ «CK '? * \

CH2-CH2-CH2-COOH

(VI)

X / H C «G

H'- "N ;-( CHa) 4-CHô y.s

H VQH

This sodium salt was obtained in the form of a white, free-flowing powder.

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).

If the procedures of Examples 1, 2, 3, 5 and 7 are repeated, but with appropriate starting materials as described above, the compounds of the formulas I, II, III and IV in question are obtained, namely

9-deoxy-6,9-epoxy-5-iodine-PGFia-,

632245

24th

9-Deoxy-6,9-epoxy-A5-PGFia-9-deoxy-6,9-epoxy-6-hydroxy-PGFia - and 9-deoxy-6,9-epoxy-6-keto-PGFi-like compounds as Methyl ester, where Ri = -COOCH3, with the following features:

16-methyl,

16,16-dimethyl,

16-fluorine,

16,16-difluoro,

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

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

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

17- (m-chlorophenyl) -18,19,20-trinor-13,14-didehydro-, 17- (p-fluorophenyl) -18,19,20-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-phenyI-l 8,19,20-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 -18,19,20-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-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro-,

17- (m-chlorophenyl) -18,19,20-trinor-l 3,14-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-13,14-dihydro-, 16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

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-difluoro-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-, 5 2,2-difluoro-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-16-fluoro-17-phenyl-18,19,20-trinor-, 2,2-difluoro-16,16-difluoro-17-phenyl-18,19,20-trinor-, 10 2 , 2-difluoro-16-phenoxy-17,18,19,20-tetranor-, 2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-,

2,2-difluoro-16- (m-chlorophenoxy) -17,18,19,20-tetranor-, 2,2-difluoro-16- (p-fluorophenoxy) -17,18,19,20-tetranor-, 15 2,2-difluoro-l 6-phenoxy-18,19,20-trinor-, 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-, 2,2-difluoro- 16-methyl-16-phenoxy-l 8,19,20-trinor-, 2,2-difluoro-16-methyl-13,14-didehydro-, 2,2-difluoro-16,16-dimethyl-13,14 -didehydro-, 20 2,2-difluoro-16-fluoro-13,14-didehydro-, 2,2-difluoro-16,16-difluoro-l 3,14-didehydro-,

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-, 25 2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dide-hydro-,

2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dide-hydro-,

2,2-difluoro-16-methyl-17-phenyl-18,19,20-trinor-13,14-dide-30 hydro-,

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-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-dide-35 hydro,

2,2-difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-didehydro-,

2,2-difluoro-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor- 13,14-didehydro-, 40 2,2-difluoro-16- (m-chlorophenoxy) -17,18, 19.20-tetranor-13.14-didehydro-,

2,2-difluoro-l 6-phenoxy-18,19,20-trinor-13,14-didehydro-, 2,2-difluoro-16-methyl-16-phenoxy-18,19,20-trinor-13, 14-didehydro-,

45 2,2-difluoro-13,14-dihydro-,

2,2-difluoro-16-methyl-13,14-dihydro-, 2,2-difluoro-16,16-dimethyl-13,14-dihydro-, 2,2,16-trifluoro-13,14-dihydro- , 2,2,16,16-tetrafluoro-13,14-dihydro-, so 2,2-difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 2,2-difluoro- 17- (m-trifluoromethylphenyl) -18,19,20-trinor-13,14-dihydro-,

2,2-difluoro-17- (m-chlorophenyl) -18,19,20-trinor-13,14-dihydro-,

55 2,2-difluoro-17- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro-,

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

2,2-difluoro-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-60 dihydro-,

2,2,16-trifluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-, 2,2,16,16-tetrafluoro-17-phenyl-18,19,20-trinor-l 3,14-dihydro,

6S 2,2-difluoro-l 6-phenoxy-17,18,19,20-tetranor-13,14-dihydro-,

2,2-difluoro-l 6- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13,14-dihydro-,

25th

632245

2,2-difluoro-16- (m-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-,

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-,

16,16-difluoro-cis-13-,

17-phenyl-l 8,19,20-trinor-cis-l 3-,

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

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

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

16-methyl-17-phenyl-18,19,20-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) -l 7,18,19,20-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-difluoro-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 -l 3, 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-fluoro-l 7-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-tetranor-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-l 6-phenoxy-18,19,20-trinor-cis-13-, 2,2-difluoro-16-methyl-16-phenoxy-l 8,19,20-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-phenyl-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-difluoro-17-phenyl-18,19,20-trinor-,

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

3-oxa-l 6- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-,

3-oxa-l 6- (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-l 6-methyl-13,14-didehydro-, 3-oxa-16,16-dimethyl-13,14-didehydro-, s 3-oxa-16-fluoro-13,14-didehydro-, 3 -Oxa-16,16-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-,

io 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-didehydro-,

3-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dide-15 hydro-,

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-, 2o 3-oxa-16- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-13, 14-didehydro-,

3-oxa-l 6- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-didehydro-,

3-oxa-16-phenoxy-18,19,20-trinor-13,14-didehydro-, 25 3-oxa-16-methyl-16-phenoxy-18,19,20-trinor-13,14-dide- hydro,

3-oxa-13,14-dihydro-,

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

3-oxa-l 6,16-dimethyl-13,14-dihydro-,

30 3-oxa-l 6-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-trifluoromethylpheny 1) -18,19,20-trinor-13,14-dihydro-,

35 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-,

4o 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-dihydro-,

3-oxa-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-, 3-oxa-l 6- (m-trifluoromethylphenoxy) -17,18,19,20-tetranor-45 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-dihydro-,

so 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-,

ss 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-l 7- (m-trifluoromethylphenyl) -18,19,20-trinor-cis-13-, 60 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-, 65 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-,

632 245

26

3-oxa-16- (m-chlorophenoxy) -17,18,19,2.0-tetranor-cis-l 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-,

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

3-oxa-l 6-methyl-13,14-dihydro-trans-14,15-didehydro-,

3-oxa-16,16-dimethyl-13,14-dihydro-trns-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-trns-14,15-

didehydro,

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

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

3-oxa-l 7- (p-fluorophenyl) -18,19,20-trinor-13,14-dihydro-trans- 14,15-didehydro-,

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

3-oxa-16,16-dimethyl-17-phenyl-18,19,20-trinor-13,14-dihydro-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-dihydro-trns-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-l 6- (m-chlorophenoxy) -17,18,19,20-tetranor-13,14-

dihydro-trans-14,15-didehydro-,

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

dihydro-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-.

Likewise, the compounds of the formulas I, II, III and IV, namely, are obtained by the processes of Examples 1, 2, 3, 5 and 7, but using appropriate starting materials as described above

9-deoxy-6,9-epoxy-5-iodine-PGFia, 9-deoxy-6,9-epoxy-A5-PGFia, 9-deoxy-6,9-epoxy-6-hydroxy-PGFia and 9 -Deoxy-6,9-epoxy-6-keto-PGFia-like compounds as methyl esters, where Ri = -COOCH3, with the following features:

2,3-didehydro-

2,2-dimethyl,

2a, 2b-dihomo,

4-oxa-4a-homo-,

7a homo,

11 -deoxy-10,11 -didehydro-,

llß-,

11-keto,

11-deoxy,

11 -deoxy-11 -methylene-,

11 -deoxy-11-hydroxymethyl-,

15ß-,

15-keto,

15-deoxy,

15-methyl-15 (S) -,

15-methyl-15 (R) - and

17,18-didehydro-,

I. 2-Decarboxy-2-aminomethyl PGF Compounds Scheme C shows the steps for the preparation of the starting compounds XIII of Scheme A, wherein Ri is -CH2N (Rs>) 2. According to Scheme C, the PGF2a or 11-deoxy-5 PGF2a-like free acid of the formula CI is converted into the various 2-decarboxy-2-aminomethyl- or 2-decarboxy-2- (substituted-iert-amino) -methyl-PGFa - or -11-deoxy-PGFa compounds of the formulas CIV, CVI, CVII, CVIII, CIX or CX.

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Scheme C

HO

HO \

/

re

Hq

HO.

CHs-Zi-COOH

CI

I.

Y, -C-C-Rt

Ii H

Wed L1

0 0

II H

^ CHa-Zx-C-O-C-Ri

Yi-C-C-Ry

II II

Mi Li

CI I

I.

0

NH;

V ^

J Yi-C-C-RT

rfe II II

Mi Li

Cll I

\ '

CH2-Zi-cH2NH2

CIV

/ Y 1 -C —C -R7 Re II II

Mi L,

HCï n 00

CH2-Zi-C-N = N = N

YI-C-C-R7

II. H

Re Mi Li

CV

27

632245

Scheme C (continued)

1

\ CH2-Zi-NH-COOR!

i-C— C-R7 II II

1

re

Mi Li

!

HO

Y, -C-C-Rt

II II Li Mi

I.

HO.

^ CH2-Zi-NL2COORi

Yi-C -C-RT

II M

Rs Mi Li

HO

I.

/

Ra

^ CH2-Zi ~ NL2L3

Mi L

Following the procedure of Scheme C, the compound of Formula CI is first converted to a mixed anhydride of Formula CII. Such mixed anhydrides are expediently prepared from the corresponding chloroform-5-alkyl-, -aralkyl-, -phenyl- or -substituted-phenyl) ester in the presence of an organic base (e.g. triethyl-C VI amine). The reaction diluents include water together with water-miscible organic solvents (e.g. tetrahydrofuran). The mixed anhydride is then converted to either the amide of the formula CHI or the azide of the formula CV.

To produce the PGF2-like amide CHI, the mixed anhydride CII is reacted with liquid ammonia or ammonium hydroxide.

15 The compound of formula CIII is also obtained if the free acid is treated by known methods for converting carboxylic acids into carboxamides. For example, the free acid is converted into the methyl ester (using known methods, for example excess ethereal diazomethane), whereupon the methyl ester is converted into the amide CIII using CVI I methods which are based on the example of the conversion of the mixed anhydride CII be described in the amide of formula CIII. The 2-decarboxy-2-aminomethyl-PGF2a or -11-deoxy-25 PGF2a-like compound is obtained from the compound CIII by carbonyl reduction. Known methods are used for this purpose, for example reaction with lithium aluminum hydride.

The azide 30 CV can also be prepared from the compound of the formula CII. This reaction is conveniently carried out in a known manner with sodium azide, see e.g. B. Fieser and Fieser, Reagents for Organic Synthesis Vol. 1, pp. 1041-1043, where reagents and reaction conditions for azide formation are described.

35 The urethane of the formula CVI is formed from the azide CV by VIII reaction with an alkanol, aralkanol, phenol or substituted phenol. If methanol is used, a compound of the formula CVI is obtained in which Ri is methyl. From this PG-like product CVI, either the product CVII or CVIII is then produced. Known methods are used to produce the primary amine of the formula CVII from the urethane CVI. For example, the urethane CVI is treated with a strong base at temperatures above 50 ° C, about 45 sodium, potassium or lithium hydroxide can be used.

The compound of formula CVI can also be used to prepare compound CVIII. If L2 is an alkyl-CIX radical, the compound of the formula CVIII is formed by reducing the urethane CVI, in which Ri is alkyl. Lithium aluminum hydride is suitable as a reducing agent for this purpose.

The product of the formula CVIII is used to prepare the urethane CIX, the secondary amine CVIII (L2 55 meaning alkyl) being reacted with an alkyl chloroformate. The reaction proceeds according to known methods for the production of carbamates from corresponding secondary amines. Finally, the product of the formula CX, in which L2 and L3 both mean alkyl, is obtained by reducing the carbamide CIX. The methods described above for the preparation of the CIN compound CVIII from the compound CVI are used. If necessary, the various reaction stages can be preceded by the use of Rio protective groups, which later have to be hydrolyzed to produce the various products mentioned above. The methods described above for the introduction and hydrolysis of Rio protective groups are used.

632245

28

The processes described above for converting compounds of the formula CII into compounds CV and the compounds which follow them lead to the (3)

the 8a side chain of the compound CI around a carbon atom. The starting material CI should therefore be selected so that the methylene group which is consumed in the above synthesis steps is compensated for. Is z. If a 2a homo product is desired, a corresponding 2a, 2b dihomo starting material of the formula CI must be used.

In scheme C, Yi means trans-CH = CH-, -C = C- or -CH2CH2-,

Wed

/ \ 15

(T).

. ■

where m is a number from 1 to 5, T, chlorine, fluorine, the trifluoromethyl radical, an alkyl radical with 1 to 3 carbon atoms or alkoxy radical with 1 to 3 carbon atoms and s is the number 0, 1, 2 or 3, where the individual T 10 radicals can be the same or different, provided that no more than 2 T radicals are different from alkyl and under the further proviso that R7 only then

Rs OH or

/ \

Rs OH

where Rs is hydrogen or methyl, Li

R.3 R4, R.3 R.4,

or a mixture of

R3 iti and R.3 R4,

where R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, with the proviso that one radical R3 or R4 is fluorine only if the other is hydrogen or fluorine,

Room

(1) cis-CH = CH-CH2- (CH2) g-CH2-,

(2) cis-CH = CH-CH2- (CH2) g-CF2-,

(3) cis-CH2-CH = CH- (CH2) g-CH2-

(4) - (CH2) 3- (CH2) g-CH2-,

(5) - (CH2) 3- (CH2) g-CF2-,

(6) -CH2-0-CH2- (CH2) g-CH2-,

(7) -C = C-CH2- (CH2) g-CH2-,

(8) -CH2-C = C- (CH2) g-CH2-,

_ JT>,

20th

25th

means when R3 and R4, which may be the same or different, are hydrogen or methyl, and Xi is a radical -CH2NL2L3, where L2 and L3 are hydrogen, alkyl radicals having 1 to 4 carbon atoms or -COORi, where Ri has the meaning given above.

(9)

ch2- (ch2) -

9

o- (ch2) -,

9

where g is the number 1, 2 or 3, Rt

(1) - (CH2) m-CH3,

~ oT '

(2)

Example IA

2-decarboxy-2-azidomethyl-PGF2a or 2-nor-PGF2a-azide (formula CV: Zi = -CH = CH- (CH2) 3 or CH = CH- (CH2) 2, 30 Rs = hydroxy, Yi = trans -CH = CH-, R3 and R4 of Li and Rs of Mi = hydrogen, R7 = n-butyl).

A. 3.01 g of isobutyl chloroformate are added to a cold (0 ° C.) solution of 7.1 g of PGF2a, 125 ml of acetone, 10 ml of water and 2.2 g of triethylamine with stirring.

The mixture is stirred at 0 ° C. for about 30 minutes, then a cold solution of 7 g of sodium azide in 35 ml of water is added. The mixture is stirred for 1 hour at 0 ° C and then diluted with 300 ml of water and extracted with diethyl ether. The organic extracts are combined, washed with water, dilute carbonate solution and saturated sodium chloride solution, dried and concentrated under reduced pressure and a water bath temperature below 30 ° C., giving the 2-nor-PGF2a azide.

B. 2-Decarboxy-2-azidomethyl-PGF2a is obtained in the following 45 reaction sequence: (1) A solution of 10 g of t-butyldi

methylsilyl chloride, 9.14 g imidazole and 3 g PGF2a in 12 ml dimethylformamide is magnetically stirred in a nitrogen atmosphere for 24 hours. The resulting mixture is then cooled in or an ice bath and the reaction is terminated by adding 50 ice water. Then the mixture is diluted with 150 ml of water and extracted with diethyl ether. The combined ether extracts are washed with water, saturated ammonium chloride solution and sodium chloride solution and then dried over sodium sulfate. The 55 solvent is removed in vacuo, giving the PGF2a-t-butyldimethylsilyl ester-9, l, l, 15-tris (t-butyldimethylsilyl ether); NMR absorptions at 0.20, 0.30, 0.83, 0.87, 0.89, 17, 27, 50, 3, 3, 4.21 and 5.385. Characteristic infrared absorptions at 970,1000,1250,1355,1460,1720 60 and 2950 cm-1.

(2) 8.71 g of the reaction product according to part (1) in 40 ml of diethyl ether 65 are added dropwise to a magnetically stirred suspension of 7.75 g of lithium aluminum hydride in 18 ml of diethyl ether over the course of 12 minutes at room temperature. After stirring for one hour at room temperature, the resulting product is cooled in an ice water bath, then saturated sodium sulfate solution is added dropwise until a milky suspension is formed. The result

29

632245

Rende product is coagulated with sodium sulfate and triturated with diethyl ether, the solvent is suctioned off.

When the diethyl ether is concentrated in vacuo, 7.014 g of 2-decarboxy-2-hydroxymethyl-PGF2a-9,11,15-tris (t-butyl-dimethylsilyl ether) are obtained, NMR absorptions at 0.03, 5 0.82.0 , 87.1.10-2.60.3.30-4.30 and 5.378. Characteristic IR absorptions at 775,840,970,1065,1250,1460,2895, 2995 and 3350 cm-1.

(3) 3.514 g of p-toluenesulfonyl chloride, 44 ml of pyridine and 7.014 g of the reaction product according to part (2) are left in the freezer at -20 ° C. for 3 days. This gives 7.200 g of 2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF2a-

9.1 l, 15-tris (t-butyldimethylsilyl ether), NMR absorptions at 0.10.0.94.0.97.1.10.2.50.4.03.3.80-4.80 , 5,45,7,35 and 7,88; IR absorptions at 775,970,1180,1190,1250,1360,, s 1470,2900 and 2995 cm-1.

(4) 2.13 g of the reaction product according to part (3) are added to 42 ml of a mixture of acetic acid, tetrahydrofuran and water (3: 1: 1) containing 0.25 ml of 10% aqueous hydrochloric acid. After stirring vigorously for 16 hours at room temperature, the reaction mixture becomes homogeneous. The resulting solution is then diluted with 500 ml of ethyl acetate, washed with saturated sodium chloride solution and ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to obtain 1.301 g of an oil. The crude product is chromatographed on 150 g of silica gel packed with ethyl acetate. Elution with ethyl acetate gives 0.953 g of 2-decarboxy-2-p-toluenesulfonyloxymethyl-PGF20.

(5) 0.500 g of the reaction product according to part (4) in 5.0 ml of 30 dimethylformamide are added with stirring to a suspension of 1.5 g of sodium azide in 20 ml of dimethylformamide. The mixture is stirred at room temperature for 3 hours, then the reaction mixture is diluted with 75 ml of water and extracted with 500 ml of diethyl ether. The ether extracts are washed successively with water and saturated sodium chloride solution and dried over sodium sulfate. After removal of the diethyl ether under reduced pressure, 0.364 g of 2-decarboxy-2-azidomethyl-PGF2 <x. A characteristic azido infrared absorption is observed at 2110cm_1.

Example 2A

2-Decarboxy-2-aminomethyl-PGF2a (formula CVII: Zi = cis-CH = CH- (CH2) 3-, Rs = hydroxy, Yi = trans-CH = CH-R3 and R4 of Li and Rs of Mi = hydrogen , R? =

n-butyl).

0.364 g of crude 2-decarboxy-2-azidomethyl-PGF2 "(see Example 1A) in 12 ml of diethyl ether are added to a magnetically stirred suspension of 0.380 lithium aluminum hydride in 20 ml of diethyl ether. The reaction temperature is kept at about 0 ° C., the lithium aluminum hydride is added dropwise over the course of 4 minutes. When the addition is complete, the resulting mixture is stirred at room temperature for 1 Vi hours and then placed in an ice bath (0 to 5 ° C). Excess reducing agent is destroyed with 55 saturated sodium sulfate solution. After the evolution of gas has ended, the resulting product is coagulated with sodium sulfate and triturated with diethyl ether, and the solid salts are filtered off. The filtrate is dried over sodium sulfate and concentrated under reduced pressure to give 0.304 g of a light yellow oil. This oil (100 mg) is then purified by preparative thin layer chromatography to give 42 mg of the title compound; NMR absorptions at 0.90.1.10-2.80, 3.28.3.65-4.25 and 5.458; characteristic infrared absorption 6s at 970,1060, 1460,2995 and 3400 cm-1. The mass spectrum shows a parent peak at 699.4786 and further peaks at 628.684.595.217 and 274.

40

45

II. 1,15-lactones of the compounds of the formulas I, II, III and. IV: The production of a 1,9-, 1,11- or 1,15-lactone is naturally relatively uncomplicated if the 9-, 11- or 15-hydroxyl group is the only free hydroxyl group with which the carboxyl function can form a lactone . If there is more than one hydroxyl group, e.g. in PGF2 «, derivatives may be formed beforehand with the hydroxyl groups not required for lactone formation. Selective methods for the formation of derivatives with all but one hydroxyl group of a prostaglandin or prostaglandin analogs which contain two or more hydroxyl groups are known. Suitable derivatives are the cyclic 9,11 -phenyl or butylboronates of 9a, 11a or 9β, 11β-dihydroxy prostaglandins and prostaglan din analogues, acylates such as acetate, silyl ethers such as tri-methylsilyl, t-butyldimethylsilyl and triphenylsilyl ether and the like. These functional derivatives are known in prostaglandin chemistry, they are used stereoselectively or, if this is not possible, with careful purification of the product mixture, whereby the desired prostaglandins and prostaglandin analogs with a protected function are obtained. If necessary, one or more hydroxyl groups are protected from lactone formation by oxidation to the ketone. After lactone formation, the ketone is reduced again to give the free hydroxyl group of the same configuration or reverse configuration as in the original compound.

It is not essential in all cases that hydroxyl groups which are present but which should not participate in the formation of lactones are protected. Lactone formation occurs at different rates with the different hydroxyl groups, depending on the stereochemistry, steric hindrances in the vicinity of the hydroxyl groups and the ring size. It is also possible to separate 1,9-, 1,11- and 1,15-lactones from one another, as described below using the example of PGF2a-l, 9-, 1.11 and 1,15-lactones. For example, the 15-methyl-15-hydroxy and 16,16-dimethyl-15-hydroxy-prostaglandin analogues in the vicinity of the C-15 are sterically hindered and the lactone formation with the hydroxyl group at the C-15 therefore does not compete with the lactone formation with the 9- or 11-hydroxyl groups. To produce a lactone with a hindered hydroxyl group such as e.g. In 15-methyl-15-hydroxy or 16,16-dimethyl-15-hydroxy compounds, any other hydroxyl groups must therefore be protected. Furthermore, the reaction time must be extended until an analysis of the reaction mixture indicates the presence of the desired product.

Prostaglandins, which are known as lower alkyl esters (e.g. methyl or ethyl esters), but not in free acid form, can be converted into the free acids in a known manner by chemical hydrolysis for the formation of lactones. Is the prostaglandin not resistant to chemical hydrolysis, e.g. the PGE2 methyl ester, PGD2 methyl ester or the like, the free acid is preferably produced by enzymatic hydrolysis, for example by the process of US Pat. No. 3,776,1356.

Under these restrictions and with the possible protection of simultaneously present hydroxyl groups, selective hydrolysis of the protected hydroxyl groups without hydrolysis of the desired lactone, separation of undesired products from the desired products and modification of the lactones by subsequent known processes such as oxidation, reduction, alkylation and the like, it is possible to do so To produce 1,9-, 1,11- and 1,15-lactones of prostaglandins and prostaglandin analogues of biological importance.

The preferred method for lactone formation between the

632245

Carboxyl group and the 9-, 11- or 15-hydroxyl group is: the method of Corey et al., J. Am. Chem. Soc. 96.5614 1974), p. a. Corey et al., J. Am. Chem. Soc. 97, 653 (1975), which is shown below in examples. Other methods can also be used, e.g. the methods of Masamure et al., J. Am. Chem. Soc. 97, 3515 (1975) and Gerloch et al., Helv. Chem. Acta 57, 2661 (1974). The 1,15-lactones of the compounds I, II, III and IV are prepared analogously to the above method and the following examples:

In the following examples, the infrared absorption spectra were measured with a Perkin-Elmer Model 421 spectrophotometer in Nojull. The NMR spectra were measured with a Varian A-60 spectrophotometer in Deutorochloroform solution with tetramethylsilane as the internal standard.

Example 1B

PGF2a-l, 15-lactone

A solution of 5.5 g of PGF2 and 1.79 g of 1-butane boronic acid in 150 ml of methylene chloride is heated under reflux for 15 minutes. Then about half of the methylene chloride is distilled off at normal pressure. The volume is brought back to 150 ml with fresh methylene chloride. This de-distillation of methylene chloride, followed by the addition of fresh methylene chloride, is repeated three times, after which all the solvent is removed in vacuo. The 9.11 cyclic boronate of PGF2a is obtained as a residue.

The residue is dissolved in 180 ml of anhydrous, oxygen-free xylene and treated with 5.128 g of 2,2'-dipyridyl disulfide and then with 6.27 g of triphenylphosphine. After 18 hours at 25 ° C. in a nitrogen atmosphere, thin-layer chromatographic analysis (solvent acetic acid / methanol / chloroform 10:10:80) shows complete conversion to the pyridine thiol ester.

The xylene solution is diluted with 300 ml of oxygen-free xylene and added dropwise over a period of 10 hours to 3.2 g of vigorously stirred xylene which refluxes in a nitrogen atmosphere. When the addition is complete, 100 ml of xylene are distilled off and the solution is heated under reflux for 24 hours. The reaction mixture is then cooled and the xylene is removed in vacuo (bath temperature 35 ° C.), a residue being obtained. This is taken up in 500 ml of tetrahydrofuran and mixed with 10 ml of 30% hydrogen peroxide and 100 ml of saturated aqueous sodium bicarbonate solution. The three-phase mixture is stirred vigorously at 25 ° C. for 30 minutes and then concentrated in vacuo to a residue. The residue is taken up in saturated sodium chloride solution / ethyl acetate and extracted carefully with ethyl acetate. The combined organic phases are washed three times with 1N aqueous potassium bisulfate solution and once with water, aqueous sodium bicarbonate solution and saturated sodium chloride solution. After drying over sodium sulfate, the solvent is removed, giving a viscous yellow oil which is chromatographed on 500 g of silica washed with acid (Mallinckrodt CC-4). The column is packed with 25% ethyl acetate / hexane and eluted with 100 ml fractions from 50% ethyl acetate / hexane. Fractions 26 to 40 containing the product and no prostaglandin-like impurities are pooled. The product is crystallized from 40 ml of ether / hexane (1: 1), the pure lactone having a melting point of 110 to 111 ° C. is obtained.

The lactone shows IR absorption at 3500.3370.3290, 3010.1700.1320, 1310, 1290, 1260, 1105, 1080, 1055, 970 and 730 cm-1 and NMR peaks at 6.00-5.75 (Vinyl; multiplet, 2H), 5.75-4.95 (vinyl and C-15H; multiplet, 3H), 4.30-3.85 (CHOH; multiplet, 2H) and 2.65 ppm (OH; broad Singlet moved downfield when cooling, 2H). The mass spectrum of the bis-trimethylsilyl derivative shows fragments at 480 (M +), 465 (M-CHÎ), 436 (M-CO2), 409 (M-CsHn), 390.380, 364.328.217.

Analysis: C20H32O4

Calc .: C: 71.39; H: 9.59 Found: C: 70.73; H: 9.31.

If the ether / hexane mixture is replaced by ethyl acetate / hexane during recrystallization, PGF2a-l, 15-lactone of mp 110.0-111.7 ° C., [-a-gt0H -71 ° is obtained.

Example 2B

17-phenyl-l 8,19,20-trinor-PGF2a-l, 15-lactone

A solution of 776 mg of 17-phenyl-18,19,20-trinor-PGF2a and 225 mg of 1-butane boronic acid in 25 ml of methylene chloride is heated under reflux. After 15 minutes, the methylene chloride is slowly distilled off. As soon as the volume has reached approximately half of the initial volume, fresh methylene chloride is added. After 90 minutes, all methylene chloride is removed in vacuo to give the cyclic boronate of the starting prostaglandin.

The boronate is dissolved in 5 ml of anhydrous, oxygen-free xylene and 660 mg of 2,2'-dipyridyl disulfide and 786 mg of triphenylphosphine are added. After 4 hours at 25 ° C., the reaction mixture is diluted with 500 ml of anhydrous, oxygen-free xylene and heated under reflux for 18 hours. The xylene is then removed in vacuo to give a residue. This is dissolved in 50 ml of methylene chloride, which contains 1 ml (11.6 millimoles) of 30% aqueous hydrogen peroxide, and treated at 25 ° C. with a solution of 1.68 g of sodium bicarbonate in 10 ml of water. The mixture is stirred vigorously for 30 minutes and then concentrated to dryness under reduced pressure. The residue is taken up in saturated sodium chloride solution / ethyl acetate and extracted carefully with ethyl acetate. The combined extracts are washed with aqueous sodium bisulfate solution, water, aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and then to a residue from crude 17-phenyl-18,19,20-trinor-PGF2a-1,15-lactone constricted.

The crude lactone is purified by chromatography on 400 g of neutral silica packed with ethyl acetate, eluting with 22 ml fractions from ethyl acetate. The fractions containing the product according to the thin-layer chromatogram are combined, giving the purified 17-phenyl-18,19,20-trinor-PGF2a-1,15-lactone. The lactone crystallizes on trituration and, after recrystallization twice from ethyl acetate / hexane, has a melting point of 116 to 117 ° C.

The infrared spectrum shows peaks at 3460.3400 Sch, 3020.1705.1650.1605.1495.1325.1300.1265.1150.1100, 1040.1020.1000.970 and 700 cm-1. The mass spectrum shows fragments at m / e 370 (M-18), 352,334,308,298,261, 243,225 (no M + peak recognizable).

Analysis: C23H30O4

Calc .: C: 74.56; H: 8.16 Found: C: 74.27; H: 7.97.

Example 3B

17-phenyl-18,19,20-trinor-PGE2-1,15-lactone

A solution of 735 mg 17-phenyl-18,19,20-trinor-PGE2,

30th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

31

632 245

628 mg of 2,2'-dipyridyl disulfide and 748 mg of triphenylphosphine in 10 ml of anhydrous, oxygen-free xylene are stirred at 25 ° C. in nitrogen for 2 hours. The mixture is then diluted with 400 ml of anhydrous, oxygen-free xylene, refluxed for 2½ hours and concentrated to dryness in vacuo at 30 ° C. The residue is chromatographed on 100 g of neutral silica, which is packed with 80% ether / hexane and eluted with 8 ml fractions from 80% ether / hexane. The fractions containing homogeneous product according to the thin-layer chromatogram are combined and give purified 17-phenyl-18,19,20-trinor-PGE2-1,15-lactone. After recrystallization from ether / hexane twice, the pure product of melting point 81 to 83 ° C. is obtained; IR peaks at 3440,3000, 1725,1605, 1500, 1330,1240, 1160, 1145, 1085, 1045,975,745,725 and 700 cm "'. The mass spectrum shows fragments at m / e 368 (M-18), 350,332, 297,296,277,264,259,241 (no M + recognizable).

Example 4B

16-phenoxy-17,18,19,20-tetranor-PGF2a-1,15-lactone

If the procedure of Example 1B is repeated, but replacing the PGF2a with 16-phenoxy-17,18,19,20-tetranor-PGF2a, a crude product of 16-phenoxy-17,18,19,20- is obtained. tetranor-PGF2a-1,15-lactone, which is a viscous yellow oil.

The crude product is purified by chromatography on neutral silica packed with 50% ethyl acetate / hexane, eluting with 50% ethyl acetate / hexane and then with 70% ethyl acetate / hexane. Those fractions which, according to the thin-layer chromatogram, contain homogeneous product are combined and give crystalline 16-phenoxy-17,18,19,20-tetranor-PGF2a-1,15-lactone. The lactone obtained in this way is recrystallized from ethyl acetate / hexane, giving pure product of mp 185 to 186 ° C. The mass spectrum of the trimethylsilyl derivative shows a peak for M + 516.2738 (theoretical value for C28H44SÌ2O5: 516.2727) and fragments at m / e 501,426,423, 409,400,333,307,217 and 181.

Example 5B

PGFia-1,15-lactone and 15-epi-PGFia-1,15-lactone

If the procedure of Example 1B is repeated, but replacing PGF2a by PGFia, the crude product obtained is a viscous yellow oil which contains PGFia-1,15-lactone.

The crude product is purified by chromatography on 700 g of neutral silica packed with 50% ethyl acetate / hexane while eluting with 50% ethyl acetate / hexane. The first two liters of the eluate are discarded, then 100 ml fractions are collected.

A 15-epi-PGFia-1,15-lactone [(15R) -PGF2a-l, 15-lactone], a product which was eluted first from the column in a smaller amount (fractions 14 to 19) and which was homogeneous according to the thin layer chromatogram, IR peaks at 3450, 1730, 1585, 1250, 1100,970 and 735 cm "1, NMR peaks (Stms 13) at 5.85-5.05 (vinyl and C-15; multiplet, 3H; 4.25 -3.85 (CHOH; multiplet, 2H) and 3.30 ppm (singlet), displacement downfield when the sample was cooled, OH; 2H).

The product later eluted from the column in fractions 21 to 28 gave pure PGFia-l, 15-lactone. The purified PGFia-1,15-lactone crystallizes after trituration with ether and is recrystallized from ethyl acetate / hexane, a pure sample having a melting point of 105 to 106 ° C. being obtained. The IR spectrum shows peaks at v max 3520.3480.3380.1710, 1300, 1290, 1265, 1250, 1235, 1160, 1110, 1075, 1055, 1000, and 965 cm- '; NMR peaks (5 $ g§13) at 6.0-5.75 (vinyl; multiplet, 2H), 5.60-5.00 (C-15H; multiplet, 1H), 4.25-3.80 (CHOH ; Multiplet, 2H) and 3.08 ppm (OH; singlet).

Example 6B

13,14-didehydro-8ß, 9ß, 11ß, 12a-PGF2a-1,15-lactone and 13,14-didehydro-PGF2a-1,15-lactone.

Repeating the procedure of Example 1B, but mk 13,14-di-dehydro-8ß, 9ß, 11ß, 12a-PGF2 "[also known as ent-13-dehydro-15-epi-prostaglandin F2a, compound 2 by J Fried and CH Lin, J. Med. Chem. 16,429 (1973)] and 13,14-didehydro-PGF2a instead of PGF2a, the title compounds are obtained.

Example 7B

13,14-Didehydro-8ß, 9ß, l 1ß, 12a-PGE2-1,15-lactone and 13,14-didehydro-PGE2-1,15-lactone.

The procedure of Example 2B is repeated, but with 13,14-didehydro-8β, 11β, 12a-PGE2 [also as ent-13-dehydro-15-epi-PGE2 (from 2a by J. Fried and CH Lin, J Med. Chem. 16,429 (1973)] and 13,14-didehydro-PGE2 instead of PGE2, the title compounds are obtained.

Example 8B

13,14-dihydro-PGF2a-1,15-lactone

If the procedure of Example 1B is repeated, but replacing the PGF2 "by 13,14-dihydro-PGF2", the title compound is obtained.

Example 9B

(15S) -15-methyl-PGF2a-1,15-lactone

If the procedure of Example 1B is repeated, but replacing the PGF2a with (15S) 15-methyl-PGF2a and extending the reaction time in refluxing xylene from 24 to 48 hours, the crude (15S) -15-methyl-PGF2a is obtained -l, 15-lactone. This crude lactone is purified by repeated chromatography and, if appropriate, by thin-layer chromatographic purification, the (15S) -15-methyl-PGF2a-1,15-lactone being obtained in virtually pure form in low yield.

Example 10B

16,16-dimethyl-PGF2a-1,15-lactone

If the procedure of Example 9B is repeated, but with 16,16-dimethyl-PGF2a instead of (15S) -15-methyl-PGF2a, the title compound is obtained.

Example IIB

Repeating the procedure of Example 4B with 16m trifluoromethylphenoxy-17,18,19,20-tetranor-PGF2a, 16m-chlorophenoxy-17,18,19,20-tetranor-PGF2a or 16-p-fluorine phenoxy-17,18,19,20-tetranor-PGF2a instead of 16-Phe-noxy-17,18,19,20-tetranor-PGF2a, the corresponding 1,15-lactones are obtained.

Example 12B

If the procedure of Example 2B is repeated, but with the PGE2 replaced by (16S) -16-methyl-, (16R) -16-methyl- and 16-methylene-PGE2, the relevant (16S) -16-methyl is obtained -, (16R) -16-methyl and 16-methylene-PGE2-1,15-lactones.

Example 13B 16,16-Dimethyl-PGE2-1,15-lactone If the procedure of Example 3 B is repeated, but with 16,16-dimethyl-PGF2a-1,15-lactone instead of PGF2a-1,15-lactone, the result is obtained one the title link.

Example 14B (15S) -15-Methyl-PGEî-1,15-lactone Repeating the procedure of Example 3 B, but with

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

632245

32

(15S) -15-Methyl-PGF2 <x-1,15-lactone instead of PGF2 «-1,15-lactone, the title compound is obtained.

Example 15B

11-Deoxy-PGE2-1,15-lactone

Repeating the procedure of Example 2B, but replacing the PGE2 with 11-deoxy-PGE2, the title compound is obtained.

If the PGE2 is replaced by 11-deoxy-PGEi, the 1 l-deoxy-PGEi-l, 15-lactone is obtained.

Example 16B

(15S) -11-deoxy-15-methyl-PGE2-1,15-lactone and 11-deoxy-16,16-dimethyl-PGE2-1,15-lactone.

Repeating the procedure of Example 2B, but replacing the PGE2 with (15S) 11-deoxy-15-methyl-PGE2 and 11-deoxy-16,16-dimethyl-PGE2 and extending the reflux time in xylene from 2 to 48 hours, so you get the relevant 1,15-lactones. The crude lactones are purified by repeated chromatography and, if necessary, by thin-layer chromatography, the (15S) -1 l-deoxy-15-methyl-PGE2-l, 15-lactone and 11-deoxy-16, 16-dimethyl-PGE2-1,15-lactone is obtained.

Example 17B 1 l-deoxy-PGF2 <xl, 15-lactone A solution of 0.5 g of 1 l-deoxy-PGE2-l, 15-lactone in 50 ml of methanol is treated at 0 ° C. with 500 mg of sodium borohydride is added in 50 mg portions at intervals of 2 minutes. Aqueous 1M sodium bisulfate solution is added until the mixture is acidic, then the product is isolated by extraction with ethyl acetate. The extract is washed, dried and concentrated to give a residue containing xo 11-deoxy-PGF2a-1,15-lactone. The residue is purified by chromatography on acid washed silica using 1% ethyl acetate / hexane to 40% ethyl acetate / hexane. Those fractions which are assessed as homogeneous according to the thin-layer chromatogram and by saponification to give the known 11-deoxy-PGF2ct are combined and give the 1 l-deoxy-PGF2a-l, 15-lactone in practically pure form.

Analogously, if 11-deoxy-PGE2-1.15-20 lactone is replaced by (15S) -1 l-deoxy-15-methyl-PGE2-l, 15-lactone, 11-deoxy-16.16-dimethyl- PGE2-1,15-lactone, PGE2-1,15-lactone, (15S) -15-methyl-PGE2-l, 15-lactone, 16,16-dimethyl-PGE2-1,15-lactone and PGEi-1, 15-lactone the 1,15-lactones of (15S) -1 l-deoxy-15-methyl-PGF2a, 11-deoxy-16,16-25 dimethyl-PGF2 <x, PGF2a, (15S) -15-methyl- PGF2a, 16,16-dimethyl-PGF2a and PGFia.

Claims (11)

632245 (1) trans-CH = CH- (1) a group of the formula î " ~ cgh2g -ch3 Re (1) a grouping of the formula -COOR3, in which R3 is a hydrogen atom, a pharmacologically acceptable 45 cation, an alkyl radical with 1-12 carbon atoms, a cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 carbon atoms, the phenyl radical, a phenyl radical with 1,2 or 3 chlorine atoms or alkyl groups 1-4 carbon atoms is substituted, a grouping of the following formulas: ch2or13 60 65 r 15 r îe (1) - (CH2) d-C (R2) 2- (1) trans-CH = CH- (1) a group of the formula I5 ' -C gHa g "CH3 R0 in which the grouping CsFhg 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, Rs and Rö are identical or different from one another and Are hydrogen atoms, alkyl radicals with 1-4 carbon atoms or fluorine atoms, provided that one of the radicals Rs and Rs is only a fluorine atom if the other of these two radicals is a hydrogen atom or also a fluorine atom, (1) - (CH2) d-C (R2> - (1) a grouping of the formula -COOR3, (1) trans-CH = CH- (1) a grouping of the formula -COOR3, in which R3 is a hydrogen atom, a pharmacologically acceptable cation, an alkyl radical with 1-12 carbon atoms, a 30 cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 carbon atoms, the phenyl radical, a phenyl radical with 1,2 or 3 chlorine atoms or alkyl groups 1-4 carbon atoms, a grouping of the following formulas: 35 0 0 CHa OR 13 is what R13 is a hydrogen atom, the tetrahydropyranyl radical, the tetrahydrofuranyl radical, the 1-ethoxyethyl radical, or a grouping of the formula HI - C-Rir Ri * -0-Ç Ri! R 13 / Vvi NH-C NH-C-CH3, 45 50 NH-C 0 NH-C-CH3, is in which R14 represents an alkyl radical with 1-18 carbon atoms, a cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 55 carbon atoms, the phenyl radical or a phenyl radical which is substituted with 1,2 or 3 alkyl radicals with 1-3 carbon atoms, Rts and Ri6 are identical to or different from one another and denote hydrogen atoms, alkyl radicals with 1-4 carbon atoms, phenyl radicals or phenyl radicals substituted with 1,2 or 3 alkyl radicals with 1 -4 carbon atoms, or R15 and Rift together form a grouping of the formula - Form (CH2) a- or - (CH2) b-0- (CH2) c-, in which a = 3, 4 or 5, b = 1, 2 or 3, and c = 1, 2 or 3, under «5 provided that b + c = 2, 3 or 4 and R17 represents a hydrogen atom or the phenyl radical, L is a residue of the formula 0 // \ N f / NX-CH = N-NH-C-NHa,. or (1) - (CH2) d-C (R2) 2- (2) cis-CH = CH-45 (3) -C = C- or (2) a grouping of the formula ] -z <y (T) s Re in which the radicals T are identical to or different from one another and mean alkyl radicals with 1-4 carbon atoms, 15 fluorine atoms, chlorine atoms, trifluoromethyl radicals or radicals of the formula -OR? -, in which R? is a hydrogen atom or an alkyl radical with 1-4 carbon atoms, s = 0 or an integer in the range from 1 to 3, provided that, however, no more than two of the radicals T 20 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 CjFhj, which has 1-9 carbon atoms, but with 1-6 carbon-25 atoms in the chain between the grouping of the formula CRäRs and the phenyl ring , and R5 and Rs have the same meanings as mentioned under (1), provided that, however, neither of the two radicals Rs and R «may be a fluorine atom if Z 30 is an oxygen atom; or 35 (2) the group of the formula -CH2OH; (2) -CH2-O-CH2-Y-or 20 (3) -CH2CH = CH- means in which d is 0 or an integer from 1 to 5, the residues R2 25 are identical to or different from one another and denote hydrogen atoms, methyl groups or fluorine atoms, provided that one radical R2 may not have the meaning of a methyl group if the other radical R2 is a fluorine atom, 30 Y is a direct bond or a group of the formula - (CH2) k-, where kl is or 2, Q one of the following groupings II / \ 35 O, H H, Rs ÖH, or / \ Rs OH is what Rs represents a hydrogen atom or an alkyl radical with 1-4 carbon atoms, 40 Ri represents one of the following radicals: (2) cis-CH = CH- (2) a grouping of the formula Î ' -c (T). "CH2- H" C = C ' iCHaCHa H (2) the group of the formula -CH2OH; (2) -CH2-O-CH2-Y- or 2. The method according to claim 1, characterized in that one carries out the iodination and cyclization in an aqueous medium which contains iodine, potassium iodide and an alkali metal carbonate or bicarbonate, or in an organic solvent system which contains iodine in the presence of an alkali metal carbonate. (2) cis-CH = CH- (2) a grouping of the formula ■ -Çs - U-Qr ( Rq in which the radicals T are identical to or different from one another and alkyl radicals with 1-4 carbon atoms, Are 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 from 1 to 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 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 Rö have the same meanings as mentioned under (1), provided that, however, none of the two residues Rs and R6 may be a fluorine atom if there is an oxygen atom; or (2) the group of the formula -CH2OH; (2) -CH2-O-CH2-Y- or 2nd PATENT CLAIMS 1. Process for the preparation of iodine compounds of the formula I (3) the grouping of the formula -ch2, ^ çh2ch3 c = c. h "h V represents a direct bond or a radical of the formula -CH2-, 40 W is a radical of the formula -CH2- or -CH2-CH2-, and X has one of the following meanings (3) a group of the formula -CH2N (R9) 2, where the residues Rs are identical to or different from one another and denote hydrogen atoms or alkyl radicals having 1-4 carbon atoms; or (3) the grouping of the formula 35 in which Di, L, Q, V, W, X and Ri and R4 have the same meaning as in formula II, produces, and this compound is reacted with a dehydroiodination reagent and converted into the enol ether of the formula II 4o. (3) -C = C- or (3) a group of the formula -CH2N (R9) 2, where the residues R9 are identical to or different from one another and denote hydrogen atoms or alkyl radicals having 1-4 carbon atoms; or (3) -CH2CH = CH- means in which d is 0 or an integer from 1 to 5, the residues R2 are identical to or different from one another and denote hydrogen atoms, methyl groups or fluorine atoms, provided that one radical R2 may 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 45 50 55 for 11 -V N> CH = N- NH-C-NHa, .or is, or a group of the formula 60 65 ■ CH-C-R10 \ Rh means what Rio is a phenyl, p-bromophenyl, p-biphenyl, p-nitro-phenyl, p-benzamidophenyl or a 2-naphthyl radical, 3. The method according to claim 1, characterized in that the corresponding ice compound of the formula s. As the starting material of the formula XIII (3) -C = C- or (3) the grouping of the formula "ch2. ^ ^ ch2ch3 c = 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) a group of the formula -CH2N (R9> 2, where the residues R9 are identical to or different from one another and denote hydrogen atoms or alkyl radicals having 1-4 carbon atoms; or 3rd 632245 is, or a group of formula 0 II -CH-C-Rio i Rh means what Rio is a phenyl, p-bromophenyl, p-biphenyl, p-nitro-phenyl, p-benzamidophenyl or a 2-naphthyl radical, and Ri l is a hydrogen atom or a benzoyl radical, (3) -CH2CH = CH- V-O-C-CH-L-Rx / / (I) means in which d is 0 or an integer from n 1 to 5, the residues R2 are identical to or different from one another and represent 10 hydrogen atoms, methyl groups or fluorine atoms, provided that one radical R2 may 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 15 - (CH2) k-, where k is 1 or 2, Q one of the following groupings in which D is a radical of the formula 20th or Is O, H H, Rs OH, or Rs OH, wherein Rs represents a hydrogen atom or an alkyl radical with 1-4 carbon atoms, Ri represents one of the following: 25th (4) -CH2CH2-, having, characterized in that according to method 50 according to claim 1, the iodine compound of formula I. 55 y-0-C-CH-L-R, «0 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, Rs and Rs are identical or different from one another and Are hydrogen atoms, alkyl radicals with 1-4 carbon atoms or fluorine atoms, provided that one of the radicals Rs and Rs is only a fluorine atom, 65 in which D, L, Q, V, W, X as well as Ri and R4 have the same meaning 632245 (4) the group of the formula , NH-N -.v II SN — N R4 means one of the following groupings: -c (4) -CH2CH2-, having, characterized in that an iodine compound of the formula Ia 20th 25th 30th I. ^ -O-C-CH-L-Ri A "W (Ia) e 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 from 1 to 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 Cjfhj, which has 1-9 carbon atoms, but 1-6 carbon atoms must be present in the chain between the grouping of the formula CRsRs and the phenyl ring , and Rs and Rö have the same meanings as mentioned under (1), provided that, however, neither Rs and Rö may be a fluorine atom if Z is an oxygen atom; or (4) the group of the formula / NH-N II SN — N R4 means one of the following groups: 4. Process for the preparation of enol ethers of the formula carbon atoms is substituted, a grouping of the following I. , 0-C = CH (II) formulas: 20th ■ CHO 25th 30th 0 0 II / = \ II NH-C-CH3, in which Di is a grouping of the formula * x '\ ✓ oA 35 40 II ^ ^ -NH-C-NH2 a'.cc or cfHaOH is Linen rest of the formula 4th II /% / \ O, H H, L - R, used. Rs OH, or Rs OH is where s Rs represents a hydrogen atom or an alkyl radical having 1-4 carbon atoms, Rt is one of the following: (4) -CH2CH2-, having, characterized in that a compound of formula XIII ho I. .V W-CH = CH-L-R X-C-R in which D, L, Q, Ri, R4, V, W and X have the same meaning as in formula I, subject to iodination and cyclization to form the iodine compound of the formula I. (4) the group of the formula R4 means one of the following groupings: (1) a group of the formula - <j) -CgH2g "CH3 Re in which the groups CgEbg mean 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, Rs and Ré are identical to or different from one another and denote hydrogen atoms, alkyl radicals having 1-4 carbon atoms or fluorine atoms, provided that one of the radicals Rs and Rö is only a fluorine atom if the other of these two radicals is a hydrogen atom or also a Fluorine atom means 5. The method according to claim 4, characterized in that as a dehydroiodination reagent, a tertiary amine, preferably l, 5-diazabicyclo (4,3,0) nonen-5-, l, 4-diazabicyclo (2,2,2) octane or 1,5-diazabicyclo (5,4,0) - 45 undecen-5, or 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 or tetraalkylammonium peroxides 50 of the formula (Ri2) 4NC> 2, in which R12 denotes an alkyl radical with 1-4 carbon atoms. 5 632 245 and Rh is a hydrogen atom or a benzoyl radical, 6 or the sodium salt of this acid or the methyl ester of this acid. 6. The method according to claim 4, characterized in that an acid of the following structure VI 55 "'H -CH -CH2-C00H 60 65 (VI) c = c H ^ C- (CH2) 4-CHS / s H OH 632245 7 632245 / T \ ml nh-c-ch3, o nh-c-nh2 CH = N-MH-C-NH2, or is, or a group of the formula 0 11: -CH-C-Rio I. Rh means what Rio is a phenyl, p-bromophenyl, p-biphenyl, p-nitro-phenyl, p-benzamidophenyl or a 2-naphthyl radical, and Rh is a hydrogen atom or a benzoyl radical, 7. The method according to claim 6, characterized in that one produces the sodium salt of the acid of formula VI in the form of a free-flowing powder. 8th point as in formula II or IV, produces, and subjecting them to dehalogenation and hydrolysis to form a mixture of the keto compound of the formula IV with the hemiketal of the formula III. 8. Process for the preparation of a mixture of the keto compound of the formula IV oh w-c-ch ^ l-ri (iv) with the corresponding hemiketal of formula III (iii) being in these formulas D a remainder of the formula \ * \ OR 13 .. <x or is where Ri3 is a hydrogen atom, the tetrahydropyranyl radical, the tetrahydrofuranyl radical, the 1-ethoxyethyl radical, or a grouping of the formula h I i # "- o-ç c-r17 is in which Ru is an alkyl radical with 1-18 carbon atoms, a cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 carbon atoms, the phenyl radical or a phenyl radical which is substituted by 1,2 or 3 alkyl radicals with 1-3 carbon atoms, represents Ris and Ri6 are identical or different from one another and represent hydrogen atoms, alkyl radicals with 1-4 carbon atoms, phenyl radicals or phenyl radicals substituted with 1,2 or 3 alkyl radicals with 1-4 io carbon atoms, or Ris and Ri6 together represent a group of the formula - (CH2 ) form a- or - (CH2) b-0- (CHz) c-, in which a = 3, 4 or 5, b = 1, 2 or 3, and c = 1, 2 or 3, under which Prerequisite that b + c = 2, 3 or 4, and 15 Ri7 represents a hydrogen atom or the phenyl radical, L is a radical of the formula 9. The method according to claim 8, characterized in that one carries out the deiodination of the compound of formula I by reaction with silver carbonate and perchloric acid in an inert organic medium, preferably tetrahydrofuran, preferably in the absence of light, and that a mixture is obtained, which contains the keto compound of the formula IV as the main component. 10. The method according to claim 9, characterized in that the main component containing the keto compound of formula IV is dissolved in an organic solvent, preferably acetone or methylene chloride, after a few days the balance between the keto compound of formula IV and the hemiketal Formula III sets. 10th if the other of these two radicals represents a hydrogen atom or also a fluorine atom, 10th 15 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 10 in which R3 is a hydrogen atom, a pharmacologically acceptable cation, an alkyl radical with 1-12 carbon atoms, a cycloalkyl radical with 3-10 carbon atoms, an aralkyl radical with 7-12 carbon atoms, the phenyl radical, a phenyl radical with or with 1,2 or 3 chlorine atoms or alkyl groups 1 -4 II 10th 15 20th 25th 30th 35 40 45 50 55 «0 65 632245 11. The method according to claim 8, characterized in that one carries out the deiodination by treating the compound of formula I in alcoholic solution, preferably methanol, with an alkali metal hydroxide, preferably potassium hydroxide, and after acidifying the mixture of the keto compound of formula IV and the hemiketal compound of the formula III which contains the acid form of the compound of the formula I as an impurity.