CH639378A5 - PROSTAGLANDIN DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The present invention relates to prostaglandin derivatives and methods for the production of prostaglandin derivatives.

The prostaglandins and their analogs are well-known organic compounds derived from prostanoic acid, which has the structure and numbering of the atoms given below:

COOH

The formulas in the manner presented below represent a special optically active isomer which has the same absolute configuration as the PGEi obtained from mammalian tissues.

In the formulas, broken lines on the cyclopentane ring or on the substituents on the side chain mean that the a configuration is present, i.e. that the substituent in question is below the level of the cyclopentane ring or the level of the side chain. On the other hand, unbroken, strongly drawn binding lines illustrate that the substituents in question are in the β configuration, that is to say that they lie above the Pattier level.

Regarding what is already known in connection with prostaglandin and prostaglandin derivatives, reference is made, for example, to the publication by Bergstrom et al. In Pharmacol. Rev. 20.1 (1968) and the publication by Pace-Asciak et al. in Biochem. 10.3657 (1971). Later, when the present invention was made, a publication by Pace-Asciak appeared in J. Am. Chem. Soc.

OR;

R,

is in which has one of the following meanings:

a) a hydrogen atom,

b) a tetrahydropyranyl radical,

c) a tetrahydrofuranyl residue,

d) a 1-ethoxyethyl radical e) a grouping of the formula rv i <4

■ G-C

1-.

17th

!

R i a

98, 2348 (1976) on 6-keto-prostaglandin-Flu, and a publication by E. J. Corey et al. in J. Am. Chem. Soc. 99,2006 (1977) on “PGX”, which can also be referred to as 6,9a-oxido-9a, 15a-dihydroxyprosta- (Z) 5, - (E) 13-dienoic acid 5.

The aim of the present invention was to provide new prostaglandin derivatives which have pharmacological activity and to develop processes for the preparation of these new prostaglandin derivatives.

io An object of the present invention is a halogen-containing prostaglandin derivative, which is characterized in that it has the formula III

15

Ria 0

«■ 0 tCH / v £ K-L - Ô-NÎRô) (R-, e) /

X-C.-R «

(III)

25 or is a mixture containing the compound of formula III and the enantiomer of the compound of formula III, wherein in formula III

for grouping the formulas

50

55

60

in which

Ru is an alkyl radical with 1 to 18 carbon atoms, including a cycloalkyl radical with 3 to 10 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical or a phenyl radical, the

'0

or

CH ^ OR

has as substituents 1, 2 or 3 alkyl radicals having 1 to 4 carbon atoms inclusive,

R15 and R16 are identical to or different from one another and have the meaning of hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms, phenyl radicals or phenyl radicals which are substituted by 1, 2 or 3 alkyl groups having 1 to 4 carbon atoms, or

Ris and R16 together represent a group of the formula - (CH2) a- or a group of the formula -CH2) b-0- (CH2) c-, where a is 3, 4 or 5 in these groups,

b represents 1, 2 or 3, and c represents the number 1, 2 or 3,

provided that the sum of b + c is 2, 3 or 4, and where

Rn represents a hydrogen atom or a phenyl radical, or is an acyl radical which has the following structures: a ') a grouping of the formula

639 378

14

^ A

A),

they were listed under a '), d') a grouping of the formula in which

A is an alkyl group of 1 to 4 carbon atoms, a bromine atom, a phenylalkyl group of 7 to 10 carbon atoms, or a nitro group, and e has a value of 0 to 5, provided that no more than two substituents A are different Have meaning than that of alkyl groups, and furthermore the total number of carbon atoms in all substituents A is not more than 10 carbon atoms,

b ') a grouping of the formula

10th

15

COOR, so what

R3Q is an alkyl radical with 1 to 4 carbon atoms inclusive, 25 c ') a grouping of the formula L.

0

30th

in which both A and e have the same meanings as Q

0,

/ V

H H

-C-R31

in which

R31 is an alkyl radical with 1 to 7 carbon atoms,

W is a methylene group or an ethylene group, L if W represents a methylene group, for one of the following groupings

(1) -CHi) d-C (R ->) -> -

(2) -CHtO-CHi-Y- or

(3) -CH2CH = CH-, in which d has a value from 0 to 5 inclusive, the radicals R2 are identical or different from one another and have the meaning of hydrogen atoms, methyl radicals or fluorine atoms, provided that one of the two Residues R2 must not have the meaning of the methyl group if the other is a fluorine atom, and

Y represents a direct bond or a grouping of the formula -CH2- or - (CH2) 2-, and that when W is an ethylene group one of the following meanings

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

(2) -O-CH1-Y- or

(3) -CH = CH-, where d, R2 and Y have the meaning given above, for one of the following structures

/ \

• R £

ORi,

or

/ Y

RÖ "Ru stands in which

R8 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms,

R13 has the meanings given in connection with the cyclopentane structures R5,

R4 for one of the following structures

R-5

45

(l) '-C -CgHag-C.Hs

R

e>

r5

(2) -c

I.

re

t T \

V <

OQ he

"y r P,

uri2 ^ ~ '3

(?)

«

stands in which

CgH2g is an alkylene group with 1 to 9 carbon atoms, in which 1 to 5 carbon atoms50

55

60

65

atoms are in the chain between the grouping of the formula -CR5R6- and the terminal methyl group,

and Rg are identical or different from one another and denote hydrogen atoms, alkyl groups having 1 to 4 carbon atoms or fluorine atoms, provided that one of the radicals R5 or Rg is a fluorine atom only if the other of these radicals is a hydrogen atom or also a fluorine atom and on the further condition that neither R5 nor R6 may represent a fluorine atom if Z is an oxa group of the formula (-0-),

stands for an oxa-oxygen atom of the formula (-0-) or a grouping of the formula CjH2j, where the structure of the formula CjH2j stands for a direct bond or an alkylene group with 1 to 9 carbon atoms, 1 to 6 carbon atoms in this alkylene group the chain that lies between the grouping of the formula -CR5R6- and the phenyl nucleus,

the radicals T are identical or different from one another, and have the meaning of alkyl radicals having 1 to 4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl groups or groups of the formula -OR7 in which R7 is alkyl radicals having 1 to 4 carbon atoms, and have a value of 0, 1, 2 or 3, provided that, however, no more than two radicals T have a different meaning than that of alkyl groups if s

15

639 378

has a value of 2 or 3,

R ,,) represents a chlorine atom, bromine atom or iodine atom, Ry represents a hydrogen atom, a methyl group or an ethyl group, and R18 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms inclusive, an aralkyl group containing 7 to 12 carbon atoms inclusive, a phenyl radical or represents a phenyl radical which is substituted by alkyl groups having 1 to 4 carbon atoms,

V represents a direct bond or a methylene group and

X for one of the following structures

(1) trans-CH = CH-

(2) cis-CH = CH-

(3) -C = - or

(4) -CH2CH2-stands.

Furthermore, the present invention relates to a prostaglandic derivative which has an enol ether structure and is characterized in that it has the following formula IV

is characterized in that it is a keto-prostaglandin derivative of the formula I.

w ^ OH o 0

V ", j

- - • \ fi. -C "CH2 -L -C-IN (RO) (R ', S)

X-C-R ^ (t)

1! ,

io Q

or is a mixture containing the keto compound of formula I and the enantiomer of this compound, or the corresponding hemiketal prostaglandin derivative of formula II

rj0H # '

v -0-C / ^ CH2-L-C-N (Rs) (r, b) U '' (II)

15

0

ll.

L-C-, N (Rb) (R18) C-H

X-C-R4

Q

25 or a mixture which contains the hemi-ketal compound of the formula II and the enantiomer of this compound or is a mixture of the keto compound of the formula I with the corresponding hemi-ketal compound of the formula II, in the formulas I and II

30 •

r 21) R9, Ris> L, Q, V, W and X have the same meaning

X-C-R «.

(IV)

or that it is a mixture which contains the compound of the formula IV and the enantiomer of the compound of the formula IV, in which formula IV

R4, R9, R18, L, Q, V, W and X have the same meaning as in the halogen-containing prostaglandin derivatives of the formula III given above. Another object of the present invention is a keto-prostaglandin derivative or hemi-ketal-prostaglandin derivative or a mixture of the keto-prostaglandin derivative with the hemi-ketal-prostaglandin derivative, which product thereby possess, as in the formula III given above. Preferred prostaglandin derivatives according to the invention of the formula III given above are those which have the following structure Illa Re Q

i 11 ■

v ^ 0 rCH ^ H-Lr e4j (Rû) (R, fi)

40 /

-W.

(Illa)

X-C-R «

45

have or are a mixture containing the compound of the formula purple and the enantiomer of the compound of the formula purple, in this formula purple

[^ 20 ^ for a grouping of the following structures or

CHaOH

639 378

16

stands.,

Q 'one of the following structures

Û,

/ "X

H H,

.. or un

Ra '• OH

. \

W, L, R4, R9, Ris, V and X have the same meaning as 10 in formula I and II, respectively.

represents in which

R8 is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms inclusive and

W, L, R4, R9, Ri8, V and X have the same meaning as in the halogen prostaglandin derivatives of the formula III, and in in formula III. the hemi-ketal prostagiandin derivatives of the formula II and naturally

Of the prostaglandin derivatives of the general formula also those in the corresponding preferred compounds of IV are particularly preferred, those which have the following formula and purple, and IIa the wavy line means the following with IVa rv sign — that the bond in the a- Configuration or the ß-

, i configuration is present.

U In the compounds of the formula Ibis IV according to the invention

L - C - N (K g} (R -, e) and the corresponding preferred compounds of the formula / u • 20 Ia up to and including IVa corresponds to a bond to the group. C - t i

'X-C -R' i

Q *

have, in this formula tion of the formula ^ R ^ qJ or the formula (R2 ±

(-i-V3.) the bonds to the

25 Cyclopentane ring in positions C-8, C-9 and C-12, the corresponding nomenclature of prostaglandin being used to define the positions. Accordingly, the three ties to the grouping of the formula

^ 2 0j Q 'have the same meaning as in formula lilac and further W, L, R4, R9, R1K, V and X have the same meaning as in formula IV.

Also of the keto prostaglandin derivatives are those of the following formula Ia

'V'0K S' I!

Vi -C -CHa-u * C-N (R &) (R'iö)

35

that a basic cyclopentane skeleton with the following bonds

40

(Ia)

and the corresponding hemiketal prostaglandin derivatives are those of the following formula IIa.

The term “prostaglandin derivatives”, as described here 45, includes the following groups of compounds:

a) PGFa compounds if in the formulas given

© for grouping the formula.

0.1

u

0

"G - C C Ha - L - C - N {R p) (Ria) 55

/

OH

U

X-C

ö4

(IIa)

or mixtures of the keto compound of the formula Ia with the hemiketal compound of the formula IIa are particularly preferred, the formulas being Ia or IIa,

b) llß, PGFa compounds, if in the given For-60 my

R 2 Q) for a grouping of the formula

65

and Q 'has the same meaning as purple in the formula and furthermore.

17th

639 378

c) 11-deoxy-l 1-keto-PGF "compounds if in the formulas given

(R2O / a grouping of the formula is

d) ll-deoxy-ll-methylene-PGFa compounds, if in the formulas given

^ 20 ^ stands for a grouping of the formula,

e) ll-deoxy-PGFa compounds if in the formulas given

R20) for a grouping of the formula

/ \

rs oh

5 means d. H. for the compounds in which the hydroxyl group on carbon atom 15 is bonded to the side chain in question in the a configuration, the configuration on this carbon atom 15 is identical to that of the naturally occurring prostaglandins, for example that of 10 PGE], which results from the tissues is obtained from mammals.

The compounds 15 epimeric with respect to the carbon atom, that is to say the 15-epimer compounds, are illustrated by the formulas X or II or III or IV, if in these compounds Q for a grouping of the following structure

15

/

^ 8

A

Oh

20 stands. These 15-epimer compounds are referred to differently in the present application, either as "15-epi", or as "15ß", or as "15R", or by using the appropriate prefix in the name. As is known to a person skilled in the art, 25 the terms “R” and “S” depend on the neighboring substituents. In this context, reference is made to the publication by R. S. Cahn in J. Chem. Ed. 41, 116 (1964).

A typical example of keto compounds which correspond to formula I are compounds which have the following formula V

Oh

0

0

II

stands,

f) ll-deoxy-10, ll-didehydro-PGFa compounds, if in the given formulas r 2 o) for a grouping of the formula

35

40

.ch2-c- (ch2) 4-c-nh2

V

oh c <

h ^ c-cshii

/ \

h oh stands

and finally g) ll-deoxy-ll-hydroxymethyl-PGFa compounds, if in the formulas given

R 2 o) for a grouping of the formula

43, and this compound is referred to as 6-keto-PGFi "amide. The compound of formula V given above is thus an example of compounds of formula I in the event that a grouping of the formula

55

often

60 is

L stands for a grouping of the formula - (CH ^ jj-, Q stands for a grouping of the formula chsoh.

For those compounds of the formulas I, II, III and IV in which Q is a structure of the following formula

65

/ \

h oh means

R! a grouping of the formula

639 378

18th

is.

0

.il

-c-nh2

R4 represents the n-pentyl radical, 5

V represents a direct bond,

W is a methylene group and X is trans-CH = CH-.

An example of hemi-ketal compounds which correspond to the formula II are those compounds which have the following formula VI

oh "0 '

* - II

c— (ch2) 4 "C -mh2.

T \

15

-H

VI

c = c:

ho h-

25th

c-cshti / \

. h oh, and these compounds are referred to as 9-deoxy-6 |, 9a-epoxy-ó ^ -hydroxy-PGFj-amide.

An example of halogen compounds which correspond to the formula III are those compounds which have the following formula VII 50

h i 0

* *, X 11

c-ch- (ch2) 3-c-nh2 ■ 0 <\ 35

H

VI I

c = c ho h ^ ^ c-cshn

/ \

h oh, and these compounds are referred to as 5îj-iodo-9-deoxy-6 |, 9a-epoxy-PGFramid.

An example of enol ethers which correspond to the formula IV are compounds which are represented by the following formula VIII

40

45

50

/

0

II

(CH2) 3-C-, NHCH3

C-'H

c

0 "\

', ch £

VI

oh h

oc

/

H

.C ^ -CsHi 1

h x0h •

! 60

65

are illustrated. This compound is referred to as (5Z) -9-deoxy-6,9a-epoxy-A5-PGFrmethylamide. In this connection, reference is made to the publication by R.A. Johnson et al., In J. Am. Chem. Soc. 99.4182 (1977). On the other hand, the compounds of formula VIII above can also be referred to as methylamide of prostacyclin (PGI2), and in this connection reference is made to the publication by RA Johnson et al., In "Prostaglandins" 12,915 (1976) and to the publication of one author mentioned, also in «Prostaglandins» 13,375 (1977). . Regarding the designation «Z» and «E» for stereo isomerism on a double bond, reference is made to the publication by J.E. Blackwood et al., In J. Am. Chem. Soc. 90.509 (1968).

Those compounds of formula I in which V is a direct bond and W is a methylene group are referred to as 6-keto-PGFla compounds by adhering to the prostaglandin nomenclature, the syllables "Homo" or "Nor" can be used to refer to variations in chain length, as is known in the art. Similarly, the corresponding compounds of formula II are referred to as 6-hydroxy compounds, and the compounds of formula III as 5-halogen compounds, and the compounds of formula III as 5-halogen compounds, regardless of the chain length.

Those compounds of formula I in which both V and W are methylene are referred to as 9-hydroxymethyl analogs. The corresponding compounds of the formula II or III or IV are referred to as 6,9-epoxymethano analogs.

If V is a direct bond and W represents an ethylene group, the compounds of the formula I are referred to as 5-keto-PGFla derivatives. The corresponding compounds of the formula II or III or IV are referred to as 5,9-epoxy PGFia derivatives, the halogen compounds of the formula III then being known as 4-halogen compounds.

The compounds of the formulas I, II and IV, and those compounds of the formula III in which R13 is a hydrogen atom, are particularly effective in causing various biological reactions. For this reason, the compounds in question are well suited for pharmacological purposes. A few of the biological modes of action of the compounds in question are the following:

Inhibiting platelet aggregation, stimulating smooth muscles, inhibiting gastric secretion and alleviating the undesirable effects in the gastrointestinal tract caused by systemic administration of inhibitors of prostaglandin synthease.

Because of these biological activities, the new compounds according to the invention are well suited for controlling a large number of different diseases and undesirable physiological conditions in mammals, including humans, and domestic animals for purposes of use and domestic animals which serve as playmates of humans, and animals in zoological gardens and further Laboratory animals such as mice, rats, rabbits and monkeys to be examined, prevented, controlled or mitigated.

The compounds of the invention can be used wherever desired to prevent platelets from clumping, to reduce the adhesive properties of platelets, and to thrombus in mammals, including humans, rabbits and rats eliminate or prevent thrombus formation. For example, the compounds in question are well suited to treat a heart attack, i.e. a myocardial infarction, or to prevent its formation.

19 639 378

this as well as a thrombosis occurring after operations during the puerperium. Treat or prevent for the latter purposes, and to keep the open state of the compounds according to the invention in the form of a

Vascular grafting after surgery, intravenous infusion immediately after abortion or around and around such conditions as atherosclerosis, arterial delivery in a dose in the range of about 0.01 to about 50

sclerosis, errors related to blood clotting due to being administered 5 per kg body weight per minute until the increased fat content in the blood (due to lipemia) and other desired effects are achieved. Then the dosing

to treat clinical conditions, the cause of which is caused by an intravenous, subcutaneous or intramuscular injection

Lipidemia is associated with an imbalance in the lipoid balance or hypertion or infusion during the puerperium. in the range of 0.01 to 2 mg per kg body weight per day

Other in vivo applications include the treatment of i "given the exact dose based on age, weight and geriatric patients to prevent seizures of brain void from the condition of the human or animal patient (cerebral ischemia), and a long-term prophy depends.

laxe after heart attacks and strokes. For the prostaglandin derivatives according to the invention, the stated purposes are also useful, in order to be administered systemically in mammals, including humans and compounds, for example by certain useful animals, for example in dogs and by travenous, subcutaneous or intramuscular administration. and pigs to reduce excessive gastric secretion, also in the form of sterile grafts, when prolonged or to be regulated, thereby seeking the likely effect. If one wishes to achieve a rapid response to the formation of ulcers in the gastrointestinal tract, as can be the case in particular in emergency situations, or the formation of such ulcers at all, the intravenous route of administration is preferred. Dosie-20 can prevent, and the healing of such ulcers, the stanchions, which are already present in the gastrointestinal tract in the range of about 0.01 to about 10 mg per kg, accelerate body weight are used, the can. For this purpose, the verbal exact doses of the age, the weight and the fertilization by intravenous, subcutaneous or intramuscular in-state of the animal or human patient as well as injection or infusion are administered, an infusion dose depending on the frequency of administration and the Administration range of about 0.1 [xg per kg of body weight per minute. is maintained, or an entire daily dosage

The addition of the compounds in question to the whole blood by injection or infusion in the range from approximately 0.01 to approximately enables in vitro applications, such as, for example, the administration of 10 mg per kg of body weight per day. Also in the formation of whole blood, which is used in heart-lung machines, this case the exact dosage depends on the age and the weight. In addition, whole blood containing these compounds and the condition of the human or animal patient can be circulated through limbs and organs, as well as the frequency of administration and the route of administration chosen, for example, by the heart or kidneys.

irrespective of whether these are now connected to the body. The compounds according to the invention are also suitable from which they originate, whether they are taken from a body in order to be kept and stored against undesirable influences in the gastrointestinal tract, or for a transplantation 35, which are prepared from the systemic administration of inflammation, or whether they originate from new body-inhibiting agents which are prostaglandin-syn-connected. A blocking of aggregated platelet inhibitors are, and the records according to the invention are fertilized by the presence of the compounds in question are used for this purpose by preventing one. For this purpose, the compounds are given all-simultaneous administration of the prostaglandin derivative and gradually in single or multiple portions to the circulating blood of the anti-inflammatory prostaglandin synthease inhibiting blood, the blood of a human donor or a gate. In this connection, reference should be made to the US animal donor, a body part which is perfused (referred to by Partridge et al. Under Perfusion Patent No. 3781429), regardless of whether it is described as having any of the ulcerative effects which is attached to or removed from a body by certain anti-inflammatory agents which are not a recipient, or two or more of such circulatory steroids, is inhibited in blood streams thereby resulting in an overall constant dose of may be that oral prostaglandi-about 0.001 to 1.0 [ig of the compound in question per ml of the ne of the E series or the A series are administered simultaneously, such as whole blood is maintained. The PGEj, PGE2, PGE3,13,14-dihydro-PGE! as well as the corre-compounds are also suitable for producing platelet-rich 11-deoxy-PGE compounds and PGA compounds from blood, these concentrates being used for treatment. The prostaglandins are useful, for example, for the treatment of Thrombocytopenia or in chemotherapy undesirable influences on the gastrointestinal tract are too low. from systemic administration of indometha-

The compounds according to the invention are extraordinarily derived from phenylbutazone and aspirin. These questionable ones are effective to induce smooth muscle stimulation- compounds are specifically described in the above-mentioned patent

fen, and they are also very active in increasing the 55 steps of Partridge et al. as anti-inflammatory agents,

Efficacy of other smooth muscle-stimulating compounds that are not based on steroids. It is known to fertilize, that is to say other stimulators for smooth muscles, furthermore that the anti-inflammatory agents mentioned contain

such as oxytocic agents such as oxytobititors for prostaglandin synthesis. The inflammatory

cin, and various ergot alkaloids, including inhibitors, which inhibit prostaglandin synthase

Derivatives and analogues of these compounds. From these greens, such as indomethacin, aspirin or phenyl

The compounds of the invention are well suited to butazone can be administered in any way known in the art instead of or in combination with less than the usual ways to combat an inflammatory state of proven amounts of these known stimulators used, for example in any Dosage range for smooth muscle to be used, for example, and after a suitable for systemic administration se the symptoms of a paralytic ileus (bowel obstruction) to 65 way.

mitigate, or to reduce atonic uterine bleeding after an abortion. The prostaglandin derivative is combined with the inflamed

or to control childbirth, or to prevent and inhibit prostaglandin synthase from inhibiting inhibition of

to facilitate the ejection of the mother cake, neither by the same route of administration nor by any

639 378 20

given another route of administration. If, for example, that is advantageously administered orally with other anti-asthma agents, i.e. anti-inflammatory agents, then anti-asthmatic agents, such as for example the prostaglandin derivative, can also be administered orally, with sympathomimetic agents such as, for example, or on the other hand the prostaglandin derivative also isoproterenol, phenylephrine, ephedrine etc. and also rectally in the form of suppositories, or, in the case of a woman, 5 xanthine derivatives such as theophylline and amino

vaginally in the form of vaginal suppositories, or one in the phylline, and further with corticosteroids, such as with

Vagina insertable slow release device ACTH and Prednisolone.

this agent, for example in the form described in US The compounds in question can be effective on human

U.S. Patent No. 3,545,439. Asthma patients through oral inhalation or through aerosol

On the other hand, if the anti-inflammatory agent is administered rectally io inhalation.

is administered, then the prostaglandin derivative can also be given when administered by oral inhalation with rectal. In addition, the prostaglandin-type nebulizers or with oxygen-aerolisato derivative can be administered orally in a convenient manner, or if it is intended to be carried out in the ren, then it is pleasant to take a woman's active case vaginally. If one decides to have available in part in the form of a diluted solution that the route of administration is both for the anti-inflammatory, preferably in these diluted solutions, a concomitant and for the prostaglandin derivative the same concentration of about 1 If part by weight of the medicament is to be manufactured, then it is generally particularly advantageous to combine the two detergents from about 100 to 200 parts by weight of the total solution to form a single dosage form. is used. Completely common additives can be used

If the prostaglandin derivative is being treated for such a purpose, to stabilize such solutions, or to be used, then the dosage range depends on the production of 20 isotonic media, and as examples of such a wide variety of factors, including the type Other additives that can be used include: the age, weight, sex and medicinal sodium chloride, sodium citrate, citric acid and the like, see the condition of the mammal that is to be treated if administration is in the form of a self-spraying, as well is also desired from the type and dosage level of the dosage unit which is suitable for the administration of anti-inflammatory inhibitors for the prostaglandin syn- active ingredient in aerosol form, which is used for inhalation theory, which is also given to the mammal in question, and therapy then together can also of the sensitivity of the respective prostate setting of the active ingredients in an inert propellant glandin derivative to be administered. Suspended, for example, which does not occur as a propellant in every person who needs treatment with a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane anti-inflammatory agents, can serve the same disadvantageous, and in such formulations can have as a gastrointestinal effects Tracts when he takes these sub-other constituents as a co-solvent, as an aid. The effect in the gastrointestinal tract will often include ethanol, flavoring materials and stabilizers - very strong both in terms of their type and in terms of their ren. Instead of a co-solvent, one can vary starch. However, it is within the discretion of the physician or veterinarian to use a dispersant in such formulations to determine that the 35's, such as oleyl alcohol. Suitable agents and pre-administration of the anti-inflammatory agent to devices for use of the inhalation therapy technique are desired side effects in the gastrointestinal tract in the person or animal treated in detail, for example, in US Pat. No. 2,868,691, and it is described.

also in its decision-making area, an effective amount of the compounds in question are included in mammals.

To prescribe prostaglandin derivatives to treat the unwanted human loan as a means of removing nasal

To significantly alleviate or completely eliminate side effects, i.e. suitable as nasal decongestants, and they will be eliminated. for this purpose in a dosage range of about 10 [xgbis

The compounds of the present invention are also useful for providing 10 mg per ml of a pharmacologically acceptable liquid carrier.

Treat asthma. For example, these compounds are used materials, or in the form of an aerosol spray, which are useful for dilating the bronchi, ie as bronchodilators, both formulations are intended for external use, and also for mediators, such as SRS-A, and.

To inhibit histamine. Mediators of this type are produced from cells. The compounds according to the invention are furthermore released in a suitable manner, which are activated by an antigen-antibody complex in order to fourth the diseases of the peripheral vessels in humans. Accordingly, combat these combat in question. The term “disease of the peripheral connections spasms and they facilitate breathing in 50 vessels”, as used here, is understood to mean illnesses such as bronchial asthma, bronchitis, or any blood vessel outside the heart, and also bronchiectasis, pneumonia (Pneumonia) and Emphy diseases of the lymphatic vessels. Examples of such crane sem. For the stated purposes, the compounds in the peripheral vessels are frostbite, diseases of a variety of dosage forms are administered, for example, due to bloodlessness in the brain vessels (ischemic orally in the form of tablets, capsules or liquids, or 55 cerebrovascular diseases), arteriovenous fistulas , blood rectal in the form of suppositories or parenteral, subcutaneous or empty leg ulcers to be attributed (ischemic leg intramuscularly, or by intravenous administration, whereby the oaths), phlebitis (phlebitis). Poor function - the latter type of administration is preferred if there is a kidney of the veins (venous insufficiency), gangrene, kidney radio emergency situation. Other types of administration for dysfunction in severe liver diseases or the implementation of such treatments are inhalation in 60 bends of the biliary system (hepatorenal syndromes), Duc form of aerosols or solutions for nebulizers tus arteriosus (connection between aorta and pulmonary artery), or also an injection, an insufflation, in the form of a bloodlessness in the intestines without constipation (not-if-powder. Dosages that are in the range of about 0.01 to 5 mg per structural mesenteric ischemia), arterial inflammation (Ar-kg body weight) up to four times a day teriitis), inflammation of the lymphatics (lymphangitis) and the like - the exact dose being dependent on age, weight and diseases. However, these examples are only given on the condition of the patient and on the frequency and to explain how differently the diseases depend on the route of administration. For the abovementioned uses, which can be treated, and the examples are intended for use, the prostaglandins according to the invention can in no way use the expression “diseases” used here

21 639 378

the peripheral vessels »somehow. For the episodes that occur approximately in the vicinity of the period of ovulation of such diseases, those according to the invention begin and stop orally or parenterally at the time of menstruation or just before these connections by injection or menstruation time. Other modes of administration Infusion administered directly into a vein or artery. There is an administration within the vagina, i.e. an intrava dose of the compounds in question in the range of 0.01 5 ginal administration or also an administration within up to 1.0 ij.g per kg body weight per hour by infusion of the uterus, i.e. one intrauterine mode of administration. Administered, or corresponding doses are also given, the expulsion of an embryo or a fetus can be a number of injections, calculated again per day, and by a similar administration of the inventive compounds, namely by injecting the appropriate injections one to four times a day administered during the first third or second third. The exact amount of dose depends on the age, weight reached during a normal pregnancy period of a mammal and on the condition of the patient and also on the.

Frequency of administration and on the route of administration. The compounds according to the invention are also well suited

Treatment is continued for 1 to 5 days, although there is no need for dilation of the cervix, i.e. a cervical generally a treatment period of only 3 days - dilatation in pregnant and non-pregnant female to ensure that long-term thera - 15 mammals for gynecological treatment

significant effect occurs. If any systemic lung or in the course of obstetrics evoke. If

Effects or side effects are observed, then want to initiate childbirth, or a clinical abortion below the dosage can be reduced until it emerges below the use of the compounds according to the invention.

Threshold, at which such systemic effects are desired, cervical dilatation is also observed,

or side effects are observed. 20 In cases of infertility, cervical dilatation can occur

Accordingly, the compounds according to the invention, which are produced with the aid of the compounds according to the invention, are particularly suitable for treating diseases of the peripheral vessels, and are useful for combating the movement of sperm to the uterine limbs in humans, which facilitate an inadequate mother. Dilation of the cervix,

Have blood circulation in these extremities. Such actions which are achieved with the aid of the prostaglandins according to the invention lead to a reduction of the remaining 25 are also useful if one has an operative gynecology

Wants to perform pain and initiate healing of ulcers, such as cervical dilation with the limbs. subsequent uterine curettage, with such a reference to a precise discussion of the type and the clinical surgical intervention a mechanical expansion of the uterus

Effects of diseases of the peripheral vessels in the cervix to perforation of the uterus, tears in the

Humans and previous procedures can lead to uterine neck (cervical tears) or infection. The

Treatment of such diseases with prostaglandins on compounds according to the invention are also well suited.

the South African patent specification No. 74/0149, which, if one has to carry out diagnostic procedures, as a presentation in Derwent Farmdoc No. 58 400V is reproduced. an enlargement of the cervix to test the

In this context, it is also necessary to publish tissue. For this purpose, the corresponding derivative of Elliott et al., In Lancet, January 18, 1975, pages 104-142, 35 prostaglandin derivative is administered either locally or systemically.

pointed out. enough.

The compounds according to the invention can be used instead of the prostaglandin derivative, for example, orally or vagi-oxytocin to treat pregnant female nal in doses of about 5 to 50 mg per treatment in animals, such as humans, cows, sheep and pigs, the one be administered to an adult female, initiating 1 to 5 births when the animals are near or at 40 such treatments within a period of 24 regular births, or at pregnant hours. On the other hand, one can intrate the compound, in which fetal muscular or subcutaneous death in the uterus has occurred at doses of about 1 to 25 mg each to cause stillbirth when given treatment. The exact dosages depend on the age of 20 weeks before or closer to the calculated date of birth of the compounds for the stated purposes. For this purpose, the compounds in question, age, weight, condition of the human being to be treated, are administered by intravenous infusion by taking out a lying or animal patient.

Dosage of 0.01 to 50 µg per kg of body weight per minute. The compounds according to the invention are furthermore well suited

uses until the second stage of childbirth, namely the output to cause abortion in pets, especially

solution of the fetus, or until the second stage of birth, that of young cows, and they also serve to

is almost reached. The compounds in question are specifically intended to facilitate the use of an oestrus or to reduce the oestrus in female

when a female or a pregnant woman regulates itself in a herd and synchronizes

one or more weeks after the calculated childbirth. Examples of pets for whom the min according to the invention is located and natural birth has not yet been able to be used for these purposes, or if 12 to 60 hours after the burst of these are horses, cattle, sheep and pigs. An adjustment

The natural birth of the amniotic sac has not yet begun 55 lation or synchronization of the oestrus. Another form of administration is oral administration, fertilization and pregnancy are more effective. design because it is for the shepherd, or the owner of a

The compounds according to the invention are also suitable for animal herds, all female animals in short, previously net, in order to have the fertility cycle pregnant during menstruating female periods. This synchronization

In mammals, including humans, to regulate the pregnancy of the animals leads to a higher ren. Under the term “menstruating female mammals, percentage of live births is achieved than the percentage

re »means animals that are mature enough to menstruate, set that is achieved when there is no intervention, but which are not yet so old that regular menstrual pregnancies wait. Prostaglandation has already stopped. For this purpose, they are injected for these purposes or together with the feed

Prostaglandin derivatives are systemically administered at dosage levels, ranging from 0.1 to 100 mg per animal, ranging from 0.01 mg to about 20 mg per kg, and the prostaglandin can be used for this purpose

Body weight of the female mammal, with other means advantageously being combined, for example with steroids,

the administration is tolerated for a period of time. The exact dosage that is used depends on the

639 378 22

animal species to be treated. For example, if a subcutaneous injection is given to mares, such injection fluids - the prostaglandin derivative being given 5 to 8 days after ovulation - then suitable sterile saline solutions can be used.

then they become fervent again. Cattle are cattle regularly. The compounds according to the invention are also treated as inflammation intervals over a period of 3 weeks, anti-dung agents in the inhibition of chronic to advantageously have all cows at the same time in heat. 5 Inflammation in mammals, including

The compounds according to the invention also lead to one of the swellings or other undesirable phenomena. Increase in blood flow in the mammalian kidneys, for which purpose methods of treatment are used, thereby increasing both the volume and the electrolyte content and dosages, which are generally increased in accordance with urine. For this purpose, those according to the invention are available, which in US Pat. No. 3 885 041 compounds are well suited to say cases of bad 10 about such treatment methods. It will therefore deal with the functioning of the kidneys, ie cases of renal dysfunction, to the entire content of the aforementioned US patent, in particular those to which a blockage is referred.

of vessels in the kidney bed occurs. Typically, the many of the biological modes of action involved in these 6-keto

Compounds of the invention useful to relieve or cure cases of oede prostaglandin derivatives, the iodine ether prostaglandin derivatives, the edema being, for example, the enol ether prostaglandin derivatives and hemiketal from extensive burns from the surface, prostaglandin derivatives occur, are also in the old, and they are also suitable for treating shocks. The prostaglandin compounds according to the invention are known for the already described prostaglandin compounds. However, the prostaglandin derivatives according to the invention are preferably fertilized first by intravenous injection in a surprisingly more specific manner in terms of their effective dosage in the range from 10 to 1000 μg per kg of body weight 20, which give biological effects similar to prostaglandin, or by intravenous infusion in a dosage in. Each of the new derivatives can therefore range from 0.1 to 20 µg per kg body weight per minute, at least from the known prostaglandin compounds Doses of the abovementioned physiological purposes are then used, intravenously, intramuscularly or subcutaneously by injection, and moreover, surprisingly and completely, or infusions in a dosage range of 0.05 to 2 mg per 25 are unexpected given more suitable for the stated purposes, given kg body weight per day. because they have fewer or fewer undesirable side effects

The prostaglandin derivatives according to the invention are also more effective than the previously known prostaglandins, and are suitable for combating rampant skin diseases in humans and those compounds of the formulas I or II or III in pets, such as psoriasis or IV, in which RI3 is not a hydrogen atom, but represents a (psoriasis), various skin inflammations such as, for example, 30 blocking group, such as, for example, tetra-atopic dermatitis, non-specific dermatitis, dermatitis hydropyranyl residue, are intermediates of the various methods of contact with primarily irritating agents and dermatitis Preparation of other useful compounds, which are caused by contact with allergy-causing agents, as either described in the present documents or are also known from the literature for the treatment of carcinomas of the basal cell layer.

and the connective tissue cells of the skin as well as for the treatment in order to achieve an optimal combination with regard to the biological treatment of fish scale disease (lamellar ichthyosis) and response, the specificity, the strength of the activity and the various skin diseases with cornification, i.e. of the duration of effectiveness, certain compound keratoses, such as epidermolytic hyperkeratosis, are preferred gen, which fall under the above formulas I, or II, or III, pre-malignant, sun-induced keratosis or non- or IV, preferred.

malignant keratosis, and they are also suitable for treatment. For example, those compounds are preferred, in the treatment of acne and other skin inflammations, such as which Q is a grouping of the formula

Skin inflammation due to increased secretion from the sebaceous glands, i.e. seborrhoeic dermatitis, in men / ^

see and atopic dermatitis, as well as mange in pets. ^ Q [- |

The compounds according to the invention alleviate symptoms 45

all of these rampant skin diseases. For example, one of those compounds, those of which particularly advantageously achieve psoriasis, in which Rg a hydrogen atom, a methyl group is relieved, if there is psoriasis-free damage in or an ethyl group.

their thickness is significantly reduced, or significantly, but not if, on the other hand, is completely healed or completely healed in the compounds according to the invention. 50 Q for a grouping of the formula

For the stated purposes, the compounds according to the invention are applied externally in the form of compositions which have a suitable pharmaceutically acceptable ✓

Contain carrier material, for example in the form of ointments, R8 OH

of lotions, of pastes, of gel-like products, of sprays 55 or of aerosols, these compositions mentioned containing basic materials for external use, then it is preferable that the radical R8 is a methyl group such as petrolatum, lanolin, polyethylene glycols and or is an ethyl group.

Alcohols. The compounds according to the invention are furthermore particularly preferred for the compositions in question to use such compositions as active constituents, at least one of the radicals R9 or R18 has the meaning, and they generally represent from about 0.1% by weight to about 15 of a hydrogen atom.

% By weight of the composition, and preferably they are in relation to the various possible structures which, in an amount of from 0.5% by weight to about 2% by weight, based on the compounds according to the invention, represent the weight of the divalent grouping Composition, before. In addition to having L, it is preferred that d be 2, 3, or 4

topical administration can also have given an injection 65, the value of 2 being particularly advantageous. If in, as an injection into the skin (intradermal injector- group Lboth residues R2 are fluorine atoms, then it is tion), as an injection into or around the damaged area (intralesio- preferable that the restRs in group Q is a Methyl-nale injection or perilesional injection), or mana is also rest, or that R4 for one of the following groupings

\

23

639 378

ch3

-c - (ch2) 3-CH3

I.

ch3

-ch2-o-

// \\

or

- (CH2) 2

// w stands.

Regarding the various options given for the group, it is preferable that these

Grouping is one of the following structures, then it is preferred if in this formula s is either 0 or 1. If s is not 0, then it is preferable that the 10 T residue is a methyl residue, a chlorine atom, a fluorine atom, a trifluoromethyl group or a methoxy group, this grouping advantageously being in the meta position or in the para position to the group Z is bound to the benzene nucleus. If Z in the indicated grouping represents an oxa-oxygen atom of the formula (-0-), it is preferable that the radicals R5 and Rg, which may be the same or different from one another, denote hydrogen atoms, methyl radicals or ethyl radicals. Furthermore, it is preferable that when the R5 and R6 groups have a meaning other than that of 20 hydrogen atoms, both the R5 and Rg groups have the meaning of methyl groups. If in the structure given above Z stands for a grouping of the formula CjH2j, then it is preferred if this grouping of the formula CjH2j means either a direct bond or a methylene group or a 25 ethylene group.

The following groups are particularly preferred radicals R4:

30th

35

-CH2-O

or

-z # J \

or owns.

If in the compounds of the formulas I or II or III or IV, the radical R4 for a grouping of the formula

I5

-C-CqH2q-CH3

I.

The present invention further provides a process for the preparation of the halogen-containing prostag-40-land derivative of the formula III

Rie 0

r »^ '7 -ä jl * 1 i 1 * v *' A. / \

! M -> • H "• - / l

50

\ r * - • «

aeon,

t 1

I!

11

Vi

(m)

then it is preferable that in this structure the group of the formula CgH2g is an alkylene group with 2, 3 or 4 carbon atoms, of which the trimethylene radical is particularly preferred. Furthermore, it is preferable that in the structure indicated the radicals Ra and R6 are hydrogen atoms, methyl radicals, ethyl radicals or fluorine atoms, the two radicals mentioned being either identical to one another or different from one another. Further, when the R5 and R6 radicals in this structure are not hydrogen atoms, it is preferred if either both the R5 and R6 radicals are methyl or both R5 and R6 are fluorine atoms. A very particularly preferred meaning which the R4 radicals can have is the n-pentyl radical, the 1,1-dimethylpentyl radical or the 1,1-difluoropentyl radical.

If in the compounds of the formula I or II or III or IV the radical R4 for a grouping of the formula in which

55 (^) W'L'Q'R4'R9'Rl8'Rl9,

V and X has the meaning given above. This process is characterized in that a compound of formula IX

60

v-gh

K 0

(^ 21 f "^

rU

(IX)

65 r 0

A "l" Kt *

639 378

24th

a halogenation and cyclization with the formation of the tertiary amines, sodium peroxide, potassium peroxide and sodium dung of formula III. According to this process, carbonate. Potassium carbonate, sodium hydroxide, potassium hydroxide, for example, a corresponding iodine-prostaglandin derivative, sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, of the formula III, in which R [9 is an iodine atom, in which sodium trifluoroacetate, potassium trifluoroacetate, sodium bicarbomane, the starting material of the formula IX is prepared either with Iodine and 5 nate, potassium bicarbonate, silver acetate or tetraalkylammonium potassium iodide in the presence of an alkali carbonate or bicarperoxides, which correspond to the following formula (R ^ NCK, bonates in an aqueous system or by which in which R12 is an alkyl radical with 1 to and including 4 is coal starting material of formula IX with iodine in the presence of a substance atom.

Alkali metal carbonates in an organic solvent. Another object of the present invention is a

Process for the preparation of a mixture of the keto prostate

puts.

10th

Another object of the present invention is a glandin derivative of the formula I Process for the preparation of prostaglandin derivatives with enol

ether structure of formula IV

.V

u

'0

II

C - M (R &) (R-, a)

\ i! '* "» M t ii / —j \ f \

(I)

with the corresponding hemiketal prostaglandin derivatives

(IV)

in which

W, L, Q, R4, R9, Ris, V and X the one given earlier

Have meaning that is characterized in that one

^ .Ori:

0 -C / ^ - 7 Ci "i2" Lmy "X (Ro) (ria)

0 î 1) •

a compound of formula IX

v'-Ufl

/

c. »c

H 0

(IX)

in these formulas the symbols 35.

(R 2 1) W, L, Q, R4, R9, Rig, V and X have the same meaning as mentioned above. This process is characterized in that a compound of formula IX

I! II

Q

7-% ü

H 0

"V 'n \! Z \

(IX)

halogenation and cyclization to form Verbin-45 (Ro "1 /

fertilize the formula III - V.

f \ ™ ^ ™ R u

Riö 0 - I!

<^. 50 Q

V ** ^ "C Ô-N (Rû) (R-, a)

f (/ halogenation and cyclization to form the compound

(R2 1 j— fertilize the formula III

V s ^

X-C-R «, (~ TZ) 55 ^

Q (k X • /

1 i j— ~ A

•• Ii -

w.

where R19 is a chlorine atom, bromine atom or iodine atom, below 60 y p ^ (—iX)

throws and this halogen compound of formula III a hydrogen halide with formation of the enol ether of formula IV.

In this process, the cleavage of the halogen in which R1S represents a chlorine atom, bromine atom or iodine atom hydrogen from the halogen prostaglandin derivative of the formula 65 is subjected, and then the halogen III obtained in this way is carried out to form the enol ether of the formula IV, prostagland derivative of the formula III a hydrogen halide by subjecting the halogen-prostaglandin derivative of the formula III to elimination under hydrolytic conditions, one of the following compounds being reacted: the mixture of equilibrium from the keto compound of

25th

639 378

Formula I obtained with the corresponding hemiketal compound of formula II.

In this production process, the hydrogen halide can be eliminated from the halogen prostaglandin derivatives of the formula III under hydrolytic conditions by treating the halogen prostaglandin derivatives of the formula III with silver carbonate and perchloric acid in an inert organic medium.

The keto-prostaglandin derivatives can be separated off from the mixture of keto-prostaglandin derivatives of the formula I and the corresponding hemiketal-prostaglandin derivatives obtained in this process, preferably by performing silica gel chromatography.

As has already been explained above, preferred compounds of the formula I, II, III and IV according to the invention are those in the grouping

Have radicals R13 in the meaning of hydrogen atoms and also in the Q group also have radicals R13 in the meaning of hydrogen atoms. These preferred compounds according to the invention therefore have the structures la, IIa, lilac or IVa given above and these therefore do not have any R13 radicals in the meaning of the protective groups indicated above, but only Ri3 radicals in the meaning of hydrogen atoms. The preferred compounds of the formulas Ia, IIa, lilac and IVa are prepared from the corresponding protected compounds by splitting off the protective group Ri3, i.e. replaced it with a hydrogen atom. Subsequently, simplified notations are also used for the compounds according to the invention, namely in the compounds of the formulas I, II, III and IV, the rest of the formula

0 II

t »-N (Re) (R-sö)

v „0 ^ c-ck2-l-r:

X-C-R4

ij.s.

As can be seen from the meanings given above, the ring systems of the formula (R 2 o) represent preferred N /

Meanings of the ring system of the formula R2 1 J, namely those in which the blocking groups or protective groups R13 which are bonded to the carbon atom 11 have been replaced by corresponding hydrogen atoms. Preferred compounds according to the invention and preferred processes for their preparation are explained in more detail below, inter alia using reaction schemes.

Corresponding compounds which have protective groups 15 are particularly useful as intermediates in the further conversion, so that compounds of the formulas III, I and II given below are obtained. Another process for the preparation of the compounds of the formulas Ia and IIa consists in starting from compounds of the formula IV 20, which will be discussed in more detail below, and subjecting these compounds of the formula IV to acid hydrolysis. If these compounds of formula IV have blocking groups, i. H. if these compounds are a ll, 15-bis (tetrahy-dropyran-2-yl) ether, then these blocking groups can be replaced by hydrogen according to methods known in the art.

The process for the preparation of the enol ethers of the formula IV is illustrated by the following preferred embodiment, in which the corresponding, unprotected compounds of the formula purple are subjected to the elimination of hydrogen halide. Accordingly, in this preferred embodiment of the production process, a compound of the following formula XII is used

30th

35

40

»20

replaced by the symbol Ri, whereby of course the same meanings apply to the radicals R9 and Ri8 contained in this radical Rj as were mentioned above. In this simplified notation, the preferred compounds of the formulas Ia and IIa given above have the following structures:

,, - OH. 0

V ü

. _ _ y; - C-CHa-L-Ri la

X-C-R4

\

"OH f-k .H

V

w ^ l-ri

: "^ x-C-R4 II Q

xi i from in which the remains

L.Q.Rj.R ^ IR 20) V, wound X the above

Have meaning, and

50 a) this compound is then in a halogen compound of formula XIII

h rls sî ^ 0-c-ch-l-r,

f R20 j— w

60

xi i i

X-C-R4

II Q

QN

converted in which the remnants

65 L, Q, Q], Rj, R4, Ri9, ^ 2Q ^ V, W, Xand ~ the above

Have meaning, and then

639 378

26

b) the product from stage a) above is subjected to a hydrogen halide, i.e. a dehydrohalogenation, using a tertiary amine or a reagent selected from the following group of materials: sodium peroxide, potassium peroxide, sodium carbonate, potassium carbonate, sodium hydroxide , Potassium hydroxide, sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, sodium trifluoroacetate, potassium trifluoroacetate, sodium bicarbonate, potassium bicarbonate, silver acetate and tetra-alkylammonium peroxides, which have the following formula, in which Rn is an alkyl radical with 1 to 4 carbon atoms inclusive. During this elimination of hydrogen halide, the enol ethers are formed, and then c) the products are separated off.

5 The following reaction schemes A illustrate the few process steps which are used to prepare compounds of the formula I or II or III according to the invention.

In the following reaction scheme A, the symbols have L, io s \ ^

Q.Qi.R ^ R ^ RuIRgo), (R21 \ V, W, Xand ~ the same

(R12) 4N02

Meaning as stated above.

r a i

Reaction scheme A

y, oh h --W ^

; c = c "

h l-ri ix x-c-r4 Ii

Qi

(a)

V /

1 I!

639 378

f-

OH

V

f \! l f Rh o J W-C-CHa-L-Ri

^ X-C-R4

b

'a

In connection with the compounds according to the invention or compounds appearing as intermediates in the production process, specific examples of the substituents specified there are now mentioned:

Examples of alkyl groups having 1 to 4 carbon atoms inclusive are the methyl radical, the ethyl radical, the propyl radical, the butyl radical and isomeric forms of these radicals.

Examples of alkyl radicals with 1 to 7 carbon atoms inclusive include the pentyl radical, the hexyl radical and the heptyl radical, including the corresponding isomeric forms, in addition to the radicals mentioned for alkyl radicals with 1 to 4 carbon atoms. Examples of alkyl radicals having 1 to 12 carbon atoms included, in addition to the alkyl radicals mentioned as examples of up to 7 carbon atoms, are also the octyl radical, the nonyl radical, the decyl radical, the undecyl radical and the dodecyl radical and the isomeric forms thereof To name leftovers.

Examples of alkyl radicals with 1 to 18 carbon atoms included are those which have already been mentioned for the alkyl radicals with 1 to 12 carbon atoms, and additionally also the tridecyl radical, the tetradecyl radical, the pentadecyl radical, the hexadecyl radical, the heptadecyl radical, the Oc-tadecyl radical, and the isomeric forms of these residues.

Examples of cycloalkyl radicals having 3 to 10 carbon atoms inclusive are the corresponding unsubstituted cycloalkyl radicals, including those cycloalkyl radicals which are alkyl-substituted cycloalkyl radicals, although the total number of carbon atoms must be in the range given. Typical examples of such residues are the residues listed below:

Cyclopropyl,

2-methylcyclopropyl,

2,2-dimethylcyclopropyl,

2,3-diethylcyclopropyl,

2-butylcyclopropyl,

Cyclobutyl,

2-methylcyclobutyl,

3-propylcyclobutyl,

2,3,4-triethylcyclobutyl,

Cyclopentyl,

2,2-dimethylcyclopentyl,

3-pentylcyclopentyl,

3-tert-butylcyclopentyl,

Cyclohexyl,

4-tert. -Butylcyclohexy 1,

3-isopropylcyclohexyl,

2,2-dimethylcyclohexyl,

Cycloheptyl,

Cyclooctyl,

Cyclononyl, and cyclodecyl.

Examples of phenylalkyl radicals with 7 to 10 carbon atoms inclusive are the following radicals:

OH

y.0 ^ C ^ CH2-L-Ri

1 (2 /

Benzyl, 15 1-phenylethyl, 2-phenylethyl,

2-phenylpropyl, 4-phenylbutyl, and

3-phenylbutyl.

20th

25th

Examples of aralkyl radicals with 7 to 12 carbon atoms are the radicals mentioned above for the phenylalkyl radicals with 7 to 10 carbon atoms and also the radicals:

2- (l-naphthylethyl) and l- (2-naphthylmethyl).

Examples of phenyl radicals which are substituted by 1,2 or 3 chlorine atoms or 30 alkyl radicals having 1 to 4 carbon atoms inclusive are the following radicals:

p-chlorophenyl, m-chlorophenyl, o-chlorophenyl,

2,4-dichlorophenyl, 2,4,6-trichlorophenyl,

p-tolyl,

m-tolyl,

o-tolyl,

p-ethylphenyl,

p-tert. -Butylphenyl,

2,5-dimethylphenyl, 4-chloro-3-methylphenyl, and 2,4-dichloro-3-methylphenyl.

35

40

45

Examples of alkylene radicals with 1 to 9 carbon atoms, in which 1 to 5 carbon atoms are present in a chain, are the radicals listed below, 50 which are examples of the grouping of the formula CgH2g given above:

Methylene, ethylene, trimethylene, tetramethylene and penta-methylene as well as those alkylene radicals in which one or more carbon atoms are bonded to one or more of the carbon atoms of the chains mentioned, for example radicals which have the following structures:

-CH (CH3) -, -C (CH3), -, -CH (CH2CH3) -, -CH2CH (CH3) -, -CH (CH3) -CH (CH3) -, -CH2-C (CH3) 2- , -CH2-CH (CH3) -CH3-, 60 -CH2-CH2-CH (CH2CH2CH3) -, -CH (CH3) -CH (CH3) -CH2-CH2-, -CH2-CH, -CH, -C (CH3) o-CH, and -CH, -CH, -CH, -CH, -CH (CH3) -.

Examples of alkylene radicals with 1 to 9 carbon 65 atoms, which have 0.1 or 2 fluorine atoms as substituents, and in which 1 to 6 carbon atoms are present in the chain, which are examples of groups of the structure CjH2j given above, are all those

639 378

28

groups mentioned in the previous section for the groupings of the formula CgH2g and also the hexamethylene radical, including hexamethylene radicals, which have 1 or more alkyl substituents on one or more carbon atoms of this hexamethylene radical, and also include those alkylene groups which 1 or 2 Fluorine substituents on one or two carbon atoms of the alkylene backbone, such as residues, which have the following structures:

-CHF-CH -, -, -CHF-CHF-, -CH -> - CH, -CF, -, -CH, -CHF-CHr, -CH, -CH, -CF (CH,) -, -CH -, - CH -> - CFj-CHI-, -CH (CH3) -CH.CH.-CHF-, -CH, -CH2-CH2-CF2-, -CHF-CH2-CH2-CH2-CH.-CHF -, -CFn-CH, -CH, -CH2-CH2-CH2-, -CH2-CH2-CH2-CF2-CH2-CH2- and -CH2-CH2-CH2-CH2-CH2-CH2-CF2.

Examples of radicals of the formula as defined above are the following radicals: phenyl,

(o-, m-, or p-) tolyl,

(o-, m-, or p-) ethylphenyl,

(o-, m-, or p-) propylphenyl,

(o-, m-, or p-) butylphenyl,

(o-, m-, or p-) isobutylphenyl,

(o-, m-, or p-) tert-butylphenyl,

2.3-xylyl,

2.4-xylyl,

2.5-xylyl,

2.6-xylyl,

3,4-xylyl,

2,6-diethylphenyl,

2-ethyl-p-tolyl,

4-ethyl-o-tolyl,

5-ethyl-m-tolyl,

2-propyl- (o-, m-, or p-) tolyl,

4-butyl-m-tolyl,

6-tert-butyl-m-tolyl,

4-isopropyl-2,6-xy ly 1,

3-propyl-4-ethylphenyl,

(2,3,4-, 2,3,5-, 2,3,6- or 2,4,5-) trimethylphenyl, (o-, m- or p-) fluorophenyl,

2-fluoro (o-, m-, or p-) tolyl,

4-fluoro-2,5-xylyl,

(2,4-, 2,5-, 2,6-, 3,4- or 3,5-) difluorophenyl,

(o-, m-, or p-) chlorophenyl,

2-chloro-p-tolyl,

(3-, 4-, 5- or 6-) chloro-o-tolyl,

4-chloro-2-propylphenyl,

2-isopropyl-4-chlorophenyl,

4-chloro-3,5-xylyl,

(2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-) dichlorophenyl,

4-chloro-3-fluorophenyl,

(3-, or 4-) chloro-2-fluorophenyl,

a, a, a-trifluoro- (o-, m- or p-) tolyl,

(o-, m- or p-) methoxyphenyl,

(o-, m- or p-) ethoxyphenyl,

(4- or 5-) chloro-2-methoxyphenyl and

2,4-dichloro (5- or 6-) methoxyphenyl.

With reference to the reaction scheme A, it should be pointed out that the starting materials of the formula IX used are either already described in the literature or can easily be prepared by processes known in the literature. In this context, reference is made, for example, to the following publications:

Derwent Farmdoc Abstract No. 46 957Y or US Pat. No. 4081478. Furthermore, Derwent Farmdoc No. 57511Y may also be mentioned. With regard to the compound 4,5-cis-didehydro-PGF] a and the derivatives of this compound, reference is made, for example, to US Pat. Nos. 3,933,889,3954835 and 4,028,419.

If protective groups with ether compounds are mentioned in the present documents, such as, for example, the tetrahydropyranyl radical, or the ethoxyethyl radical or other radicals which come under the meaning of the radical R13, reference should be made in connection with these groups, for example, to the publication by Corey et al ., in J. Am. Chem. Soc. 92, 397 (1970).

If the R13 group is a carboxyacyl group, an example of such a group is the benzoyl group. When such carboxyacyl groups are introduced, it is preferable to introduce them into halogen compounds of formula III using methods known in the literature. For example, benzoyl chloride can be reacted with a compound of formula III in the presence of a tertiary amine, such as, for example, in the presence of pyridine, at a temperature of 20 to 60 ° C. in an inert solvent, for example benzene, toluene or chloroform. In this connection, reference is made, for example, to US Pat. No. 3,778,450. Likewise, protecting groups or blocking groups, such as the tetrahydropyranyl radical or the ethoxyethyl radical, can be introduced into halogen compounds of the formula III by methods which are known in the literature. With regard to the introduction of the tetrahydropyranyl residue, it is possible, for example, to use the 2,3-dihydropyran in an inert solvent, such as methylene chloride, using temperatures of 20 to 50 ° C., and an acidic condensing agent is also present, such as p-toluenesulfonic acid. In this connection, reference is made, for example, to US Pat. No. 3944593.

In step a) of reaction scheme A, the starting material of formula IX is subjected to halogenation and cyclization, the halogen compounds of formula III being obtained. Various working methods can be carried out for this purpose. If you want to make the iodine compounds, you can use an aqueous system containing iodine and potassium iodide and an alkali carbonate or bicarbonate, or you can use an organic solvent, such as dichloromethane, which contains elemental iodine, operating in the presence of an alkali metal carbonate becomes. The reaction is carried out at temperatures below 25 ° C, preferably in the range of 0 to 5 ° C. The reaction time is generally 10 to 20 hours. The reaction mixture is then poured into sodium sulfite and sodium carbonate, and the compound of the formula III is separated off from the reaction mixture.

If you want to produce appropriate bromine compounds, then a suitable brominating agent is N-bromosuccinimide or N-bromoacetamide. In this connection, reference is made to Fieser et al., Reagents for Organic Synthesis, volume 1, pages 74 and 78, volume IV, page 51, published by John Wiley and Sons, Inc., N.Y. pointed out. If one wants to produce chlorine compounds, various working methods are available, for example the replacement of a bromine atom by a chlorine atom, using the silver salt of dichloridefluoroacetic acid. In this context, reference is made to I. T. Harrison et al., Compendium of Organic SyntheticMethods, page 346, 1971, Wiley Interscience, N.Y.

The halogen compounds of formula I are in the form of

5

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15

20th

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30th

35

40

45

50

55

60

65

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639 378

receive two isomers, one in a smaller amount and the other in a larger amount. The two isomers differ from one another in their mobility when performing chromatographies.

These C-5 and C-6 isomers can be separated from one another by silica gel chromatography, the elution, for example using methylene chloride (10-50%) acetone, first being the less polar (5S, 6S) isomer or (4S, 5S) isomers in an amount of about 8%, based on the total weight of product, and secondly the more polar (5R, 6R) isomer or (4R, 5R) isomer.

Usually these isomers do not have to be separated because each of the two possible isomers in reaction stage b) of reaction scheme A then provides the desired products.

In reaction stage b) of reaction scheme A, the halogen compound of formula III is converted into an equilibrium mixture of the 6-keto compound of formula I and the 6-hydroxy compound of formula II by bringing the compound of formula III together with silver carbonate and perchloric acid. This reaction is carried out in an inert organic medium, for example in tetrahydrofuran, and then a thin layer chromatography is then carried out in order to determine whether the reaction has already ended completely. Completion of the reaction will generally have taken place at a temperature of about 25 ° C after 15 to 24 hours. The reaction is preferably carried out in the absence of light.

Although the product of reaction step b) usually contains both compounds of the formula I and compounds of the formula II, a further adjustment of the equilibrium can nevertheless be achieved by merely preparing a solution of the product in question in an organic solvent, for example in acetone or in dichloromethane, and let this solution stand for several days. The mixture thus obtained is then concentrated and separated, for example by performing silica gel chromatography.

In the reaction step c) of reaction scheme A which may be carried out, protective groups or blocking groups which have the meanings as defined under R) 3 are split off from the products of reaction step b), provided such groups are present in the starting materials used Formula IX were present. After the protective groups have been split off, if any, the compounds of the formula Ia or IIa are obtained.

5 Working procedures described in the specialist literature can be used to split off the protective groups. For example, a mild, acidic hydrolysis can be carried out if tetrahydropyranyl groups or similar protective groups bonded via ether compounds are present, io one to carry out such hydrolysis, for example dilute acetic acid, aqueous citric acid or aqueous phosphoric acid in a solvent which contains both the starting material and the acids in question dissolves, such as tetrahydrofuran. If the protecting groups are 15 carboxyacyl groups, mild agents that release acyl groups, such as potassium carbonate in methanol, can be used at a temperature of about 25 ° C.

A preferred process for the preparation of amides which have the formula XV or the formula XVI

c-ch2-l-c-n (r9) (r18)

xv or

30th

35

oh 0

II

v-0-c-ch2-l-c-n- (r9) (ria)

v £ XVI

^ - ^^ X-C-R ^

fi, '

. Q

40 is that illustrated in Reaction Scheme B below. In this reaction scheme B

have the symbols L, Q ', R4, R9, Ri8, Ri9, ^ R ^ p ^ V, W, X and -

45 have the same meanings as given above.

Reaction scheme B

XVI

»

v

639 378

30th

ì

Ris 0

-? 11, w ^ CH-L-C-N (Rg) (R18)

XVI

(b)

\ /

-OH 0

--W ~ c-CH2-L-C-N (R9) (R18)

XV

+ "

0

II

—- CH2-L-C-N (R9) (Rie)

In this reaction scheme a B, a halogen acid of the formula XVII is used as the starting material and this is then converted into the corresponding amide of the formula XVIII, for example by the mixed acid anhydride process. For this purpose, the compound of formula XVII is treated with isobutyl chloroformate in the presence of a tertiary amine, for example in the presence of triethylamine, and an amine of the following formula is then used

HN (R9) (R] 8)

to in which the radicals R9 and Ri8 have the meanings given above. The amide of halogen acid thus obtained, which has the formula XVIII, is then subjected to a reductive dehalogenation, as described above in connection with the preparation of the mixture from the

XVI

Products of the formula X and XI in connection with the reaction scheme A has already been explained. In the present case, the reductive dehalogenation of the compounds of the formula XVIII results in a mixture of compounds 45 of the formula XV and XVI. If necessary, the products thus obtained can be separated from one another, for example by performing silica gel chromatography.

The following reaction scheme C describes the steps which are necessary to prepare the enol ethers 50 of the Formula V. In the reaction scheme C, the symbols have

L, Q ', R1; R4, r19, (^ 20) V, W, X and ~

55 has the same meaning as in the previous reaction scheme A.

31

639 378

(b)

V

L-Ri /

C-H

In Reaction Scheme C, the starting material can, for example, be the case when converting to

Compounds of formula XII used, which either already 55 want to carry out other useful compounds, are then described in the literature (in this context, such protected compounds can be easily obtained by referring to the literature that in connection with the compounds of formula XII or XIII have been mentioned in a suitable manner in reaction scheme A) or the compounds protected in this way have been replaced, or by simply working or described in the literature the end products obtained according to reaction scheme C of the process. Reacting the starting materials of formula IV above with a suitable reagent. If the given formulas XII do not differ from the starting material protecting groups in a last working step, the formulas of the formula IX which are used in reaction scheme A, in order then to obtain a product of the type it becomes, in that they have no protecting groups , illustrated by formula IV, then it is preferable that the halogen intermediates of formula XIII now that the protecting groups in question are not those which are bound by an ether group via and also the enol ethers of formula IV free of any 65, for example no Te Protection groups can be obtained. trahydropyranyl protecting groups because such protecting groups

If enol ethers corresponding to formula IV, which are normally removed by acid hydrolysis,

however, have protecting groups, such as when a product of the type defined by the

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32

Formula IV is illustrated, is contacted with an acid, then this product is easily converted to the corresponding 6-keto compound of Formula I.

In step a) of the reaction scheme C, the starting materials of the formula XII are subjected to halogenation, or in another way converted into the halogen compounds of the formula XIII, by carrying out such working procedures as described above in connection with the reaction scheme A have already been described.

In reaction step b) of reaction scheme C, the halogen compounds of the formula XIII thus obtained are then converted into the enol ether compounds of the formula IV by subjecting the compounds of the formula XIII to hydrogen halide elimination by bringing them together with a reagent suitable for carrying out such dehydrohalogenations. With regard to such reagents, reference is made, for example, to Fieser and Fieser, “Reagents for Organic Synthesis”, page 1308, published by John Wiley & Sons, Inc., New York, N.Y. (1967). Preferred materials used to carry out reaction step b) are tertiary amines and reagents selected from the following group of materials: sodium peroxide, potassium peroxide, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, sodium trifluoroacetate , Potassium trifluoroacetate, sodium bicarbonate, potassium bicarbonate, silver acetate and also tetraalkylammonium peroxides, which correspond to the following formula (Rn ^ NO;, in which R12 is an alkyl radical having 1 to 4 carbon atoms inclusive.

Of the tertiary amines, the amines given below are preferred:

1,5-diazabicyclo [4,3,0] nonen-5, abbreviated as «DBN»;

1,4-diazabicyclo [2,2,2] octane, abbreviated as «DABCO», and further

1,5-diazabicyclo [5,4,0] undecen-5, abbreviated as «DBU».

Other preferred reagents are sodium peroxide, potassium peroxide and also tetramethylammonium peroxide. For further information on peroxides that can be used, reference is made to the publication by Johnson and Nidy in J. Org. Chem. 40, 1680 (1975). If you want to carry out a synthesis on a large scale, electrochemical formation of the peroxides is recommended. In this connection, reference is made to the publication by Dietz et al. In J. Chem. Soc. (B), 1970, pages 816-820.

The reaction step in which the hydrogen halide is removed is generally carried out in an inert organic medium, for example in dimethylformamide, and this reaction is generally carried out by thin layer chromatography in order to observe how the starting material gradually disappears. This reaction takes place at a temperature of 25 ° C and can be accelerated by allowing it to take place at a temperature of 40 to 50 ° C.

When working up the reaction mixture, it is advantageous to maintain basic conditions, for example using triethylamine, in order to prevent decomposition of the products under acidic conditions or a change in the structure of the products. The purification can be accomplished by performing crystallization, followed by separation of impurities or starting material, these products remaining in the mother liquor, or purification by column chromatography. If you carry out a chromatographic separation, then a column filled with magnesium silicate, namely the product "FlorisilR", should be preferred to such a column filled with silica gel. A

Decomposition of the product can be avoided by subjecting the column to pretreatment with triethylamine.

As already mentioned above, the compounds of the formula I, II and IV can be administered in different ways and for different purposes, for example by intravenous, intramuscular, subcutaneous injection or infusion, and furthermore orally, intravaginally, rectally, buccally, sublingually and externally , or in the form of sterile implants if an extended effect is desired.

If an intravenous injection or infusion is desired, sterile aqueous isotonic solutions are preferred for this purpose. Tablets, capsules and liquid preparations, such as syrups, elixirs and simple solutions, are prepared using conventional pharmaceutical carrier materials when oral administration or sublingual administration is desired. If one wishes to produce a formulation that can be administered rectally or vaginally, one creates suppositories as is known to a person skilled in the art. If one wants to produce tissue implants, one uses a sterile tablet or a sterile capsule made of silicone rubber or another shaped body which contains the desired substance or is impregnated with the desired substance.

It should be noted that despite the fact that formulas which have a special configuration are represented in the reaction schemes, both with regard to the formulas of the starting materials and of the end products, the production steps described here nevertheless do not only optically relate to one or the other sourcing active isomers, but should also relate to mixtures, including race-mix mixtures or mixtures of enantiomeric forms.

If optically active products are desired, then optically active starting materials or optically active intermediates are used, or if racemic starting materials or racemic intermediates are used, the products obtained are separated by methods known to those skilled in the prostaglandin field .

The products which form in each reaction step are often mixtures and, as is known to those skilled in the art, they can be used as such for carrying out a subsequent reaction step or, if appropriate, they can also be used by customary methods of fractionation Separate column chromatography, liquid-liquid extraction or similar methods before proceeding with the further reaction steps.

Compounds corresponding to formula I, II, III or IV can be converted to one another by working procedures known in the art. For example, the compound of formula V is a compound derived from formula I

is included if the group / Rg 0) for a grouping of the formula V. J

OH

stands. This compound can be converted into another compound of the formula I in which the radical (Rg or another cyclopentane ring

5

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15

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25th

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35

40

45

50

55

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25th

which falls under the meaning given for the rest,

and, for example, an 11-deoxy compound, can be converted using procedures 5 that are either already known from the literature or are described here. A compound in which the grouping C13-Q4 represents a group of the formula trans-CH = CH- can be converted into another corresponding compound in which the group 10

C13-C14 stands for one of the following groupings cis-CH = CH-, -C = C-, or -CHjCTL-. For example, a corresponding group of the formula -C = C- can be prepared by performing a selective bromination and a hydrogen bromide elimination. 15

The invention will now be explained in more detail with reference to the following examples.

In these examples, all temperatures are given in ° C.

Infrared absorption spectra were recorded on an infrared spectrometer from Perkin-Elmer, model 421. Unless expressly stated otherwise,

then all recordings are carried out using undiluted, i.e. pure, samples.

Nuclear magnetic resonance spectra were recorded on Varian A-60, A-60D, T-60 or XL-100 spectrophotometers, recording in solutions in deuterochloroform using tetramethylsilane as the internal standard.

The mass spectra were recorded on a mass spectrometer 30 from Varian, model MAT CH7, a CEC model HOB double-focusing mass spectrometer of high resolution or a combination on a gas chromatograph with a mass spectrometer. For the latter purpose, the LKB Model 900 Gas Chromatograph-35 Mass Spectrometer was used, the ionization voltage being 22 ev or 70 ev, and the samples were generally made using trimethylsilyl derivatives as the tested compounds.

The term “sodium chloride solution” is understood here to mean an aqueous saturated sodium chloride solution.

The abbreviation «DBN» means 1,5-diazabicyclo- [4,3,0] nonen-5.

The abbreviation "D ABCO" means 1,4-diazabicyclo [2.2.2] octane. 45

The abbreviation «DBU» means 1,5-diazabicyclo [5,4,0] un-decen-5.

The abbreviations "E" and "Z" are used here in the same way as that of Blackwood et al. is explained in the literature cited above. 50

The product with the “Florisil” trademark is a magnesium silicate for chromatography purposes, which is produced by Floridin Co. In this connection it is also to Fieser et al., "Reagents for Organic Synthesis", page 393, publisher John Wiley and Sons, Inc., New York, 55 N.Y. (1967).

The abbreviation «TLC» means thin layer chromatography.

The term “silica gel chromatography” also means the work steps in which an elution is carried out 60 and the collection of fractions and also the union of those fractions with one another in which the thin-layer chromatograms showed that they released the desired product of unreacted raw material and contaminants. f> 5

The term “HPLC” means high pressure liquid chromatography.

The term “concentrate” or “concentrate” means a concentration under reduced pressure, preferably a pressure of less than 50 mm of mercury at temperatures which are below 35 ° C.

The abbreviation «DIB AL» means diisobutylaluminium hydride.

Preparation I

Preparation of the less polar isomer and more polar isomer of ^ -iodo-9-deoxy-6§, 9a-epoxy-PGFramides

The compound mentioned in the title corresponds to the formula XVIII, where the substituents have the following meaning:

L is a grouping of the formula - (CH2) 3-

Q stands for a group of the formula y ^ \

h oh

R4 represents the n-pentyl radical,

R9 and R18 represent hydrogen atoms,

Rw is an iodine atom, and the rest

R2 o) has the following structure and

X represents the group trans-CH = CH-,

In the production process described here, reference is made to reaction scheme B.

A solution of the mixed isomers of iodoic acid, which corresponds to the formula III or the formula XVII (example 4.5.0 g), in 50 ml of acetone is cooled to about −10 ° C. and mixed with 3.0 ml of triethylamine and 3, 0 ml of isobutyl chloroformate ester treated. After 5 minutes, 100 ml of acetic nitrile saturated with ammonia are added and the reaction mixture is allowed to warm to about 25 ° C. The mixture is then filtered and the filtrate concentrated. The residue obtained is taken up in ethyl acetate and water. The organic phase is washed with water, then dried over magnesium sulfate and then concentrated.

The residue thus obtained is then subjected to silica gel chromatography, eluting the mixtures of acetone + methylene chloride, starting with 25% acetone and increasing to 100% acetone. This gives 0.02 g of the less strongly polar isomer of iodo ether amide of the formula XVIII. This less polar isomer has an Rf value of 0.4 in thin layer chromatography on silica gel with acetone as the eluent.

A fraction is also obtained which contains 2.2 g of a mixture of the less polar isomer and more polar isomer, and finally 1.5 g of the more polar isomer. This last-mentioned product shows an Rf value of 0.37 in thin layer chromatography on silica gel, using acetone as eluent.

In the infrared spectrum it has absorptions at 3250.3150, 1660, 1610, 1085, 1065, 1050 and 965 cm "1.

In the nuclear magnetic resonance spectrum, peaks can be found at 6.4, 5.5, 3.5-4.7 and 0.9 ô.

Preparation II

Preparation of the mixed isomers of 5ç-iodo-9-deoxy-6ij, 9a-epoxy-PGF | -methylamides'

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34

The compound mentioned in the title corresponds to the formula XVIII, where R9 is a hydrogen atom and R18 represents a methyl group.

Reference is made to Reaction Scheme B. A solution of the mixed isomers of 5 | -iodo-9-deoxy-6§, 9a-epoxy-PGFi, which correspond to formula III or formula XVII (example 4,4,66 g) in 50 ml of acetone is mixed with 1 , 42 ml of triethylamine and cooled to -5 ° C. 1.3 ml of isobutyl chloroformate are then added with stirring at a temperature of 0 ° C. over a period of 5 min and then 25 ml of a 3 molar solution of methylamine in acetic acid nitrile. The solution is stirred for a further 20 min and during this time it warms up to about 25 ° C. The mixture is then filtered off and concentrated. The oily residue is triturated with methylene chloride and filtered to remove a precipitate. The filtrate is subjected to silica gel chromatography, using mixtures of acetone + methylene chloride as the eluent, starting with 50% acetone and increasing to finally 90% acetone. The mixed isomers of 5 | -iodo-9-deoxy-6 |, 9a-epoxy-PGFr methylamides are obtained in an amount of 3.45 g. These mixed isomers showed peaks at 6.3, 5.4-5.7, 3.2-4.7, 2.78 and 0.7-2.65 ô in the nuclear magnetic resonance spectrum.

Preparation III Preparation of the Mixed Isomers of 5 | -Iodine-9-deoxy-

6§, 9a-epoxy-PGFi-n-butylamides The compound mentioned in the title corresponds to the formula XVIII, where R9 is a hydrogen atom and R18 is the n-butyl radical.

Reference is made to Reaction Scheme B. A solution of the mixed isomers of iodoic acid, which corresponds to formula III or formula XVII (example 4.5.0 g) in 50 ml of acetone is cooled to about -10 ° C. and with 2.0 ml of triethylamine and 1.9 ml Isobutyl chloroformate treated. After 6 minutes, a solution of 15 ml of n-butylamine in 20 ml of acetone is added. After about 15 minutes, the reaction mixture is allowed to warm to 25 ° C. and stirred for 3 hours. The mixture is then concentrated and the residue taken up in ethyl acetate. The solution is washed with water and with brine, then dried over magnesium sulfate and concentrated. The residue obtained is chromatographed on silica gel, eluting with mixtures of acetone + methylene chloride, starting with 5% acetone and ending with 100% acetone. 5.3 g of the compound mentioned in the title are obtained.

The product thus obtained is chromatographed again to remove the color and silica gel is used and eluted with a mixture of acetone + methylene chloride in a mixing ratio of 1: 3.

0.48 g gives the compounds mentioned in the title in the form of a pale yellow oil in an amount of 0.35 g. This product has an Rf of 0.63 on thin layer chromatography on silica gel using acetone on eluent. In the infrared spectrum it shows peaks at 3300, 3100, 1735, 1715, 1645, 1555, 1070, 1055, 1020 and 965 cm'1.

Preparation IV Preparation of the Mixed Isomers of 5 | -Iodine-9-deoxy-

6§, 9a-epoxy-PGFrbenzylamides The compound mentioned in the title corresponds to the formula XVIII, where R9 is a hydrogen atom and RJ8 stands for the benzyl radical.

Reference is made to Reaction Scheme B. In compliance with the procedures described in Preparation I, 4.66 g of the mixed isomers of 5 |

15

Iodine-9-deoxy-6ï |, 9a-epoxy-PGFi, which correspond to the formula III or XVII, is used, 1.08 g of benzylamine now being used instead of the methylamine used in preparation I. The crude product obtained is tographed on chroma-5 silica gel, eluting with mixtures of acetone plus methylene chloride, starting with 50% acetone and ending with 70% acetone, the mixed isomers of 5c-iodine-9-deoxy-6'§ being , 9a-epoxy-PGFrbenzylamides obtained. The yield of this product is 4.1 g, and in the nuclear magnetic resonance spectrum it shows peaks at 7.3.6.6.5.3-5.7 and 3.5-4.6 Ô.

Preparation V

Preparation of the mixed isomers of 5§-iodine-9-deoxy-6'§, 9a-epoxy-PGFranilides

The compound mentioned in the title corresponds to the formula XVIII, where R9 is a hydrogen atom and R1S represents the phenyl radical.

Reference is made to Reaction Scheme B. 20 In compliance with the working procedure of preparation I, 4.66 g of the mixed isomers of 5 | -iodo-9-deoxy-6 |, 9a-epoxy-PGFi are used, which correspond to formula III or XVIII. Furthermore, 0.94 g of 25 aniline is used as the starting material. The crude product obtained is chromatographed on silica gel, eluting the mixtures of acetone + methylene chloride, starting with 10% acetone and ending with 50% acetone. The mixed isomers of 5 | -iodo-9-deoxy-6 | -9a-epoxy-PGFi-anilides are obtained in an amount of 4.0-30 g. This product showed peaks at 8.4, 6.9-7.7, 5.3-5.7 and 3.4-4.7 ô in the nuclear magnetic resonance spectrum.

example 1

Preparation of the mixed isomers of 51-iodo-9-deoxy-35 6 | , 9a-epoxy-PGFrmethyl ester, and also the separated

Isomers

The compound mentioned in the title corresponds to the formula III, the substituents having the following meanings: L is a grouping of the formula - (CH2) 3-40 Q, stands for the following structure

/ \

h oh

45 Ri is a grouping of the formula -COOCH3, R4 means the n-pentyl radical,

R19 stands for an iodine atom,

© is a grouping of the formula

55

and

60 X means the group trans-CH = CH-,

Reference is made to reaction scheme A, stage a).

A suspension of the PGF2a methyl ester, which corresponds to the formula IX, is used in the form of the corresponding 11,15-bis (tetrahy-65 dropyranyl) ether. The suspension contains 2.0 g of this derivative in 23 ml of water and is treated with 0.7 g of sodium bicarbonate and cooled in an ice bath. 1.93 g of potassium iodide and 2.82 g are added to the solution thus obtained

35

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Iodine is added and the mixture is stirred at a temperature of 0 ° C. for 16 h. A solution of 1.66 g of sodium sulfite and 0.76 g of sodium carbonate in 10 ml of water is then added. After a few minutes, the mixture is extracted with chloroform. The organic phase is washed with brine, dried over sodium sulfate and concentrated to give mainly the bis (tetrahydropyranyl) ether of the compound mentioned in the title, in an amount of 2.2 g in the form of an oil. This ether is then hydrolyzed in a mixture of acetic acid + water + tetrahydrofuran in a mixing ratio of 20: 10: 3, whereby mainly the compound mentioned in the title is obtained, which is then further purified by silica gel chromatography. When performing thin layer chromatography on silica gel using a mixture of acetone + dichloromethane in a mixing ratio of 30:70 as the eluent, this product gives an Rf value of 0.20. In the mass spectrum, the trimethylsilyl derivative of the compound of the formula III shows peaks at 638,623,607, 567, 548, 511 and 477.

The above-mentioned mixed isomers are separated by silica gel chromatography, eluting the mixtures of methylene chloride + acetone, starting with 15% methylene chloride and ending with 50% methylene chloride. About 4.0 g of the mixed isomers yield 0.29 g of the less polar (5S, 6S) isomer and 3.36 g of the more polar (5R, 6R) isomer. The Rf values are 0.42 for the less polar isomer and 0.40 for the more polar isomer when thin-layer chromatography is carried out on silica gel using ethyl acetate as the eluent.

The procedure described in Example 1 was now repeated, and the reaction scheme A was used again. However, the starting material of the formula IX used in Example 1 has now been replaced by the further compounds of the formula IX listed below, or the C-II derivatives which are indicated below and which likewise fall under the formula IX:

15-Methyl-PGFitt

15-ethyl-PGF2a

16,16-dimethyl-PGF2a ""

16,16-difluoro-PGF2a

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

PGD2 (this product can also be called ll-Desxoy-ll-oxo-PGF2a)

ll-deoxy-PGF2a

2a, 2b-Dihomo-PGF2a

3-oxa-PGF2a

3-oxa-17-phenyl-18,19,20-trinor-PGF2a

When these starting materials are used, the iodine compounds corresponding to formula III are obtained. Those iodine compounds which are obtained from unprotected compounds of the formula IX are illustrated in the reaction scheme C by the formula XII.

Example 2

Preparation of the 6-Ket0-PGFlo-methyl ester and the 9-deoxy-6 '£, 9a-epoxy-6 | -hydroxy-PGF1-methyl ester The 6-keto-PGFia-methyl ester mentioned in the title corresponds to the formula I, the substituents have the following meaning:

L, Ri, R4 and X have the same meaning as in Example 1. Q stands for a grouping of the formula

R 2 oi illustrates a grouping of the formula h oh and

10th

The second methyl ester mentioned in the title corresponds to formula II.

Reference is made to reaction scheme A, stage b).

15 A solution of 0.45 g of the methyl ester of the iodine compound of the formula III, which was obtained by the process according to Example 1, in 20 ml of tetrahydrofuran is treated with 0.250 g of silver carbonate and 0.10 ml of 70% perchloric acid, and the mixture is stirred a temperature of about 25 ° C for 20 24 h. Then the mixture is diluted with 25 ml of ethyl acetate and the organic phase is washed with saturated sodium carbonate solution and with brine, dried and concentrated to give 0.41 g of an oil.

When the product is separated by silica gel chromatography, by eluting with a mixture of ethyl acetate + Skellysolve B in a mixing ratio of 3: 1, the keto compound of the formula I mentioned in the title is mainly obtained, this compound being more polar than the starting material used of formula III. 0.32 g of an oil is obtained as 30 product, which shows the following Rf values in thin layer chromatography on silica gel: When using the upper phase of a mixture of ethyl acetate -I-methanol + water in a mixing ratio of 8: 2: 5, the is referred to as the M-2 system, the eluent is the 35 Rf value 0.38.

When using ethyl acetate as the eluent, the Rf value is 0.20.

When using a mixture of acetone + dichloromethane in a mixing ratio of 1: 1, the Rf value is 0.26. 40 The infrared spectrum shows the peak of the carbonyl group at 1740 cm "1.

The nuclear magnetic spectrum shows peaks at 5.5, 3.2-4.8, 3.7, 2.1-2.7 and 0.9 Ô.

In the mass spectrum, the trimethylsilyl derivative of the product provides lines at 600.3669.585.569.529.510.495.485.420, 349, 217 and 173.

The product can be made to crystallize with difficulty. Crystals of acetone + hexane have a melting point of 50 to 65 ° C, and crystals of ether + hexane 50 have a melting point of 68 to 74 ° C. The 6-hydroxy compound of formula II is also present in the product.

The infrared absorption spectrum of the paste-like pulp shows bands at 3380.1740 and 1710 cm "1. The infrared spectrum of a melted sample shows bands at 3390.1740.1720, 551245, 1200, 1170, 1090, 1055, 1020 and 970 cm" 1-

In compliance with the working procedure of Example 2, but replacing the iodine compound of the formula III used in Example 2 with those iodine compounds of the formula III which were subsequently listed in Example 1, 60 are obtained the corresponding keto compounds of the formula I and hydroxy compounds of the formula II.

Example 3

Preparation of the 9-deoxy-6'§, 9a-epoxy-6 ^ -methoxy-PGFr methyl ester

The compound mentioned in the title corresponds to the formula XIV. A solution of 0.32 g of the 6-keto compound of the formula I, which was obtained by the process according to Example 2, in 10

65

639 378

36

ml of methanol is left to stand at about 25 ° C for 2 days. The mixture is then concentrated and the product obtained is chromatographed on silica gel, using mixtures of ethyl acetate in Skellysolve B as the eluent, and one begins with 50% ethyl acetate and ends with 100 c / c ethyl acetate. This chromatography gives 0.10 g of the compound of the formula XIV mentioned in the title.

Thin-layer chromatography on silica gel, using a mixture of acetone + dichloromethane in a mixing ratio of 1: 1 as the eluent, gives an Rf value of 0.45.

The nuclear magnetic resonance spectrum provides' H NMR peaks at 5.5.4.35.4.0.3.68.3.12 and 0.9 ô, and 13C NMR peaks at 111.48 and 47.79 ppm, based on the tetramethylsilane.

In the mass spectrum, the tetramethylsilane derivative peaks at 512, 3498, 527, 511, 510, 471, 452, 439 and 427.

Example 4

Preparation of the 5§-iodo-9-deoxy-6'§, 9a-epoxy-PGFrmixed isomers of the formula III and the 9-deoxy-6 |, 9a-epoxy-6tj-hydroxy-PGFi of the formula II and the 6-keto -PGFla of formula I.

Reference is made to Reaction Scheme A.

A solution of 1.0 g of the product obtained by the process according to Example 1, namely the methyl ester of an iodine compound which corresponds to the formula III, in 30 ml of methanol is mixed with 20 ml of a 3-normal aqueous potassium hydroxide solution at about 0 ° C for about 5 min treated, and then at about 25 ° C for 2 h. The mixture is then acidified using 45 ml of a 2 normal acid potassium sulfate and 50 ml of water until a pH of 1.0 is reached, and the solution is saturated with sodium chloride and extracted with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and then concentrated to give 1.3 g of an oil.

This oil is subjected to chromatography on silica gel using mixtures of acetone 4-dichloromethane as the eluent, starting with a mixing ratio of 30:70 and ending with a mixing ratio of 50:50. This gives first the free acid of the formula III and then the mixtures of compounds of the formula I and II as a more polar fraction.

The compound of formula III was obtained in an amount of 0.33 g in the form of an oil, and it showed on thin layer chromatography on silica gel using a mixture of acetone + dichloromethane in a mixing ratio of 1: 1, with the addition of 2% acetic acid Eluent, an Rf value of 0.33.

Their optical rotation is [a] D = + 20 ° (C = 0.992 in chloroform).

In the infrared spectrum, it shows peaks at 3360, 2920, 2860, 2640, 1730, 1710, 1455, 1410, 1380, 1235, 1185, 1075, 1050, 1015, 970 and 730 cm "1.

In the mass spectrum, the trimethylsilyl derivative of the compound of the formula III showed peaks at 696.2554,681,625,606,569, 535, 479 and 173.

The mixture of the 9-deoxy-6 |, 9a-epoxy-6 ^ -hydroxy-PGF and the 6-keto-PGFlct is a solid and was obtained in an amount of 0.113 g and had a melting point of 93 to 98 ° C. This product did not contain iodine. It showed on thin layer chromatography on silica gel, using a mixture of acetone + dichloromethane in a mixing ratio of 1: 1. plus an additional 2% acetic acid as eluent, an Rf value of 0.13.

In the mass spectrum, the trimethylsilyl derivative showed peaks at 587, 568, 553, 497, 485, 478, 407, 395, 388 and 173.

Example 5

Preparation of the (5Z) -9-deoxy-6,9a-epoxy-A5-PGFramide The compound mentioned in the title corresponds to the formula IV, where the substituents have the following meaning: L is a grouping of the formula - (CH2) 3-,

Q stands for the following structure

/ \

h oh

R] is a grouping of the formula

0

II

-c-nh2

R4 represents the n-pentyl radical,

stands for a grouping of the formula oh and

X is the grouping trans-CH = CH-).

Reference is made to Reaction Scheme C.

A solution of 2.46 g of the 5 | -iodo-9-deoxy-6ç, 9a-epoxy-PGFramides prepared according to preparation I, which corresponds to the formula XIII, in 125 ml of benzene is mixed with 5 ml of 1,5-diazabicyclo- [ 4,3,0] nonen-5, abbreviated as «DBN», treated in 5 ml methylene chloride at 40 to 45 ° C for about 16 h. The mixture is cooled, diluted with ice water and shaken with benzene and methylene chloride, leaving a few drops of triethylamine in the organic phase. The combined organic phases are washed twice with water, dried and concentrated. The residue is recrystallized from ether and chloroform, 0.13 g of a product which has a melting point of 103 to 106 ° C. is then obtained from 0.25 mg of material. This product shows an Rf value of 0.42 on thin-layer chromatography on silica gel using acetone as the eluent.

In the infrared spectrum, the material shows absorption peaks at 3440.3360.3200, 1690, 1645, 1615, 1315, 1285, 1140, 1090, 1050 and 970 cm "1.

Example 6

Preparation of the (5Z) -9-deoxy-6,9a-epoxy-A5-PGFrmethyl amide

The compound mentioned in the title corresponds to the formula IV,

where the substituents L, Q, R4, and X are the same

Have meaning as in Example 5, and Rt is a grouping of the formula -C (0) NHCH3).

Reference is made to Reaction Scheme C.

A solution of 1.2 g of the mixed isomers of 5 | -iodo-9-deoxy-6 ^, 9a-epoxy-PGF1-N-methylamide, that is to say the product of the formula XIII prepared according to preparation II, in 75 ml of benzene treated with 3 ml of «DBN» at 40 ° C for 24 h and then refluxed for 3 h. The mixture thus obtained was cooled, diluted with 25 ml of benzene and washed with ice water. The organic phase was dried over sodium sulfate and concentrated. The residue was

5

10th

15

20th

25th

30th

35

40

45

SO

55

60

65

37

639 378

recrystallized from a mixture of acetone + hexane to give 0.27 g of the compound mentioned in the title, which had a melting point of 87-94.6 ° C. A mass spectrum of the trimethylsilyl derivative of this product with high resolution showed a peak at 581, 3740.

Example 7

Preparation of the (5Z) -9-deoxy-6,9a-epoxy-A5-PGF | -butvl amide

The compound mentioned in the title corresponds to the formula IV,

where the substituents L, Q, R4, ^ R ^ o) and X are the same

Have meaning as in Example 5, and Rt stands for a grouping of the formula -C (0) NHC4H9)

Reference is made to Reaction Scheme C. A solution of 3.5 g of the 5 ^ -iodo-6 |, 9a-epoxy-PGFi-n-butylamide prepared in preparation III in 100 ml of benzene is mixed with 8 ml of «DBN» at 40 to 45 ° C for about 16 h treated. The mixture is cooled, diluted with ice water and shaken with chloroform, leaving a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried and finally concentrated, giving 3.64 g of an oil. 3.1 g of this oil are taken up in warm diethyl ether and the ether solution provides 1.5 g of a product which is mainly solid when cooled. This product was recrystallized from ether and gave 0.85 g of a product with a melting point of 102 to 104 ° C.

Example 8

Preparation of the (5Z) -9-deoxy-6,9a-epoxy-A: '- PGFi-anilides The compound mentioned in the title corresponds to the formula IV,

where the substituents L, Q, R4, i and X are the same

R

L.Q.Rj. r20 I and X have the same meaning as in

Example 5

5 and R] stands for a grouping of the formula -C (0) NHCH2QH;).

Reference is made to Reaction Scheme C. A solution of 1.8 g of the 5 | -iodo-9-deoxy-6 |, 9a-epoxy-PGF] -benzylamide prepared in preparation IV in 100 ml of 10% benzene is mixed with 4 ml of «DBN» at about 40 ° C treated for 22 h. The mixture is then cooled, diluted with 50 ml of benzene and washed with ice water. The organic phase is dried and concentrated to give the compound mentioned in the title.

15

Example 10

Preparation of the 6-keto-PGFla amide and the 9-deoxy

6 '£, 9a-epoxy-6ç-hydroxy-PGFramides The 6-keto-PGFlcI-amide mentioned in the title corresponds to formula 20, the individual groups having the following meanings:

L is a grouping of the formula - (CH2) 3-Q represents the structure of the formula

H OH.

Ri represents a group of the formula -C (0) NH2,

R4 is the n-pentyl radical, and

30th

{R 2 o] has the structure of the formula

35

Have meaning as in Example 5, and

Ri is a grouping of the formula -C (0) NHC6H5).

Reference is made to Reaction Scheme C.

A solution of 1.8 g of the 9-deoxy-6 |, 9a-epoxy-PGFranilides prepared according to preparation V in 100 ml of benzene is treated with 4 ml of «DBN» at 40 ° C. for 22 h. The mixture is then cooled to about 25 ° C., diluted with 50 ml of benzene and washed with ice water. The organic phase is dried over sodium sulfate, treated with 1 ml of triethylamine and concentrated. 1.8 g of a product which is crystallized from ethyl acetate-hexane and recrystallized from acetone-hexane are obtained as the residue, giving 0.58 g of the compound mentioned in the title.

In thin-layer chromatography on silica gel, using a mixture of acetone + methylene chloride in a mixing ratio of 1: 1 with the addition of 1? C triethylamine as the eluent, this compound has an Rf value of 0.38.

In the mass spectrum, the trimethylsilyl derivative of this compound shows a peak at 643.3876. The infrared spectrum of the liquid melt showed absorption peaks at 3300.3140, 3060, ì 690.1665.162oT1600.1545.1500.1310.1295.1255.1130. 1085, 1045, 970, 755 and 695 cm'1.

Example 9

Preparation of the (5Z) -Deso. \ Y-6,9a-epoxy-A: '- PGF | -benzvl-amide

The compound mentioned in the title corresponds to the formula IV, the groups

40

and

X stands for the grouping trans-CH = CH-,

The 9-deoxy-6ç, 9a-epoxy-6ç-hydroxy-PGFramid mentioned in the title corresponds to the formula II.

43 A solution of 2.0 g of the (5Z) -9-deoxy-6.9ct-epoxy-A-PGFr amide prepared in accordance with the process according to Example 5 in 50 ml of tetrahydrofuran is treated with 3 ml of a 109% potassium hydrogen sulfate. After 10 to 20 minutes the mixture is concentrated. The residue is taken up in water and 50 ethyl acetate. The solution is then saturated with sodium chloride and diluted with acetone, the amount of acetone added corresponding to one fifth of the volume of the ethyl acetate. The organic phase is separated off and the aqueous phase is shaken out again with ethyl acetate 55. Then the organic phases are combined. washed with saline and concentrated.

The residue obtained is chromatographed on silica gel. eluting with mixtures of acetone plus methylene chloride, starting with 75 cc acetone and ending with 100 cc 60 acetone. and 0.25 g of the mixture of compounds mentioned in the title is obtained.

This mixture has an Rt 'value of 0.31 on thin-layer chromatography on silica gel using acetone as the eluent.

05 The trimethylsilyl derivative of the mixture shows peaks at 655, 3930, 640, 624, 552, 477, 243, 217 and 173 in the mass spectrum.

The infrared spectrum shows peaks at 3360. 1705. It> 70. 1020, 1455, 1410, 1090, 1050 and 970 cm'1.

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38

Example 11

Preparation of the 6-keto-PGFia-methylamide and the 9-deoxy-61,9a-epoxy-6§-hydroxy-PGFi-methylamide

The 6-Ket0-PGFlo-methylamide mentioned in the title corresponds to the formula I, the individual groups having the following meanings:

L, Q, R4, and X have the same meaning as in Example 10,

and Rj is a grouping of the formula -C (0) NHCH3).

The 9-deoxy-6§, 9a-epoxy-61-hydroxy-PGFi-methylamide mentioned in the title corresponds to the formula II.

A solution of 0.29 g of the (5Z) -9-deoxy-6,9a-epoxy-A5-PGFj-methylamide which has been prepared by the process according to Example 6 and which corresponds to the formula IV in 5 ml of tetrahydrofuran is mixed with about 1 ml treated with a 5% aqueous hydrochloride solution and stirring at 25 ° C for one hour. The mixture is diluted with 50 ml of saline and shaken out with ethyl acetate. The organic phase is washed with a saturated aqueous bicarbonate solution and a brine, then dried over sodium chloride and concentrated.

A second batch is made in the same manner, and the two products are combined and then chromatographed on silica gel. A mixture of acetone + methylene chloride is used as the eluent, starting with 50% acetone and ending with 100% acetone. This gives 0.17 g of the mixture of products mentioned in the title in the form of an oil. The trimethylsilyl-methylboronate derivative of this oil shows a line at 479.3223 in the high-resolution mass spectrum. In the nuclear magnetic resonance spectrum, peaks can be found at 6.7, 5.3-5.7, 3.5-4.9 and 2.78 ô.

Example 12

Preparation of the 6-keto-PGFia-n-butylamide and the 9-deoxy-6 |, 9a-epoxy-6 | -hydroxy-PGFi-n-butylamide

The 6-keto-PGFia-n-butylamide mentioned in the title corresponds to the formula I, where the individual substituents have the following meaning:

L, Q, R4, (R 2 0 / unc * X have the same meaning as in Example 10, "

Ri stands for a grouping of the formula -C (0) NHC4Hçi).

The second compound mentioned in the title corresponds to formula II.

A solution of 3.0 g of the (5Z) -9-deoxy-6,9a-epoxy-A5-PGFrn-butylamide prepared in Example 7 in 25 ml of tetrahydrofuran is treated with a sufficient amount of a 10% aqueous solution of potassium hydrogen sulfate, to bring the pH to 5.0. The mixture is then concentrated to remove the tetrahydrofuran and the rest is taken up in water and ethyl acetate. Sodium chloride is then added until saturation is reached and the organic phase is then separated off. The aqueous phase is shaken with a mixture of acetone plus ethyl acetate in a mixing ratio of 1: 4, and the organic phases are combined. Then the organic phases are washed with brine, dried and concentrated. The residue is 2.10 g and it is chromatographed on silica gel, using mixtures of acetone + methylene chloride, starting with 35% acetone and ending with 100% acetone, as eluent. This chromatography gives a 1: 1 mixture of the compounds mentioned in the title. This mixture shows an Rf value of 0.57 on thin-layer chromatography on silica gel using acetone as the eluent.

The mixture thus obtained is dissolved in 10 ml of tetrahydrofuran and acidified using an aqueous solution of potassium hydrogen sulfate. The mixture is converted almost completely into the 6-keto-PGFla-n-butylamide

5 converts. This product shows an Rf value of 0.58 in thin-layer chromatography on silica gel using acetone as the eluent. The product is obtained by concentrating the solution and dividing it between ethyl acetate and water. The organic phase is mixed with saline

10 solution washed and concentrated to give 1.90 g of an oil. This oil shows a peak at 641.4258 in the high-resolution mass spectrum in the form of its trimethylsilyl derivative.

Example 13

15 Preparation of 6-keto-PGFla-benzylamide and 9-de-oxy-6i, 9a-epoxy-6i-hydroxy-PGFrbenzylamide The 6-keto-PGFla-benzylamide mentioned in the title corresponds to formula I, the individual groups being the have the following meaning:

20th

L, Q, R4, (^ 2oj and X have the same meaning as in

25 Example 10, and

Rx stands for a grouping of the formula -C (0) NHCH2C6H5. The second product mentioned in the title corresponds to Formula II.

Process stage I:

30th

First, the bis (tetrahydropyranyl) ether of formula III is made. For this purpose, a solution of 2.0 g of the 5 | -iodo-9-deoxy-6§, 9a-epoxy-PGFrbenz-ylamides prepared according to preparation IV, which corresponds to the formula III, in 30 ml of methylene chloride with 2.5 ml of dihydropyran and 25 mg of p-toluenesulfonic acid 35 monohydrate at 25 ° C. for 25 min. The resulting mixture is diluted with 100 ml of methylene chloride and washed with 25 ml of a saturated aqueous sodium bicarbonate solution and 25 ml of brine. The organic phase is dried over sodium sulfate and concentrated. The residue 40 is then chromatographed on silica gel using mixtures of acetone + methylene chloride as eluent, starting with 5% acetone and ending with 25% acetone. This chromatography gives the bis (tetra-hydropyranyl) ether, which is subsequently referred to as bis (THP) ether-45, in an amount of 2.4 g.

This product in thin layer chromatography, using mixtures of acetone + methylene chloride, in a mixing ratio of 1: 1, as an eluent, has an Rf value of 0.73 on silica gel.

50

Process stage II:

Next, the enol ether-N-benzylamide-bis (THP ether of the formula IV is prepared. A solution of 2.4 g of the bis (THP) ether produced by process stage I in 100 ml 55 benzene is mixed with 4 ml " The mixture is then cooled, diluted with 25 ml of benzene and washed with 25 ml of ice water. The organic phase is dried and concentrated. The residue consists of the corresponding enol ester, ie of the (5Z) -9-deoxy-6,9a-60 epoxy-As-PGF1-benzylamide-bis (THP) ether, with the abbreviation “bis (THP) ether” for the “bis (tetrahy-dropyranyl ) -ether »stands.

The product obtained has an Rf value of 0.73 on silica gel, using acetone + methylene chloride in a mixing ratio of 1: 1 as the 65 eluent.

The product obtained is treated with a solution of 45 ml of tetrahydrofuran and 5 ml of a 5% aqueous hydrochloric acid at about 25 ° C. for 15 minutes. The received

39

639 378

ne mixture is diluted with 50 ml of saline and extracted with ethyl acetate. The organic phase is washed with brine, dried and concentrated to give the bis (THP) ether of the compound mentioned in the title in an amount of 2.0 g as an oil.

This oil shows an Rf value of 0.50 in thin layer chromatography on silica gel, using acetone + methylene chloride in a mixing ratio of 1: 1 as the eluent.

Process stage III:

The compound mentioned in the title of this example is obtained by hydrolytically cleaving the tetrahydropyranyl groups. For this purpose, 1.0 g of the product obtained according to process stage II is treated with 20 ml of a mixture of acetic acid + water + tetrahydrofuran in a mixing ratio of 20: 10: 3 at 40 to 45 ° C. for 3 1/2 hours. The mixture is then diluted with 30 ml of water and freeze-dried. The residue obtained is dissolved in methylene chloride and chromatographed on Florisil. The mixture is then eluted with mixtures of acetone plus methylene chloride, starting with 20% acetone and ending with 70% acetone. This gives 0.47 g of the impure product, which is chromatographed again on silica gel. This is eluted with mixtures of acetone + methylene chloride, starting with 50% acetone and ending with 100% acetone. This gives 0.34 g of the compound mentioned in the title. In thin layer chromatography on silica gel, using acetone + methylene chloride in a mixing ratio of 1: 1 as the eluent, this compound shows an Rf value of 0.07.

The nuclear magnetic resonance spectrum showed peaks at 7.26, 6.6-7.0, 5.2-5.6, 4.2-4.5, 3.5-4.2 and 0.7-3.0 O.

Example 14

Preparation of the (4R, 5R) -4-iodine-9-deoxy-5,9a-epoxy-PGF! -

methyl ester and the (4S, 5S) -4-iodo-9-deoxy-5,9a-epoxy-PGFj methyl ester

The two methyl esters mentioned in the title correspond to formula III.

Reference is made to Reaction Scheme A.

A solution of iodine in methylene chloride, namely 112 ml of a 2.5% solution (10.9 mmol) is added dropwise over a period of 35 min at room temperature to a stirred mixture of 2.01 g (5.45 mmol) of the cis -A4-PGFia-methyl-esters, which corresponds to the formula IX, which is dissolved in 260 ml of methylene chloride and 92 ml of a saturated aqueous solution of sodium bicarbonate. After 2 hours, the reaction mixture is worked up by first adding 1300 ml of methylene chloride and then shaking out with 80 ml of a 0.2 molar aqueous sodium thiosulfate solution. The two layers are quickly separated from one another and the organic layer is washed successively with 360 ml of water, with 140 ml of a buffer solution with a pH of 2 and again with 360 ml of water. The aqueous layer is then dried over magnesium sulfate, concentrated and the residue obtained is chromatographed on three high-pressure liquid chromatography columns from Merck (Merck B HPLC columns).

Using a mixture of acetone + hexane in a mixing ratio of 1: 3 as the eluent, the (4R, 5R) -4-iodo-9-deoxy-5,9a-epoxy-PGFrmethyl ester is first eluted in an amount of 1.215 g as a colorless oil.

This product shows an Rf value of 0.38 on thin layer chromatography using a mixture of acetone + hexane in a mixing ratio of 40:60.

Furthermore, the trimethylsilyl derivative of this product shows the following peaks in the mass spectrum: 638.2308.623.567.548, 517, 511, 477, 451 and 173.

In the nuclear magnetic resonance spectrum, recorded in deuterochloroform, the following proton resonances ('H NMR) are obtained at 5.50.3.98.3.67 and 0.88 ô. The following resonances are also obtained for carbon 13 (I3C NMR), again using deuterochloroform: 173.0.135.3, 132.4.79.6.79.0.78.1.72.8.52.5, 51.6.42.7.41.3.37.1.34.0, 5 32.2 31.7, 25.9, 25.2, 22.6, 21.7 and 14.0 Ô.

As a second product, the (4S, 5S) -4-iodo-9-deoxy-5,9a-epoxy-PGFrmethyl ester is eluted from the column in an amount of 0.440 g. This is a crystalline material that is available in the form of fine needles made of ether-hexane and has a melting point of 72 to 74 ° C.

In thin-layer chromatography on silica gel, using acetone + hexane in a mixing ratio of 40:60 as the eluent, this product gives an Rf value of 0.32.

In the nuclear magnetic resonance spectrum, recorded in 15 deuterochloroform, the product provides the following proton resonances ('H NMR) at 5.49.4.34.4.10.3.67 and 0.88 ô. Furthermore, the nuclear magnetic resonance spectrum, also recorded in deuterochloroform, provides the following resonances for carbon 13 (13CNMR) at 173.0.135.8.132.6, 20 75.9.73.0.71.3.54.4.51.7, 41.6.40.0.37.0.34.2.31.7.31.225.2, 24.4, 22.6, 20.7 and 14.0 Ô.

Example 15

25 Preparation of the mixed isomers of 4§-iodine-9-deoxy-5 ^, 9a-epoxy-PGF! and a mixture of 9-deoxy-5 |, 9a-epoxy-51-hydroxy-PGFj and 5-keto-PGFla

The first isomer mixture mentioned in the title corresponds to the formula III, the second product to the formula II and the last-mentioned compound to the formula I.

Reference is made to Reaction Scheme A.

A solution of 1.0 g of the methyl ester of the iodine compound obtained according to Example 14, which corresponds to the formula III, in 30 ml of methanol is treated with 20 ml of a 3-normal 35 aqueous solution of potassium hydroxide at about 0 ° C. for about 5 minutes and then at a temperature of 25 ° C for about 2 h. The mixture is then acidified using 45 ml of 2-normal acidic potassium sulfate and 50 ml of water until a pH of 1.0 is reached, then saturated with sodium chloride and shaken out with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated to give an oil. The oil obtained is subjected to silica gel chromatography, eluting using a mixture of acetone + dichloromethane.

In this chromatography, the compound of formula III is obtained first in the form of the free acid, and then the mixture of the compounds of formula I and II, which is the more polar fraction in this chromatography.

50 Example 16

Preparation of the 4 | -iodo-9-deoxy-5'§, 9a-epoxy-PGFramides, namely the less polar isomer and the more polar isomer

55 The compounds mentioned in the title correspond to formula XVIII, the groupings having the following meanings:

L is a grouping of the formula (-CH2). R Q stands for the following structure

60

/ \

h oh

65

R4 means the n-phenyl radical, R, j and RIg are hydrogen atoms, Rjq stands for an iodine atom,

is a grouping of the structure

639 378

40

\

/

OH

V means a single bond,

W is a methylene group and X stands for a grouping trans-CH = CH-.

Reference is made to Reaction Scheme B.

A solution of 5.0 g of the mixed isomers of iodoetheric acid of the formula III or XVII prepared by the process according to Example 15 in 15 ml of acetone is cooled to about -10 ° C., and this solution is then treated with 3.0 ml of triethylamine and 3.0 ml isobutyl chloroformate. After 5 minutes, 100 ml of acetic acid nitrile saturated with ammonia are added and the reaction mixture is allowed to warm to about 25 ° C. The mixture is then filtered and the filtrate concentrated. The residue is taken up in ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The residue thus obtained is subjected to silica gel chromatography, using a mixture of acetone + methylene chloride as the eluent. This gives the iodoether amide, which corresponds to the formula XVIII, as a less polar isomer and a fraction which is a mixture of the less polar and the more polar isomer, and finally the more polar isomer.

Example 17

Preparation of the mixed isomers of 4§-iodine-9-deoxy-5§, 9cc-epoxy-PGF rmethylamides

The compound mentioned in the title corresponds to the formula XVIII, where

R is a hydrogen atom and R; s represents the methyl radical.

Reference is made to Reaction Scheme B.

A solution of 4.66 g of the mixed isomers of 4§-iodine-9-deoxy-5§, 9a-epoxy-PGF], which correspond to the formula III or XVII, prepared by the process according to Example 15, in 50 ml of acetone treated with 1.42 ml triethylamine and cooled to -5 ° C. Subsequently, 1.3 ml of isobutyl chloroformate is added with stirring at 0 ° C. for 5 min, and then 25 ml of a 3 molar solution of methylamine in acetic acid nitrile. The solution thus obtained is stirred for a further 20 minutes, during which time it warms up to about 25 ° C. The mixture is filtered and concentrated. The oily residue obtained is triturated with methylene chloride and filtered to remove a precipitate. The filtrate is subjected to silica gel chromatography using mixtures of acetone + methylene chloride as eluent. This chromatography gives the mixed isomers of 4 ^ -iodo-9-deoxy-5 |, 9a-epoxy-PGFi-methylamides.

Example 18

Preparation of the mixed isomers of 4'§-iodo-5ç, 9 «-epoxy-PGF, -n-butylamides

The mixed isomers mentioned in the title correspond to the formula XVIII, where R; is a hydrogen atom and Rlk stands for the n-butyl radical.

Reference is made to Reaction Scheme B.

A solution of 5.0 g of the according to the procedure

Example 15 prepared mixed isomers of iodoetheric acid, which correspond to the formula III or XVII, in 50 ml of acetone is cooled to about -10 ° C, and treated with 2.0 ml of triethylamine and 1.9 ml of isobutyl chloroformate. After 6 minutes, a solution of 15 ml of n-butylamine in 20 ml of acetone is added.

After about 15 minutes, the reaction mixture is allowed to warm to about 25 ° C and stirred for 3 hours. The mixture obtained is concentrated and the residue is taken up in ethyl acetate. This organic solution is then washed with water and brine, dried over magnesium sulfate and concentrated.

The residue thus obtained is chromatographed on silica gel, using mixtures of acetone and methylene chloride as the eluent. You get the connection mentioned in the title. The product obtained in this way is chromatographed again in order to obtain it colorless, silica gel being used in this second chromatography and eluting using mixtures of acetone + methylene chloride.

Example 19

Preparation of the mixed isomers of 42j-iodo-9-deoxy-5§, 9a-epoxy-PGF i-benzylamides

The compound mentioned in the title corresponds to the formula XVIII, where

R9 is a hydrogen atom and Rlg represents the benzyl radical.

Reference is made to Reaction Scheme B.

The process described in Example 17 is carried out, using 4.66 g of the mixed isomers of 4 | -iodo-9-deoxy-5'§, 9a-epoxy-PGFi prepared by the process according to Example 15 as starting materials, which correspond to the formula III or XVII and also now uses 1.08 g of benzylamine instead of the methylamine used in Example 17. The crude product obtained is chromatographed on silica gel and eluted with mixtures of acetone + methylene chloride. The product obtained is the mixed isomers of 4§-iodine-9-deoxy-5§, 9a-epoxy-PGFj-benzyl-amides.

Example 20

Preparation of the (4Z) -9-deoxy-5,9a-epoxy-A4-PGF1 amide

The (4Z) -9-deoxy-5,9a-epoxy-A4-PGFr amide mentioned in the title corresponds to the formula IV, the individual groups having the following meanings:

L is a grouping of the formula - (ŒL ^ -, Q illustrates the structure h oh

R] means the group

0

il

. -c-nh23

R4 is the n-pentyl radical, and the radical ^ Rp ^ o) illustrates the structure

/

0h

V means a direct bond,

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W is a methylene group and X stands for the grouping trans-CH = CH-.

Reference is made to Reaction Scheme C.

A solution of 2.46 g of the 4 | -iodo-9-deoxy-5ç, 9a-epoxy-PGFp 5 amide, which is prepared by the process according to Example 16, which corresponds to the formula XIII, in 125 ml of benzene is mixed with 5 ml of l, 5- Diazabicyclo [4,3,0] nonen-5, abbreviated as DBN, treated in 5 ml methylene chloride at 40 to 45 ° C for about 16 h. The mixture obtained is cooled, diluted with ice water and extracted with benzene and methylene chloride, 10 leaving a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried and concentrated to give the compound mentioned in the title.

15

Example 21

Preparation of the (4Z) -9-deoxy-5,9a-epoxy-A4-PGF1-methyl amide

The compound mentioned in the title corresponds to the formula IV, the individual groupings having the following meanings 20:

L, Q, R4 (Rscj ^ V, W and X have the same meaning as in Example 20, and

Ri stands for a grouping of the formula -C (0) NHCH3).

Reference is made to Reaction Scheme C.

A solution of 1.2 g of the mixed isomers of 4ï | -iodo-9-deoxy-5 |, 9a-epoxy-PGFrN-methylamides prepared from the process according to Example 17, which have the formula XIII, in 75 ml of benzene is mixed with Treat 3 ml of DBN at 40 ° C for 24 h and then reflux for 3 h. The mixture is then cooled, diluted with 25 ml of benzene and washed with ice water. The organic phase is dried over sodium sulfate and concentrated to give the compound mentioned in the title.

25th

L, Q, R4, (R2o) y, W and X have the same meaning as in Example 20,

Ri stands for a grouping of the formula -C (0) NHCH2QH5. Reference is made to Reaction Scheme C.

A solution of 1.8 g of the 4 ^ -iodo-5ij, 9a-epoxy-PGFrbenzylämi-des prepared by the method according to Example 19 in 100 ml of benzene is treated with 4 ml of DBN at a temperature of about 40 ° C for 22 h . The mixture obtained is cooled, diluted with 50 ml of benzene and washed with ice water. The organic phase is dried and concentrated to give the compound mentioned in the title.

Example 24

Preparation of the 5-keto-PGFia-amide and the 9-deoxy-5,9a-epoxy-5 £ -hydroxy-PGFr amide The 5-keto-PGFla-amide mentioned in the title corresponds to the formula I, the individual groups being as follows Have meaning:

L represents a grouping of the formula - (CH2) 3-,

Q stands for the following structure h oh.

Ri means a group of the formula -C (0) NH2 R4 is the n-pentyl radical, the rest

30th

35

R20) means the structure oh

Example 22

Preparation of the (4Z) -9-deoxy-5,9a-epoxy-A4-PGFrn-butyl amide

The compound mentioned in the title corresponds to formula IV, the individual groups having the following meanings:

L, Q, R4, ^ 2oj [v, Wund X have the same meaning as in Example 20, and

Ri stands for a grouping of the formula -C (0) NHC4Hc |.

Reference is made to Reaction Scheme C.

A solution of 3.5 g of the 4S-iodo-5 ^, 9a-epoxy-PGFrn-butylamine-des prepared in 100 ml of benzene according to the method of Example 18 is mixed with 8 ml of DBN at 40 to 45 ° C for about 16 h treated.

The mixture obtained is cooled, diluted with ice water and extracted with chloroform, leaving a few drops of triethylamine in the organic phase. The organic phases thus obtained are combined, washed with ice water, then dried and finally concentrated to give the compound mentioned in the title.

Example 23

Preparation of the (4Z) -9-deoxy-5,9a-epoxy-A4-PGFrbenzyl amide

The compound mentioned in the title corresponds to formula IV, the individual groups having the following meanings:

40

V stands for a direct bond,

W is a methylene group and X illustrates the structure trans-CH = CH-.

The 9-deoxy-5,9a-epoxy-5 ^ -hydroxy-45 PGFi-amide mentioned in the title corresponds to the formula II.

A solution of 2.0 g of the (4Z) -9-deoxy-5,9a-epoxy-A4-PGFr amide prepared by the process according to Example 20 in 50 ml of tetrahydrofuran is treated with 3 ml of 10% potassium hydrogen sulfate. After 10-20 minutes the mixture is concentrated. The residue is taken up in water and ethyl acetate. The solution is saturated with sodium chloride and diluted with acetone using an amount of acetone equal to one fifth of the volume of the ethyl acetate. The organic phase is separated from the aqueous phase and this is shaken out again with ethyl acetate. The combined organic phases are washed with brine, dried and concentrated. The residue is chromatographed on silica gel, using mixtures of acetone + 60 methylene chloride as eluent. A mixture of the compounds mentioned in the title is obtained.

Example 25

Preparation of the 5-keto-PGFk, -methylamide and the 9-deoxy-f> 5 5,9a-epoxy-5î; -hydroxy-PGF 1 -methy lamides

The 5-keto-PGFlu-methylamide mentioned in the title corresponds to the formula I, the individual groups having the following meanings:

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42

l.q.r4. v, w and x have the same meaning as in Example 24,

ri stands for a grouping of the formula -c (0) nhch3.

The 9-deoxy-5,9a-epoxy-5 | -hydroxy-PGFrmethylamide mentioned in the title corresponds to the formula II.

A solution of 0.29 g of the (4Z) -9-deoxy-5,9a-epoxy-A4-PGFr methylamide, which is prepared by the process according to Example 21, and which corresponds to the formula IV, in 5 ml of tetrahydrofuran is mixed with about 1 ml of a Treated 5% aqueous hydrochloric acid and stirred at 25 ° C for 1 h. The mixture is diluted with 50 ml of sodium chloride solution and shaken out with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and a saline solution, then dried over sodium chloride and concentrated.

A second batch is made in the same manner and the two products are combined and then chromatographed on silica gel. A mixture of acetone + methylene chloride is used as the eluent, the mixture of the compounds mentioned in the title being obtained as a product.

Example 26

Preparation of the mixed isomers ds 5 | -iodo-9-deoxy-6 ^, 9a-epoxymethano-PGFrmethyl ester and the corresponding separate isomers. The compounds mentioned in the title correspond to formula III, the groups having the following meaning: L is a grouping of Formula - (CH ^ r,

qi stands for the following structure

/ \

H OH

Ri means the rest of the formula -COOCH3,

R4 is the n-pentyl radical,

Ri9 means an iodine atom,

(r2 i) is a grouping of the formula

OH

V and W represent methylene radicals, and X has the structure trans-CH = CH-.

Reference is made to reaction scheme A, step a.

A suspension of 2.0 g of the 9-deoxy-9a-hydroxymethyl-PGF2a methyl ester, in the form of the corresponding 11,15-bis (te-trahydropyranyl) ether (this compound corresponds to the formula IX) in 23 ml of water treated with 0.7 g sodium bicarbonate, and cooled in an ice bath. 1.39 g of potassium iodide and 2.82 g of iodine are added to the solution thus obtained, and the mixture is stirred at about 0 ° C. for 16 h. Then a solution of 1.66 g of sodium sulfite and 0.76 g of sodium carbo is added -nat added in 10 ml of water. After a few minutes, the mixture is shaken out with chloroform. The organic phase is washed with brine, dried over sodium sulfate and concentrated to give mainly the bis (te-trahydropyranyl) ether of the compound mentioned in the title. When this ether is hydrolysed in a mixture of acetic acid + water + tetrahydrofuran in a mixing ratio

20: 10: 3, the compound mentioned in the title is mainly obtained, which is then further purified using silica gel chromatography.

Example 27

Preparation of the mixed isomers of 5ç-iodine-9-deoxy-6 ^, 9a-epoxymethanol-PGFi and 9-deoxy-6 |, 9a-epoxy-methano-61-hydroxy-PGFt and 9-deoxy-9a-hydroxy -

methyl-6-keto-PGFla The mixed isomers mentioned first in the title correspond to formula III.

The 9-deoxy-6 |, 9a-epoxymethano-6 ^ -hy-droxy-PGF! corresponds to formula H.

Finally, the keto compound mentioned last in the title corresponds to Formula I.

Reference is made to Reaction Scheme A. A solution of 1.0 g of the iodine compound methyl ester, which has the formula III and prepared by the process according to Example 26, in 30 ml of methanol is treated with 20 ml of a 3-normal aqueous potassium hydroxide solution at about 0 ° C. for about 5 minutes. and then at about 25 ° C for about 2 hours. The resulting mixture is acidified using 45 ml of a 2 normal solution of acidic potassium sulfate and 50 ml of water until a pH of 1.0 is reached, and then the solution is saturated with sodium chloride and shaken with ethyl acetate. The organic phase is washed with brine, dried over sodium sulfate and concentrated to give an oil. This oil is subjected to chromatography on silica gel, using mixtures of acetone and dichloromethane as eluent. Elution gives first the compound which is a free acid and corresponds to the formula III, and then the mixture of the compounds of the formula I + II in the form of a more polar fraction.

Example 28

Preparation of the 5r§-iodo-9-deoxy-6 |, 9a-epoxymethano-PGFr amide in the form of the less polar isomer and the more polar isomer. The isomers mentioned in the title correspond to formula XVIII, the individual groups having the following meanings:

L is a grouping of the formula - (CH2) 3-,

Q stands for the structure

H OH

R4 is the n-pentyl radical,

R9 and R18 represent hydrogen atoms,

R19 stands for an iodine atom, the rest illustrates the structure

\

OH

V and W are methylene and X has the structure trans-CH = CH-.

Reference is made to Reaction Scheme B.

A solution of 1.0 g of the mixed isomers prepared by the method of Example 27, which are iodoether acids of formula III or XVII, in 10 ml of acetone is cooled to about -10 ° C and this mixture is treated with 0.6 ml of triethylamine and 0.6 ml of isobutyl chloroformate. After 5 min, 20 ml of acetic nitrile saturated with ammonia are added and the reaction is allowed to 5

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heat the mixture to about 25 ° C. The resulting mixture is filtered and the filtrate concentrated. The residue obtained is taken up in ethyl acetate and water. The organic phase is washed with water, dried over magnesium sulfate and then concentrated. The residue obtained is chromatographed on silica gel, using mixtures of acetone + methylene chloride as the eluent, starting with 25% acetone and ending with 100% acetone.

This gives a fraction which contains the less strongly polar isomer of iodine ether amide of the formula XVIII, and a further fraction which is a mixture of the less strongly polar isomer and the more polar isomer. Finally, the third fraction is the more polar isomer.

Example 29

Preparation of the mixed isomers of 5ç-iodo-9-deoxy-6ç, 9a-epoxymethano-PGFrmethylamides

The mixed isomers mentioned in the title correspond to the formula XVIII, the substituents having the following meanings:

Rt) is a hydrogen atom and Ris means the methyl radical.

Reference is made to Reaction Scheme B.

A solution of 1.0 g of the mixed isomers of 5§-iodo-9-deoxy-ó ^ cc-epoxymethano-PGF !, which correspond to the formula III or XVII, prepared by the method according to Example 27, in 10 ml of acetone treated with 0.3 ml of triethylamine and cooled to -5 ° C. Then 0.26 ml of the isobutyl ester of chloroformic acid is added with stirring at a temperature of 0 ° C. for 5 min and then 5 ml of a 3 molar solution of methylamine in acetic acid nitrile. The solution obtained is stirred for a further 20 min, during which time it is allowed to warm to about 25 ° C. The mixture is then filtered and concentrated. This gives an oily residue which is triturated with methylene chloride and then filtered to remove the precipitate formed. The filtrate is subjected to chromatography on silica gel, using mixtures of acetone + methylene chloride as the eluent, starting with 50% acetone and ending with 90% acetone. The mixed isomers of 5 | -iodo-9-deoxy-6 |, 9a-epoxymethano-PGFi-methylamides are obtained.

Example 30

Preparation of the mixed isomers of 5 | -iodo-6 |, 9a-epoxy-methano-PGF1-n-butylamide

The mixed isomers mentioned in the title correspond to the formula XVIII, the individual substituents having the following meanings:

R9 is a hydrogen atom and R18 represents the n-butyl radical.

Reference is made to Reaction Scheme B.

A solution of 1.0 g of the mixed isomers of iodoetheric acid, which correspond to the formula III or the formula XVII, prepared according to the method according to Example 27, in 10 ml of acetone is cooled to about -10 ° C. and with 2.0 ml Triethylamine and 38 ml of isobutyl chloroformate treated. After 6 minutes, a solution of 3 ml of n-butylamine in 4 ml of acetone is added. After a reaction time of about 15 minutes, the mixture is allowed to warm to about 25 ° C. and is stirred at this temperature for 3 hours. The mixture is then concentrated and the residue taken up in ethyl acetate. The solution thus obtained is washed with water and with brine and then dried over magnesium sulfate and concentrated. The residue obtained is chromatographed on silica gel, using mixtures of acetone plus methylene chloride as the eluent, starting with 5% acetone and ending with 100% acetone. This chromatography gives the isomers mixed in the title.

The product obtained in this way is then chromatographed again to remove its color, again chromatographed on silica gel and a mixture of 1 part acetone + 3 parts methylene chloride is used as the eluent.

Example 31

Preparation of the mixed isomers of 5 | -iodo-9-deoxy-ól ^ a-epoxymethano-PGFj-benzylamide

The mixed isomers mentioned in the title correspond to formula XVIII, the substituents having the following meanings:

R9 is a hydrogen atom and R18 represents the benzyl radical.

Reference is made to Reaction Scheme B.

The procedure described in Examples 28 and 29 is followed, using 1.0 g of the mixed isomers of 5§-iodine-9-deoxy-6§, 9a-epoxymetha-no-PGFj as starting material, which is of the formula III and XVII correspond. Furthermore, 0.22 g of the benzylamine is used as the starting material instead of the methylamine used in Example 29. The crude product obtained is chromatographed on silica gel, using mixtures of acetone + methylene chloride as eluent, starting with 50% acetone and ending with 70% acetone. This chromatography gives the mixed isomers of 5§-iodo-9-deoxy-6 |, 9a-epoxymethano-PGFrbenzylamides.

Example 32

Preparation of the mixed isomers of 5 | -iodo-9-deoxy-6 ^, 9a-epoxymethano-PGFi-anilides

The mixed isomers mentioned in the title correspond to formula XVIII, the substituents having the following meanings:

R9 is a hydrogen atom and Ris means the phenyl radical.

Reference is made to Reaction Scheme B.

The procedure is carried out in compliance with the working procedures described in Example 28 and Example 29, and 1.0 g of the mixed isomers of 5 | -iodo-9-deoxy-6§, 9a-epoxymethano-PGF !, which are used as starting material correspond to the formula III or XVII and also 0.1 g of aniline. The crude product obtained in this reaction is chromatographed on silica gel, using mixtures of acetone + methylene chloride as the eluent, starting with 10% acetone and ending with 50% acetone. The product obtained is the mixed isomers of 5§-iodine-9-deoxy-6§, 9a-epoxymethano-PGFi-anilides.

Example 33

Preparation of the (5Z) -9-deoxy-6,9a-epoxymethano-A5-PGFr amide

The (5Z) -9-deoxy-6,9a-epoxymethano-A5-PG framide mentioned in the title corresponds to the formula IV, the individual groups having the following meanings:

L stands for a group of the formula - (CHjV, Q illustrates the structure

H OH o

Ri means a group of formula 11

-C-NH2,

5

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15

2C

21st

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40

45

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55

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639 378

44

Rj is the n-pentyl residue, the residue (r? O) illustrates the structure

OH

V and W represent methylene radicals, and X means the grouping trans-CH = CH-.

Reference is made to Reaction Scheme C. A solution of 2.46 g of the 5 | -iodo-9-deoxy-6§, 9a-epoxymethano-PGFj-amide, which is prepared by the process according to Example 28, which corresponds to the formula XIII, in 125 ml of benzene is mixed with 5 ml of l, 5 -Diazabicyclo [4,3,0] nonen-5, abbreviated as DBN, treated in 5 ml of methylene chloride at a temperature of 40 to 45 ° C for about 16 h. The mixture obtained is diluted with ice water, shaken out with benzene and methylene chloride, leaving a few drops of triethylamine in the organic phase. The organic phases are combined, washed with ice water, dried and concentrated. The residue obtained is purified by chromatographing it on «Florisil», and the compound mentioned in the title is obtained.

Example 34

Preparation of the (5Z) -9-deoxy-6,9a-epoxymethano-A5-PGFr methylamide

The (5Z) -9-deoxy-6,9a-epoxymethano-A5-PGFrmethylamide mentioned in the title corresponds to the formula IV, the individual substituents having the following meanings:

L, Q, R4, (^ 2 ^ and X have the same meaning as in Example 33, and

Ri stands for the grouping -C (0) -NHCH3.

Reference is made to Reaction Scheme C. A solution of 1.2 g of the mixed isomers of 5c-iodine-9-deoxy-6t, 9a-epoxymethano-PGFi-N-methylamides, which correspond to the formula XIII, prepared in accordance with the method according to Example 29, in 75 ml of benzene was mixed with 3 ml of DBN treated at 40 ° C for 24 h and then the solution was refluxed for 3 h. The resulting mixture was cooled, diluted with 25 ml of benzene and washed with ice water. The organic phase is dried over sodium sulfate and concentrated. The residue obtained is purified by chromatography on «Florisil», and the compound mentioned in the title is obtained.

Example 35

Preparation of the (5Z) -9-deoxy-6,9a-epoxymethano-A3-PGFrn-butylmamide

The compound mentioned in the title corresponds to formula IV, the individual groups having the following meanings:

L, Q, R4, (Rao) and X have the same meaning as in Example 33, and

R, is a grouping of the formula -C (0) NHC4Hy.

Reference is made to Reaction Scheme C.

A solution of 3.5 g of the 5S-iodo-6H, 9a-epoxymethano-PGF | -n-butylamide prepared in the process according to Example 30 in 100 ml of benzene is mixed with 8 ml of DBN at a temperature of 40 to 45 ° C during treated for about 16 h. The mixture obtained is cooled, diluted with ice water and extracted with chloroform, leaving a few drops of triethylamine in the organic phase. The combined organic phases are washed with ice water, dried and concentrated. The residue obtained is chromatographed on «Florisil», giving the compound mentioned in the title.

Example 36

Preparation of the (5Z) -9-deoxy-6,9a-epoxymethano-A: i-PGF1-anilide

The compound mentioned in the title corresponds to the formula IV, where the substituents have the following meanings:

L, Q, R4. (J ^ êo) and X have the same meaning as in Example 33, and

R! represents a radical of the formula -C (0) NHC6H5.

Reference is made to Reaction Scheme C. A solution of 1.8 g of the 9-deoxy-6ç, 9cc-epoxymethano-PGF r anilides prepared by the process according to Example 32 in 100 ml of benzene is treated with 4 ml of DBN at 40 ° C. for 22 h. The mixture is then cooled to about 25 ° C. and diluted with 50 ml of benzene and washed with ice water. The organic phase is dried over sodium sulfate, treated with 1 ml of triethylamine and concentrated. The residue obtained is purified by chromatography on "Florisil", whereby the compound mentioned in the title is obtained.

Example 37

Preparation of the (5Z) -9-deoxy-6,9a-epoxymethano-A6-PGFr benzylamide

The compound mentioned in the title corresponds to the formula IV, the individual substituents having the following meanings:

L, Q, R4, (^ o) and X have the same meaning as in Example 33, and

Rj stands for the grouping of the formula -C (0) NHCH2C6H5. Reference is made to Reaction Scheme C. A solution of 1.8 g of the 5 ^ -iodo-6 |, 9a-epoxymethano-PGFrbenzylami-des prepared in 100 ml of benzene according to the method of Example 31 is treated with 4 ml of DBN at about 40 ° C for 22 h. The mixture thus obtained is then cooled, diluted with 50 ml of benzene and washed with ice water.

The organic phase is dried and concentrated to give the compound mentioned in the title.

Example 38

Preparation of the 9-deoxy-9a-hydroxymethyl-6-keto-PGF10 amide and the 9-deoxy-6,9a-epoxymethano-6 | -hydroxy-PGF, amide

The 9-deoxy-9a-hydroxymethyl-6-keto-PGF | "-amide mentioned in the title corresponds to the formula I, where the substituents have the following meanings:

L stands for a grouping of the formula -CH ^ Xt, Q illustrates the structure

Ri means a grouping of the formula -C (0) NH2,

s

10th

15

20th

25th

30th

35

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639 378

R4 is the n-pentyl radical. the rest

(R p n illustrates the structure

OH

V and W are methylene groups, and X represents the structure trans-CH = CH-.

The 9-deoxy-6,9a-epoxymethano-6§-hydroxy-PG framide mentioned in the title corresponds to the formula II.

A solution of 2.0 g of the (5Z) -9-deoxy-6,9a-epoxymethano-A5-PGFramides prepared in accordance with the procedure of Example 33 in 50 ml of tetrahydrofuran is treated with 3 ml of a 10% solution of potassium hydrogen sulfate. After 10 to 20 minutes the mixture is concentrated. The residue is taken up in water and ethyl acetate. The solution is saturated with sodium chloride and diluted with acetone, using an amount of acetone which corresponds to one fifth of the volume of the ethyl acetate used. The organic phase is separated off and the aqueous phase is shaken out again with ethyl acetate. The combined organic phases are then washed with brine, dried and concentrated. The residue obtained is chromatographed on silica gel, using mixtures of acetone plus methylene chloride as eluent. A mixture of the compounds mentioned in the title is obtained.

Example 39

Preparation of the 9-deoxy-9a-hydroxymethyl-6-keto-PGFi-methylamide and the 9-deoxy-6,9a-epoxymethano-6 ^ -hydroxy-PGFj-methylamide

The 9-deoxy-9a-hydroxymethyl-6-keto-PGFrmethylamide mentioned in the title corresponds to the formula I, the individual groups having the following meanings:

L, Q, R4, and X have the same meaning as in

Example 37, and

Rj stands for a group of the formula -C (0) NHCH3.

The 9-deoxy-6.9cc-epoxymethano-6§-hydroxy-PGFi-methylamide mentioned in the title corresponds to formula II.

A solution of 0.29 g of the (5Z) -9-deoxy-6,9a-epoxymethano-A ^ -PGFi-methylamide, which corresponds to the formula IV, prepared according to the method in Example 34, in 5 ml of tetrahydrofuran is mixed with about 1 ml of a 5% aqueous hydrochloric acid treated and stirred at 25 ° C for 1 h. The mixture is diluted with 50 ml of saline and shaken out with ethyl acetate. The organic phase is washed with a saturated aqueous sodium bicarbonate solution and with brine, and then dried over sodium chloride and concentrated.

A second batch is prepared in the same way, and the two products are combined and the combined material is chromatographed on silica gel. In this chromatography, a mixture of acetone + methylene chloride is used as the eluent. You get the connection mentioned in the title.

Example 40

Preparation of 9-deoxy-9ra-hydroxymethyl-6-keto-PGF2l-n-butyiamide and 9-deoxy-6,9a-epoxy-6-hydroxy-PGFrn-butylamide

The 9-deoxy-9a-hydroxymethyl-6-keto-PGFpn-butylamide mentioned in the title corresponds to the formula I, the individual groups having the following meanings:

L, Q, R4, | R2 and X have the same meaning as in Example 37, and

10 Rj stands for a grouping of the formula -C (0) NHC4H9.

The 9-deoxy-6,9a-epoxy-6-hydroxy-PGFr n-butylamide mentioned in the title corresponds to the formula II.

A solution of 3.0 g of the (5Z) -9-deoxy-6,9a-epoxymethano-15A ^ -PGFj-n-butylamide prepared in accordance with the process according to Example 35 in 25 ml of tetrahydrofuran is diluted with a sufficient amount of 10% treated aqueous solution of potassium hydrogen sulfate to bring the pH of the solution to 5.0. The resulting mixture is then concentrated to remove the tetrahydrofuran and the residue 20 is taken up in water and ethyl acetate. Then sodium chloride is added to saturation and the organic phase is separated off. The aqueous phase is shaken with a mixture of acetone + ethyl acetate in a mixing ratio of 1: 4, and the organic phase obtained is combined with the first organic phase. These combined organic phases are then washed with brine, dried and concentrated. The residue obtained is chromatographed on silica gel, using mixtures of acetone + methylene chloride as the eluent. A mixture of the compounds mentioned in the title is obtained.

Example 41

Preparation of the 9-deoxy-9a-hydroxymethyl-6-keto-PGF1-35 benzylamide and the 9-deoxy-6,9a-epoxymethano-6-hydroxy-PGFrbenzylamide

The 9-deoxy-9a-hydroxymethyl-6-keto-PGFpbenzylamide mentioned in the title corresponds to the formula I, the individual groups having the following meanings:

25th

30th

40

L, Q, R,

and X have the same meaning as in

Example 37, and

45 Ri stands for a grouping of the formula -CfOJNHCrLQHs-The 9-deoxy-6.9cc-epoxymethano-6-hydro-xy-PGFrbenzylamide mentioned in the title corresponds to the formula II.

Reaction stage I:

So first the bis (tetrahydropyranyl) ether, which is called

Until (THP) ether is abbreviated, the compound of formula III is prepared.

A solution of 2.0 g of the 5 | -iodo-9-deoxy-6'ç, 9a-epoxy-PGFr 55 benzylamide of the formula III prepared in accordance with the method of Example 31 in 30 ml of methylene chloride is mixed with 2.5 ml of dihydropyran and 25 mg of p-toluenesulfonic acid monohydrate were stirred at 25 ° C. for 25 minutes. The mixture is then diluted with 100 ml of methylene chloride and washed with 25 ml of a saturated aqueous sodium bicarbonate solution and further with 60 25 ml of a saline solution. The organic phase is dried over sodium sulfate and concentrated. The residue obtained is chromatographed on silica gel and eluted with a mixture of acetone + methylene chloride, giving the corresponding bis (THP) ether.

65

Reaction stage II:

Next, the enol ether-N-benzylamide bis (THP) ether corresponding to formula IV is prepared.

639 378 46

A solution of 2.4 g of the obtained after reaction stage I: where the bis (THP) ether of the bis (THP) ether mentioned in the title is dissolved in 100 ml of benzene with 4 ml of 1,5-compound receives.

Diazabicyclo [4,3,0] nonen-5, abbreviated as «DBN», in one

Temperature of 40-45 ° C for 22 hours. The mixture reaction stage III:

is cooled, diluted with 25 ml of benzene and with 25 ml of ice water 5 The compound mentioned in the title is obtained by washing. The organic phase is then dried hydrolytically and the THP groups are split off.

and focused. The residue thus obtained consists of for this purpose 1.0 g of the enol ether, i.e. So from the (5Z) -9-deoxy-6,9a-epoxy product obtained with 20 ml of a mixture of acetic acid + methano-A5-PGF1-benzylamide-bis (THP) ether. This backwater + tetrahydrofuran in a mixing ratio of 20: 10: 3 was then treated with a solution of 45 ml of tetrahydrofuran and 10 at 40-45 ° C for 3/4 h. The mixture is diluted with 30 5 ml of a 5% aqueous hydrochloric acid in 1 ml of water and freeze-dried. The resulting return temperature of about 25 ° C was treated for 15 min. The resulting solution is dissolved in methylene chloride and the mixture obtained on “Florisil” is diluted with 50 ml of sodium chloride solution and matographed. Mixtures with ethyl acetate are shaken out as the eluent. The organic phase from acetone + methylene chloride and thereby receives the title is washed with brine, dried and concentrated 15- compound.

m

Claims (20)

639 378 PATENT CLAIMS 1. Halogen-containing prostaglandin derivative, characterized in that it has the formula III 0 R 1 3 0 ^ CH ~ CH-L-C-N (IO (Ris) / (III) or is a mixture which contains the compound of the formula III and the enantiomer of the compound of the formula III, where in the formula III OR 13 > 1 3 ^ s 1) for a grouping of the formulas • 0 CHe * / <X ' stands in which R13 has the following meanings: a) a hydrogen atom, b) a tetrahydropyranyl radical, c) a tetrahydrofuranyl residue, d) a 1-ethoxyethyl radical, e) a grouping of the formula H Ri. Ri: R>: '1 4 -o-c L C-Rir I. Rie 40 45 in which an alkyl radical with 1 to 18 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical or a phenyl radical, as substituents 1, 2 or 3 alkyl radicals with 1 to 4 carbon atoms has, is and Rif, are identical to or different from one another and the meaning of hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms, phenyl radicals or phenyl radicals which are substituted by 1, 2 or 3 alkyl groups having 1 to 4 carbon atoms , has, or and R! 6 together for a grouping of the formula - (CH;) a- or a grouping of the formula - (CH2) b-0- Rr 50 bleak CHaORia (CH2) c-, where a is 3, 4 or 5 in these groups, b represents 1, 2 or 3, and c represents the number 1, 2 or 3, provided that the sum of b + c2, 3 or 4, and wherein represents a hydrogen atom or a phenyl radical, or f) is an acyl radical which has the following structures: a ') a grouping of the formula 0, (A) a 55 60 in which A is an alkyl group of 1 to 4 carbon atoms, a bromine atom, a phenylalkyl group of 7 to 10 carbon atoms, or a nitro group, and e has a value of 0 to 5, provided that no more than two substituents A are different Have meaning than that of alkyl groups, and furthermore the total number of carbon atoms in all substituents A is not more than 10 carbon atoms, b ') a grouping of the formula 65 0 "-GT COOR30 3rd 639 378 C) w L in which Rai is an alkyl radical with 1 to 4 carbon atoms, a grouping of the formula 0 d ') in which both A and e have the same meanings as given under a '), a grouping of the formula 0 II -c ■ R 31 in which R31 is an alkyl radical with 1 to 7 carbon atoms inclusive, is a methylene group or an ethylene group, if wine represents methylene group, for one of the 10th 15 L 20th Q / \ H H following groupings (1) - (CH:) d-C (R:) r (2) -CH2-0-CH, -Y- or (3) -CH2CH = CH-, in which d has a value from 0 to 5 inclusive, the radicals R2 are identical or different from one another and have the meaning of hydrogen atoms, methyl radicals or fluorine atoms, provided that one of the two Residues R2 must not have the meaning of the methyl group if the other is a fluorine atom, and Y stands for a direct bond or a grouping of the formula -CH2- or - (CH2) 2-, and that if wine is an ethylene group, one of the following meanings (1) - (CH2) d-C (R2) 2- (2) -O-CH2-Y- or (3) -CH = CH-, has, where d, R2 and Y have the meaning given above for one of the following structures / \ RQ OR 13 or Ra / \ OR ii stands in which Rg represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, 30th R4 R13 has the meanings given in connection with the cyclopentane structures, for one of the following structures re (l) -C-CgHag-CH3 RE (2) R5 I -C-Z I. re (T): or (5) -CH2 ^ ^ -CtìsCHs C = C ^ H- ^ H stands in which CgH2g is an alkylene group with 1 to 9 carbon atoms, with 1 to 5 carbon atoms in the chain between the grouping of the formula -CR5R6- and the terminal 50 methyl group, R5 and R6 are the same or different from one another and denote hydrogen atoms, alkyl groups with 1 to 4 carbon atoms or fluorine atoms, provided that only one of the radicals 55 Rj or Rf is a fluorine atom if the other of these radicals is R19 Is hydrogen atom or also a fluorine atom, and R9 with the further proviso that neither the radical R5 nor the radical R (, may be a fluorine atom if Z is a Rls oxa grouping of the formula (-0-), 60 Z for an oxa oxygen atom of the formula (-0-) or one Grouping of the formula CjII:], the structure of the formula CjH2j representing a direct bond or an alkylene group having 1 to 9 carbon atoms, in this alkylene group there are 1 to 6 65 V carbon atoms in the chain. between the grouping of the formula -CR5Rfr and the phenyl nucleus X lies. the radicals T are identical or different from one another and have the meaning of alkyl radicals having 1 to 4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl groups or groups of the formula -OR7, in which R7 is alkyl radicals having 1 to 4 carbon atoms, and have a value of 0, 1, 2 or 3, provided that, however, no more than two radicals T have a meaning other than that of alkyl groups if s has a value of 2 or 3, represents a chlorine atom, bromine atom or iodine atom, represents a hydrogen atom, a methyl group or an ethyl group, and a hydrogen atom, an alkyl group having 1 to 4 carbon atoms inclusive, an aralkyl group having 7 to 12 carbon atoms inclusive, a phenyl radical or a phenyl radical having alkyl groups 1 to 4 carbon atoms inclusive, means represents a direct bond or a methylene group and for one of the following structures (1) trans-CH = CH- 639 378 4th (2) cis-CH-CH- (3) -C = C- or (4) -CH2CHr stands. 2. Prostaglandin derivative according to claim 1. characterized in that it has the following formula purple R 1 B 0 , or is a mixture containing the compound of the formula purple and the enantiomer of the compound of the formula purple, purple in the formula R2o) for a grouping of the following structures V / ■ <x ok says Q 'one of the following structures H H, or chaoh OH or Re oh represents in which R8 is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, and W, L, R4, R9, R] g, R! 9, V and X have the same meaning as in Formula III. 3. Connection according to claim 2, characterized in that in it the grouping * the following structure * 50 55 / / owns, OH L for a grouping of the formula- (CH2) n-, in which n den Has value 3, 4 or 5, Q 'for one of the following groupings 60 stands in what R8 is a hydrogen atom, a methyl group or an ethyl group, and R4 is the n-pentyl radical, the 1,1-dimethylpentyl radical, the 1,1-difluoropentyl radical, a radical of the formula .CH.-O-0 or the formula -CaH "- // W is. 0 or OH 65 4. A compound according to any one of claims 1 to 3, characterized in that in it R19 represents an iodine atom. 5. A compound according to claim 4, characterized in that it is one of the following compounds c 639 378 5§- J od-9-deoxy-bç, 9a-epoxy-PGF] -methy lamide, 5; -iodo-9-deoxy-6'Ç, 9'-epoxy-PGFrn-butylamide, 5ç-iodo-9-deoxy-6§, 9a-epoxy-PGFrbenzylamide, 5'5-iodo-9-deoxy-6 £, 9a-epoxy-PGFranilid, 4ç-iodo-9-deoxy-5 |, 9a-epoxy-PGFramid, 4ç-iodo-9-deoxy-5 |, 9a-epoxy-PGFrmethylamide, 4 ^ -iodo-9-deoxy-5'§, 9a-epoxy-PGF1-n-butylamide, 4'-iodo-9-deoxy-5'§, 9a-epoxy-PGFrbenzylamide, 5 | -iodo-9-deoxy-6 ^, 9a-epoxymethano-PGFramid, 5'ç-iodo-9-deoxy-6'§, 9a-epoxymethano-PGFrmethylamide, 5ç-iodo-9-deoxy-6ç, 9a-epoxymethano-PGFrn-butyl-amide, or 5 | -Iodine-9-deoxy-6ç, 9a-epoxymethano-PGFrbenzy! Amide. 6. Connection according to claim 4, characterized in that it is a 5'5-iodo-9-deoxy-6'§, 9a-epoxy-PGFramid of the following formula vn ... 0 II (CH2) 3 "C-NH 2 7. Prostaglandinderivat, which has an enol ether structure, characterized in that it has the following formula IV 0 II 10th IR21 V-W L-C-N (R9) (Ria) / C-H 15 X-C-R4 II Q (iv) or has a mixture which contains the compound of the formula IV and the enantiomer of the compound of the formula IV 20, where in the formula IV for grouping the formulas C = C H C-C5H11 \ H OH (VI I) 25th 30th is. OR 1 3 > 1 3 / \ CHa CC ' bleak CHaORi3 R, R ,. R, has the following meanings: a) a hydrogen atom, b) a tetrahydropyranyl radical, c) a tetrahydrofuranyl residue, d) a 1-ethoxyethyl radical, e) a grouping of the formula H 45 50 Ri 4-0-C C-Riv 15 Ris in which an alkyl radical with 1 to 18 carbon atoms inclusive, a cycloalkyl radical with 3 to 10 carbon atoms inclusive, an aralkyl radical with 7 to 12 carbon atoms inclusive, a phenyl radical or a phenyl radical with 1,2 or 3 alkyl radicals with 1 to inclusive as substituents Has 4 carbon atoms, and RIfl are identical to or different from one another and have the meaning of hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms inclusive, phenyl radicals or phenylene radicals which are substituted by 1,2 or 3 carbon atoms, or 55 60 65 R15 and Rtó together represent a group of the formula - (CH / Oa- or a group of the formula - (CHi) b-O- (CH2) c-, where a is 3, 4 or 5, b represents 1, 2 or 3, and c represents the number 1, 2 or 3, provided that the total value of b + c is 2, 3 or 4 and where Rn represents a hydrogen atom or a phenyl radical, or f) is an acyl radical which has the following structures: a ') a grouping of the formula -0 " , (A), in which A is an alkyl group of 1 to 4 carbon atoms, a bromine atom, a phenylalkyl group of 7 to 10 carbon atoms, or a nitro group, and e has a value of 0 to 5, provided that no more than two substituents A are different Have meaning than that of alkyl groups. and that the total number of coal 639 378 6 staffatomeli in all substituents A not more than 10 Carbon atoms is b ') a grouping of the formula i -a " COOR30 in which R30 is an alkyl radical with 1 to 4 carbon atoms, c ') a grouping of the formula 10th 15 in which both A and e have the same meanings as were given under a '), d ') a grouping of the formula R31 is an alkyl radical with 1 to 7 carbon atoms inclusive W is a methylene group or an ethylene group, L when W represents a methylene group, for one of the following groupings (1) - (CH2) d-C (R2) 2- (2) - (CHi) -O-CHtY- or (3) -CH2CH = CH-, in which d has a value from 0 to 5 inclusive, the radicals R2 are identical or different from one another and have the meaning of hydrogen atoms, methyl radicals or fluorine atoms, provided that one of the two Residues R2 must not have the meaning of the methyl group if the other is a fluorine atom, and Y stands for a direct bond or a grouping of the formula -CH2- or - (CH2) 2-, and in which 0 II -C-R31 / \ h h if W is an ethylene group, one of the following meanings (1) - (CH2) d-C (R2) 2 (2) -0-CH2-Y- or 25 (3) -CH = CH-, owns Q for one of the following structures / \ Re OR 13 or Re / \ or ii stands in which Rs represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, Rj3 has the meanings given in connection with the cyclopentane structures, R4 for one of the following structures R5! (l) -C-CgH2g ~ CH3 (2) Re r5 '(t). or (2) -ch = / ch2ch3 > = C \ H stands in which C „H2 is a alkylene group with 1 to 9 carbon atoms, including 1 to 5 carbon atoms in the chain, which is between the grouping of the formula -CRsRf, - and the terminal methyl group. 35 40 45 50 55 60 65 Rs and R6 are the same or different from one another and represent hydrogen atoms, alkyl groups having 1 to 4 carbon atoms inclusive or fluorine atoms, provided that one of the radicals R5 or R6 is a fluorine atom only if the other of these radicals is a hydrogen atom or also a fluorine atom , and under the further condition that neither R5 nor R6 may represent a fluorine atom if Z is an oxa group of the formula (-0-), stands for an oxa-oxygen atom of the formula (-0-) or a grouping of the formula CjH2j, where the structure of the formula C; H2j stands for a direct bond or an alkylene group with 1 to 9 carbon atoms inclusive, 1 to 6 inclusive in this alkylene group Carbon atoms are in the chain that lies between the grouping of the formula -CR5Rä- and the phenyl nucleus, the radicals T are identical or different from one another and have the meaning of alkyl radicals having 1 to 4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl groups or groups of the formula -OR7, in which R7 is alkyl radicals having 1 to 4 carbon atoms, and have a value of 0, 1, 2 or 3, provided that, however, no more than two radicals T have a meaning other than that of alkyl groups if s has a value of 2 or 3, R9 represents a hydrogen atom, a methyl group or an ethyl group, and Ria represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, a phenyl radical or a phenyl radical which is substituted by alkyl groups having 1 to 639 378 including 4 carbon atoms substituted- (2) cis-CH = CH- indicates (3) -C = C- or V represents a direct bond or a methylene group (4) -CHjCHo- and stands. X for one of the following structures 5 8. Prostagland derivative according to claim 7, thereby (1) trans-CH = CH- characterized that it has the following formula IVa 0 \\ l-G-N (R g) (Ri8) .C-H v-o ^ -W (IVa) or is a mixture which is the compound of, Q. Formula IVa and the enantiomer of the compound of formula ^ z0J for a grouping of the following structures IVa, wherein in the formula IVa • » q'h stands Q 'one of the following structures or O. cha0h ' * i 0, H H, R a OH or g \ e OH represents in which R8 is a hydrogen atom or an alkyl radical with 1 to 1 L. is finally 4 carbon atoms, 55 and W, L, R4, Rq, R18, V and X have the same meaning, Q 'as in formula IV. 9. A compound according to claim 8, characterized in that it has the grouping, for a grouping of the formula - (CH2) n, in which n den Has value 3, 4 or 5, for one of the following groupings the following structure 60 65 0 or Rt OH stands in what Rg is a hydrogen atom, a methyl group or an ethyl group, and R4 is the n-pentyl radical, the 1,1-dimethylpentyl radical, the 1,1-difluoropentyl radical, a radical of the formula -CH3-0 ~ <f ^) 639 378 H or the formula -cohi is. 10. Connection according to claim 8, characterized. that they are one of the following compounds: (5Z) -9-deoxy-6,9a-epoxy-A3-PGFramid, (5Z) -9-deoxy-6,9a-epoxy-A "-PGFrn-butylamide, (5Z) - 9-deoxy-6,9a-epoxy-A: '- PGFi-anilide, (5Z) -9-deoxy-6,9a-epoxy-A'-PGFpbenzylamide, (4Z) -9-deoxy-5,9a-epoxy -A4-PGFi-amide, (4Z) -9-deoxy-5,9a-epoxy-A4-PGFi-methylamide, (4Z) -9-deoxy-5,9a-epoxy-A4-PGFrn-butylamide, (5Z) -9-deoxy-6,9a-epoxymethano- A3-PGF ramid, (5Z) -9-deoxy-6,9a-epoxymethano-A5-PGF1-methylamide, (5Z) -9-deoxy-6,9a-epoxymethano- A5-PGFrn-butylamide, (5Z) -9-deoxy-6,9a-epoxymethano-A5-PGFrbenzylamide, or that (5Z) -9-Deoxy-6,9a-epoxy-A'-PGF methylamide of formula VIII 0 II (CH2) a-C ~ NHCH3 is. 11. Keto-prostaglandin derivative or hemi-ketal-prostaglan-dine derivative or mixture of the keto-prostaglandin derivative with the hemi-ketal-prostaglandin derivative. characterized in that it is a keto-prostaglandin derivative of the formula I ^ 0H o IC 0 w -C -Ch'2 -L -C-N (Rs) (Rne) (I) 15 / c-h 25th 30th 0- I. \ or is a mixture which contains the keto compound of the formula I and the enantiomer of this compound or the corresponding hemi-ketal prostaglandin derivative of the formula II r-> 0H lì. .0-c / ^ ch2-l-c-n (rb) (rn8) Q- / x-c-r4 ö (II) ch £ VI oh h c = c h or is a mixture which contains the hemiketal compound of the formula II and the enantiomer of this compound or 35 is a mixture of the keto compound of the formula I with the corresponding hemiketal compound of the formula II, in the formulas I and II ^ C-C5H1i / \ h oh 40 f R 2 1 J for grouping the formulas \ - * x • » orx; v ✓ <X; che oaer stands in which Ri3 has the following meanings: a) a hydrogen atom, b) a tetrahydropyranyl radical, c) a tetrahydrofuranyl residue, d) a 1-ethoxyethyl radical, e) a grouping of the formula 65 Ch'aOR 13 H R1 4-O -C - ■ - "C - R i7 ^ 15 i e 9 639 378 in which Rw is an alkyl radical with 1 to 18 carbon atoms, a cycloalkyl radical with 3 to 10 carbon atoms, an aralkyl radical with 7 to 12 carbon atoms, a phenyl radical or a phenyl radical which has 1, 2 or 3 alkyl radicals with 1 to 4 carbon atoms as substituents is is R! 5 and Rif are the same or different from one another and the meaning of hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms, phenyl radicals or phenyl radicals which are substituted by 1, 2 or 3 alkyl groups having 1 to 4 carbon atoms , own, or Ris and Ri6 together represent a grouping of the formula - (CH2) a- or a grouping of the formula - (CH2) n-0- (CH2) c-, in which groupings a is 3, 4 or 5, b represents 1, 2 or 3, and c represents the number 1, 2 or 3, provided that the sum of b + c2, 3 or 4, and where Rh represents a hydrogen atom or a phenyl radical, or is an acyl radical which has the following structures: a ') a grouping of the formula 10th 15 20th 25th 0 (a), in which A is an alkyl group of 1 to 4 carbon atoms, a bromine atom, a phenylalkyl group of 7 to 10 carbon atoms or a nitro group 35, and e has a value of 0 to 5, provided that no more than two substituents A are one have a different meaning than that of alkyl groups and that the total number of carbon atoms in all substituents A is not more than 10 carbon atoms, b ') a grouping of the formula 40 0 tl -c COOR30 45 / \ h h in which Raa is an alkyl radical with 1 to 4 carbon atoms, c ') a grouping of the formula in which both A and e have the same meanings as those given under a'), d ') a grouping of the formula 0 II -c-r31 in which R31 is an alkyl radical with 1 to 7 carbon atoms W is a methylene group or an ethylene group, L if W represents a methylene group, for one of the following groupings (1) - (CH2) d-C (R2) 2- (2) - (CH2) -0-CH2-Y- or (3) -CH2CH = CH-, in which d has a value from 0 to 5 inclusive, the radicals R2 are identical or different from one another and have the meaning of hydrogen atoms, methyl radicals or fluorine atoms, provided that one of the two Residues R2 must not have the meaning of the methyl group if the other is a fluorine atom, and Y stands for a direct bond or a grouping of the formula -CH2- or - (CH2) 2-, and that if W is an ethylene group, one of the following meanings (1) - (CH2) d-C (R2) 2- (2) -O-CHtY- or (3) -CH = CH-, owns Q for one of the following structures / \ rq 0riq or Ra / \ ^ a òr stands in which Rs represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R13 has the meanings given in connection with the cyclopentane structures, for one of the following structures Rs 55 60 Rs / _ / (T) s (2) Re or (l) -C-CgHag-CH3 65 O) -CH2 / CHaCHa H 639 378 10th stands in which CgHig is an alkylene group with 1 to 9 carbon atoms, with 1 to 5 carbon atoms in the chain between the grouping of the formula -CRjR6- and the terminal methyl group, R5 and R6 are identical or different from one another and denote hydrogen atoms, alkyl groups with 1 to 4 carbon atoms or fluorine atoms, provided that one of the radicals Rj or R6 is a fluorine atom only if the other of these radicals is a hydrogen atom or also a Is fluorine atom, and under the further condition that neither R5 nor R6 may represent a fluorine atom if Z is an oxa group of the formula (-0-), Z for an oxa oxygen atom of the formula (-0-) or one Grouping of the formula CjH2j, where the structure of the formula CjH2j stands for a direct bond or an alkylene group having 1 to 9 carbon atoms inclusive, in which alkylene group there are 1 to 6 carbon atoms in the chain between the grouping of the formula -CR5Ré - and the phenyl nucleus, the radicals T are identical to or different from one another and have the meaning of alkyl radicals having 1 to 4 carbon atoms, fluorine atoms, chlorine atoms, trifluoromethyl groups or groups of the formula -OR7, in which R7 is alkyl radicals having 1 to 4 carbon atoms, and s have a value of 0, 1, 2 or 3, provided that, however, no more than two radicals T have a meaning other than that of alkyl groups if s has a value of 2 or 3, R9 represents a hydrogen atom, a methyl group or an ethyl group, and R18 denotes a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an aralkyl group with 7 to 12 carbon atoms, a phenyl radical or a phenyl radical which is substituted with alkyl groups with 1 to 4 carbon atoms, V represents a direct bond or a methylene group and X for one of the following structures (1) trans-CH = CH- (2) cis-CH = CH- (3) -C = C- or (4) -CH2CH2-stands. 12. Prostaglandindérivat according to claim 11, characterized in that it is a keto-prostaglandin of formula Ia ^ OH o 0 - W -C-CH'2 "L" C-N (Ro) (Ria) x-c-r4 Q * (Ia) or the corresponding hemiketal prostaglandin derivative of the formula IIa ^ 0H Ì .0-C / ^ CH2-L-C-N (R9) (Rn8) / 'U' (IIa) 25th X-C-FU 15 * 30th 35 40 45 or a mixture of the keto compound of the formula Ia with the hemiketal compound of the formula IIa, where in the formula Ia or IIa Rao) for a grouping of the following structures Oh stands Q 'one of the following structures or CHaOH 0, h h, ra oh or ra 0h 11 639 378 represents in which Rs is a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms, and W, L, R4, R9. Rlg, V and X have the same meaning as in formula I and II. 13. A compound according to claim 12, characterized in that in the keto compound of the formula Ia or the corresponding hemiketal of the formula IIa R20) the following structure v ^ a / / oh owns L for a grouping of the formula - (CH2) n-, in which n den Has value 3, 4 or 5, Q 'for one of the following groups or that they are one of the following hemiketal compounds of the formula IIa 9-deoxy-6§, 9a-epoxy-6§-hydroxy-PGFrmethylamide, 9-deoxy-65,9a-epoxy-6§-hydroxy-PGFrbenzylamide, 5 9-deoxy-6 ^, 9a-epoxy-6§- hydroxy-PGF1-anilide, 9-deoxy-5'Ç, 9a-epoxy-5îj-hydroxy-PGF1-amide, 9-deoxy-5ç, 9a-epoxy-5 | -hydroxy-PGF1-amide, 9-deoxy-5 §, 9a-epoxy-5§-hydroxy-PGFrmethylamide, 9-deoxy-6 |, 9a-epoxymethano-6 ^ -hydroxy-PGF1-amide, 10 9-deoxy-6 |, 9a-epoxymethano-6 ^ -hydroxy- PGFi-methylamide, 9-deoxy-6 |, 9a-epoxymethano-6 | -hydroxy-PGFrbenzylamide, 9-deoxy-6 |, 9a-epoxymethano-6 | -hydroxy-PGF1-butylamide or the 9-deoxy-6 |, 9a-epoxy-6 ^ -hydroxy-PGF1-amide of the formula VI OH 0 î Ii C - (CHa) 4-C-NHa 15 0 or r « oh stands in what Rg is a hydrogen atom, a methyl group or an ethyl group, and R4 is the n-pentyl radical, the 1,1-dimethylpentyl radical, the 1,1-difluoropentyl radical, a radical of the formula -CHa-0— ^ or the formula - C a H, is. ~ o 14. A compound according to claim 11, characterized in that the compound of formula Ia one of the following compounds: 6-keto-PGFla-methylamide, 6-keto-PGFia-benzylamide, 6-Ket0, PGFlo-anilide, 5-keto-PGFla-amide, 5-keto-PGFia-methylamide, 9-deoxy-9-hydroxymethyl-6-keto-PGFla-amide, 9-deoxy-9-hydroxymethyl-6-keto-PGFla-methylamide, 9-deoxy-9-hydroxymethyl-6- keto-PGFia-benzylamide, 9-deoxy-9-hydroxymethyl-6-keto-PGFi "-butylamide or the 6-keto-PGFia-amide of the formula V 0 0 oh h h \ 20th -H VI c = c. 25 HO H C-CsHn / \ H OH is. 30 15. Process for the preparation of the halogen prostaglandin derivatives of the formula III Ì 11 0 rCH / ^ C Rl9 0 H-L / - C-N (Rp) (Rie) (iii) according to claim 1, in which 43 ^ 2 iJW, L, Q, R4, R9, R18i R19, V and X have the same meaning as in claim 1, characterized in that a compound of formula IX 50 55 , V- ° S S c «c h 0 R91 V .-- W ^ 'xL-C-N (RB) (Rne) -CH2-C- (CH2) 4 "C-NH2 / C = CC OH H ^ C-C5Hi 1 H OH X-C-Ra I! Q halogenation and cyclization to form the compounds of formula III. 16. The method according to claim 15, characterized in that a corresponding iodine-prostaglandin derivative of the formula III is prepared, in which R19 is an iodine atom, by mixing the starting material of the formula IX with either iodine and potassium iodide in the presence of an alkali carbonate or Bikar-65 reacting bonates in an aqueous system or by reacting the starting material of formula IX with iodine in the presence of an alkali metal carbonate in an organic solvent. 639 378 12 17. Process for the preparation of prostaglandin derivatives with enol ether structure of the formula IV 0 L »C-N (R9) (Rte) .C-H (R 21 V ~ W (IV) ^ ^ * - X-C-R4 OH o II 0 10th 15 according to claim 7, in which W, L, Q, R4, R9, R1S, V and X have the same meaning -0 have, as in claim 7, characterized in that that a compound of formula IX 7 "° S / H 0 ^ C-C II R2i) "" 'W> i.-C-N (Rt>) (R, e) \\ 30th --W -C-CH2-L-C-N (R9} (Ria) (I) with the corresponding hemiketal prostaglandin derivatives ^ UH II Q ^ 0-G ^ CH2-L-C-N (RB) (RIB) X-C-R « (II) according to claim 11, in which W, L, Q, R4, R9, Rjg, V and X have the same meaning as in claim 11, characterized in that a compound of formula IX V-OH / \ -W ' oc H 0 halogenation and cyclization to form the compounds of the formula III X-C-Ru II Q xL-C-N (R9) (R, e) (IX) wherein 50: R19 is a chlorine atom, bromine atom or iodine atom, and this halogen compound of the formula III undergoes hydrogen halide elimination to form the enol ether of the formula IV. 18. The method according to claim 17, characterized in that the hydrogen halide is split off in the halogen prostaglandin derivative by reacting it with one of the following compounds: Tertiary amines, sodium peroxide, potassium peroxide, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, 60 sodium benzoate, potassium benzoate, sodium acetate, potassium acetate, sodium trifluoroacetate, potassium trifluoroacetate, sodium bicarbo-nate, potassium bicarbonate, silver acetate or the tetraalkylammonium (4) corresponding to formula 4 or tetraalkylammonium, which correspond to the following formula: in which Rj2 is an alkyl radical with 1 to 4 carbon atoms. 19. Process for the preparation of a mixture of keto-prostaglandin derivatives of the formula I. in which R] 9 represents a chlorine atom, bromine atom or iodine atom, subjecting and then subjecting the halogen prostaglandin derivative of the formula III thus obtained to hydrogen halide elimination under hydrolytic conditions, the equilibrium mixture being obtained from the keto compound of the formula I with the corresponding hemiketal compound of the formula II. 20. The method according to claim 19, characterized in that one carries out the hydrogen halide under hydrolytic conditions by treating the halogen compound of formula III with silver carbonate and perchloric acid in an inert organic medium. 21. The method according to claim 19 or 20, characterized in that the keto-prostaglandin derivative is separated from the corresponding hemiketal-prostaglandin derivative, preferably with the aid of silica gel chromatography. 13 639 378