CH630897A5 - Process for preparing novel prostaglandin analogues having a triple bond between C-13 and C-14. - Google Patents

Description

The present invention relates to processes for the preparation of new analogues of some known prostaglandins which differ from the relevant known prostaglandins in that they have a triple bond between C-13 and C-14, that is to say the C-13 / C-14 -Rest consists of -O ^ C.

The known prostaglandins include the PGE compounds, e.g. Prostaglandin egg (PGEi), prostaglandin E2 (PGE2), prostaglandin Es (PGE3) and dihydroprostaglandin egg (Dihydro-PGEi), furthermore PGFa compounds e.g. Prostaglandin Fla (PGFia), Prostaglandin F2a (PGF2a), Prostaglandin F3a (PGFia) and Dihydroprostaglandin Fi «(Dihydro-PGFia), also PGFp compounds, e.g. Prostaglandin Fiß (PGFiß), Prostaglandin F2ß (PGF2ß), Prostaglandin Fass (PGF3ß) and Dihydroprostaglandin Fiß (Dihydro-PGFiß), also PGA compounds, e.g. Prostaglandin Ai (PGAi), Prostaglandin A2 (PGA2), Prostaglandin A3 (PGA3) and Dihydroprostaglandin Ai (Dihydro-PGAi), and PGB compounds, e.g. Prostaglandin Bi (PGBi), Prostaglandin B2 (PGB2), Prostaglandin B3 (PGB3) and Dihydroprostaglandin Bi (Dihydro-PGBi). «S

Each of these known prostaglandins is a derivative of prostanoic acid, which has the following formula and numbering:

50 dihydro-PGEi:

c00h

55

60

PGFi «:

h oh c00h h oh

PGF2 «:

COOH

Dihydro-PGFip:

PGF3 «:

COOH PGAi:

\ Y NOH

20th

H OH

COOH

25th

Dihydro-PGFia:

H OH

COOH

pga2:

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H 'vOH

COOH

35

PGFip:

H OH

PGA3:

40

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H vOH

PGF2ß:

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Dihydro-PGAi:

55

H OH

COOH

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PGFjiî:

PGBI:

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OOH

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PGBa:

cooh

PGBs:

cooh

Hx NOH

cooh

Dihydro-PGBi:

15

20th

25th

h x) H

In the formulas above, as well as in the formulas shown later, dashed lines to the cyclopentane ring denote substituents in the a configuration, that is to say below the level of the cyclopentane ring. Bold lines of excellent bond to the cyclopentane ring denote substituents in the β configuration, that is, above the level of the cyclopentane ring. Wavy lines (~) denote the binding of the substituents in the a or β configuration or in a mixture of the a and β configuration.

The side-chain hydroxyl group at C-15 is in the formulas above in the S configuration. For a discussion of the stereochemistry of prostaglandins, see Nature 212.38> 1966). Designations such as C-13, C-14, C-15 and the like refer to the carbon atom in the prostaglandin analogue which is in the position which corresponds to the position with the same number in the prostanoic acid.

Molecules of the known prostaglandins have several centers of asymmetry and can be present in racemic (optically inactive) form or in one of two enantiomeric (optically active) forms, i.e. right-handed or left-handed. The formulas shown each reflect the specific optically active form of the prostaglandin in question, which can be obtained from certain mammalian tissues, e.g. Vesicular glands of sheep, pig lungs or human seminal plasma, or by carbonyl and / or double bond reduction of such a prostaglandin (see e.g. Bergstrom et al., Loc. Cit.). The mirror images of all formulas represent the other enantiomers of the prostaglandins in question. The racemic form of a prostaglandin contains the same number of enantiomeric molecules, and one of the above formulas and their mirror image is required to correctly display the corresponding racemic prostaglandin. When the term prostaglandin or “PG” is later used, the optically active form of prostaglandin with the same absolute configuration as PGEt from mammalian tissue is to be understood. If the racemic form of one of these prostaglandins is to be referred to, the prostaglandin name is preceded by the word racemic or the term “dl”. 5 In the present description, a “prostaglandin-like” (PG-like) product is understood to mean any cyclopentane derivative which is useful for at least one of the pharmacological purposes known for the prostaglandins. A prostaglandin-like intermediate is generally understood to be a cyclopentane derivative which is suitable for producing a prostaglandin-like product.

Those formulas which represent a prostaglandin-like product or an intermediate which is suitable for producing a prostaglandin-like product each give the stereoisomer of the prostaglandin-like product in question with the same relative stereochemical configuration as the prostaglandin in question from mammalian tissues or the stereoisomer of the intermediate in question which is used to prepare the stereoisomer of the prostaglandin-like product is suitable again.

A "prostaglandin analog" means that stereoisomer of a prostaglandin-like product that has the same relative stereochemical configuration as the prostaglandin in question from mammalian tissues or a mixture of this stereoisomer and its enantiomers. If a formula is used to represent a prostaglandin-like compound, the term prostaglandin analogue refers to the compound of this formula or a mixture of this compound and its enantiomers.

The various prostaglandins described above, their esters, acylates and pharmacologically acceptable salts are extremely effective in causing various biological reactions, compare e.g. Bergstrom et al., Pharmacol. Rev. 20.1 (1968) and bibliography there.

With PGE compounds, these biological reactions include:

(a) lowering blood pressure (measured e.g. in anesthetized and pentolinium-treated rats),

(b) stimulation of the smooth muscles (demonstrated e.g. by tests with guinea pig ileum, rabbit duodenum or colon of voles),

(c) lipolytic activity (demonstrated by the antagonism against the release of glycerin induced by isolated epinephrine from isolated rat fat pads),

(d) inhibiting gastric secretion and reducing undesirable gastrointestinal effects when systemically administered prostaglandin synthetase inhibitor

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55 goals,

(e) combating cramping and breathing relief in asthmatic conditions,

60 (f) swelling of the nasal passages,

(g) the reduction in the platelet adhesion (demonstrated by the adhesion of the platelets to glass) and the inhibition of the effects of various physical effects (eg arterial injury) or chemical effects (eg ATP, ADP, serotinin, thrombin and collagen) , caused platelet aggregation and thrombus formation,

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(h) exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical dilators, regulators of oestrus and the menstrual cycle and

(j) accelerating the growth of epidermal cells and keratin in animals.

For PGFa compounds, these biological reactions include:

(a) the increase in blood pressure (measured e.g. in anesthetized and pentolinium-treated rats),

(b) stimulation of the smooth muscles (demonstrated e.g. by tests with guinea pig ileum, rabbit duodenum or colon of voles),

(c) inhibiting gastric secretion and reducing undesirable gastrointestinal effects with systemic administration of prostaglandin synthetase inhibitors,

(d) combating cramps and breathing relief in asthmatic conditions,

(e) swelling of the nasal passages,

(f) the reduction in platelet adhesion (demonstrated by the adherence of the platelets to glass) and the inhibition of platelet aggregation and thrombus formation caused by various physical influences (e.g. arterial injury) or chemical influences (e.g. ADP, ATP, serotinin, thrombin and collagen) and

(g) the effects on the reproductive organs of mammals as a means of inducing labor, for abortion, as cervical dilators, regulators of the heat and the menstrual cycle.

For PGFp compounds, these biological reactions include:

(a) the lowering of blood pressure (measured e.g. in anesthetized and pentolinium-treated rats),

(b) stimulation of the smooth muscles (proven by tests with guinea pig ileum, rabbit duodenum or colon of voles),

(c) inhibiting gastric secretion and reducing undesirable gastrointestinal effects with systemic administration of prostaglandin synthetase inhibitors,

(d) combating cramps and breathing relief in asthmatic conditions,

(e) swelling of the nasal passages,

(f) the reduction in platelet adhesion (demonstrated by the adherence of the platelets to glass) and the inhibition of platelet aggregation caused by various physical effects (eg arterial injury) or chemical effects (eg ADP, ATP, serotinin, thrombin and collagen) and thrombus formation and

(g) Exposure to mammalian reproductive organs as a means of inducing labor, abortion, cervical dilators, regulators of oestrus and the menstrual cycle.

5

With PGA compounds, these biological reactions include:

(a) the lowering of blood pressure (measured e.g. in io anesthetized and pentolinium-treated rats),

(b) stimulation of the smooth muscles (proven by tests with guinea pig ileum, rabbit duodenum or colon of voles),

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(c) inhibiting gastric secretion and reducing undesirable gastrointestinal effects with systemic administration of prostaglandin synthetase inhibitors,

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(d) combating cramps and breathing relief in asthmatic conditions,

(e) swelling of the nasal passages and

(f) increasing blood flow in the kidney.

With PGB compounds, these biological reactions include:

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(a) stimulation of the smooth muscles (proven by tests with guinea pig ileum, rabbit duodenum or colon of voles) and

35 (b) accelerating the growth of epidermal cells and keratin in animals.

Because of these biological responses, these known prostaglandins are useful in the study, prevention, control, or relief of numerous diseases and undesirable physiological conditions in birds and mammals including humans, farm animals, pets and zoological species, as well as laboratory animals such as mice, rats, 45 rabbits and monkeys .

The prostaglandins referred to above as hypotensive agents are suitable for reducing the blood pressure in mammals and humans. For this purpose, the compounds are infused intravenously in an amount of about 0.01 to about 50 µg / kg body weight per minute or in one or more doses of about 25 to 500 µg / kg body weight per day.

The PGFa compounds are useful for increasing blood pressure in mammals and humans. These Verbin-55 fertilizers are therefore suitable for the treatment of shocks (hemorrhagic shock, endotoxin shock, cardiogenic shock, surgical shock or toxic shock). The shock is characterized by pallor and cold skin, reduced blood pressure, weak and fast 60 pulse, reduced breathing, restlessness, anxiety and occasional loss of consciousness. The shock usually occurs after injuries and trauma. Professional and rapid emergency measures are required to successfully treat such shock conditions. The prostaglandins can be used in combination with a pharmaceutical carrier suitable for intramuscular, intravenous or subcutaneous administration, particularly in the early stages of shock, when an increase in blood pressure causes a critical

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It is described as a factor to support and maintain that the ulcerogenic effect of maintaining the required blood flow, perfusing certain non-steroidal inflammatory vital organs and exercising a pressure reamer in rats by simultaneous oral administration Narrowing of the veins and increased blood levels of certain prostaglandins in the E and A series to normal levels. The prostaglandins are therefore finally PGEi, PGE2, PGE3, 13, 14-dihydro-PGEi and are useful for preventing an irreversible shock which is affected by the 11-deoxy-PGE and -PGA compounds in question by a sharp drop in blood pressure, vein dilation and inhibition . Prostaglandins, for example, are characterized by useful accumulation of venous blood. In order to reduce the undesirable effects on gastric shock treatment, the prostaglandin is administered in an amount and intestine resulting from the systemic administration of 0.1-25 mcg / kg / min. infused. It can advantageously result with 10 indomethacin, phenylbutazone or aspirin, known vasoconstrictors such as phenoxybenzamine, Nore- These substances are combined in US Pat. No. 3,781,429 as no pinephrine or the like. Anti-inflammatory drugs called steroids. you are

Treatment of shock, prostaglandin is also known as prostaglandin sythetase inhibitors,

Appropriately combined with steroids (e.g. hydrocortisone The anti-inflammatory synthetase inhibitor, e.g. or methylprednisolone), with tranquilizers and antibiotics is indomethacin, aspirin or phenylbutazone, is used in (e.g. lincomycin or clindamycin). administered in a known manner to an inflammatory

The condition to facilitate the smooth muscle condition as effective stimulators, for example in any of the compounds mentioned, are also highly active in the known dosage regimen for systemic strengthening of the administration of other known smooth muscle stimulants.

nature, for example of oxytocin agents such as oxytocin and 20. Prostaglandin, together with the inflammatory ergot alkaloids including inhibitory prostaglandin synthetase inhibitor, is either present on its derivatives and analogues. These compounds are administered in the same or different ways. Is at-

therefore, for example, usable instead of or together, for example, with the anti-inflammatory substance orally administered with less than the usual amounts of these known sticks, the prostaglandin can also be administered orally or rectally, e.g. to relieve the symptoms of paraly- 25 suppositories or in women in the form of a table ileus or to fight or prevent atoni vaginal suppositories or a vaginal device for uterine bleeding after miscarriage or delivery, for slow delivery (see, for example, the US PS 3 545 439) are given rejection of the placenta as well as during the puerperium. If, on the other hand, the anti-inflammatory substance is administered intra rectally for the latter purposes, the prostaglandin can also be administered rectally by venous infusion directly after the miscarriage or delivery. Oral or, in women, a dose of about 0.01 to about 50 ng / kg body vaginal administration is also possible. Is the route of administration important per minute until the desired effect for anti-inflammatory substance and prostaglandin der-

is achieved. Subsequent doses are taken during the same, so it is useful to combine both substances in

Weekly bed in an amount of 0.01 to 2 mg / kg body in a single dosage form.

daily intravenous, subcutaneous, or intramuscular injections. The dosage regimen for prostaglandin depends on whether or not, the exact dose depending on age, in this case of various factors including type,

Weight and condition of the patient depends. Age, weight, gender and medical condition of the

As mentioned, the PGE compounds are potent anti-mammals, the anti-inflammatory agonist dosing scheme of epinephrine-induced mobilization-inducing synthetase inhibitor, the sensitivity of the freeze-boiled fatty acids. For this reason, this compound is suitable for the synthetase inhibitor with regard to the stomach / manure in experimental medicine for investigations into intestinal effects and the prostagland to be administered in vitro and in vivo in mammals such as rabbits and rats. For example, Not every patient who has an inflammatory and human need for understanding, prevention, anti-aging substance, serves the same uncomfortable relief and healing of diseases that take away gastrointestinal effects. These often change abnormal lipid mobilization and high levels of free 45 in type and extent. It is within the physician's experience to connect fatty acids, e.g. Diabetes mellitus, vascular or veterinarian determine whether the administration of the disease and hyperthyroidism. anti-inflammatory substance undesirable gastrointestinal

Those prostaglandins which have been described above as having no useful effects in humans or animals and which prescribe the amount of prostaglandin which is effective for reducing and controlling excessive gastric secretions, with which tion have been designated, reduce or prevent these effects are thus essentially eliminated can. Wise ulceration in the stomach and intestines and accelerating. The neces described as suitable for the treatment of asthma, the healing of already existing ulcers in the gastro-prostaglandins are useful, for example, as bronchial-rointestinal tract. For this purpose, the compounders or as inhibitors of mediators such as SRS-A are fertilized intravenously, subcutaneously or intramuscularly and injected histamine, which is infused by an antigen / antibody or at an infusion dose of approximately 0.1 to ss complex, is released will. The verbin - about 500 µg / kg of body weight per minute, or with a fertilizer, therefore combats cramps and facilitates the total dose per day by injection or infusion of about breathing in conditions such as bronchial asthma, bronchitis, 0.1 to 20 mg / kg body weight, with bronchiectasis, pneumonia and emphysema. For this exact amount of age, weight and condition of the patient, the compounds are administered in various dosage or animal and frequency and route of administration, e.g. orally in the form of tablets. Capsules or liquids, rectally in the form of supposito-

These compounds are also useful for reducing, parenterally, subcutaneously, or intramuscularly, with intramation of undesirable gastrointestinal effects preferred from venous administration in emergency situations, systemic administration of anti-inflammatory products by inhalation in the form of aerosols or solutions for staglandin synthetase inhibitors result, and they nebulizers or by sniffing in the form of Pul are for this purpose by simultaneous administration vern. Doses of about 0.01 to 5 mg / kg body weight of the prostaglandin with the anti-inflammatory prostate are applied 1 to 4 times a day, being given the exact glandin synthetase inhibitor. In the US PS amount of age, weight and condition of the patient and

Frequency and route of administration depends. For the above purposes, these prostaglandins can advantageously be combined with other anti-asthmatics, for example with sympathomimetics (isoproterenol, phenylephrine, epinephrine and the like), xanthine derivatives (theophylline and aminophylline) and corticosteroids (ACTH and prednisolone). With regard to the use of these compounds, reference is made to US Pat. No. 3,644,638.

The prostaglandins designated as suitable for swelling the nose can be used for this purpose in doses of approximately 10 μg to approximately 10 mg / ml of a pharmacologically suitable liquid carrier or in the form of an aerosol spray, each for topical use.

The above-mentioned prostaglandins are useful for inhibiting platelet aggregation, reducing platelet adhesion, and eliminating or preventing thrombi in mammals including humans, rabbits and rats. For example, the compounds are useful for the treatment and prevention of myocardial infarctions, for the treatment and prevention of post-operative thromboses, for accelerating the opening of vascular grafts after surgical interventions and for the treatment of conditions such as atherosclerosis, arteriosclerosis, blood clotting due to lipemia and against other clinical conditions where the underlying etiology is related to lipid imbalance or hyperlipidemia. For the purposes mentioned, the connections are systemic, e.g. administered intravenously, subcutaneously, intramuscularly or in the form of sterile implants for prolonged action. For rapid uptake, especially in emergency situations, intravenous administration is preferred. Doses of about 0.05 to about 20 mg / kg body weight per day are used, the exact amount depending on the age, weight and condition of the patient and the frequency and mode of administration.

These compounds are also useful as additives to blood, blood products, blood substitutes and other fluids used for the artificial out-of-body circulation and perfusion of isolated body parts, e.g. used by limbs and organs that are still on the donor body, separated from it and preserved, or that are prepared for transplantation or that are already on the body of the recipient. During these circulations, aggregated platelets tend to block the blood vessels and parts of the circulation device. This blocking is avoided in the presence of the above compounds. For the stated purpose, the compounds are added gradually or in one or more portions to the circulating blood, the donor's blood, the perfused part of the body, the recipient or two or all of these stages in a steady total dose of about 0.001 to 10 mg / l of circulating fluid . The compounds are particularly useful when administered to laboratory animals such as cats, dogs, rabbits, monkeys and rats to develop new methods and techniques for organ and limb transplantation.

The prostaglandins, which have been said to be useful in place of oxytocin, are used to induce labor in pregnant females such as cows, sheep and pigs and in humans, at or near the time of birth, or in the case of intrauterine death of the fetus approximately 20 weeks before Time of birth. For this purpose, the compounds are infused intravenously at a dose of 0.01 to 50 μg / kg body weight per minute until or almost until the end of the second stage of labor, that is to say the expulsion of the fetus. The compounds are particularly useful when one or more meh630897

The natural contractions have not started yet several weeks after the time of birth, or 12 to 60 hours after the membrane has torn without the natural contractions having started. Oral administration is also possible.

These compounds are also useful for controlling the conception cycle in menstruating female mammals and humans. Menstruating female mammals are understood to mean those that are already mature enough to menstruate, but are not yet so old that regular menstruation has ceased. For the above purpose, the prostaglandin is administered systematically in an amount of from 0.01 to about 20 mg / kg of body weight, expediently during the period that begins approximately at the time of ovulation and ends approximately at the time of the menses or shortly before. Intravaginal and intrauterine administration are also possible. Furthermore, embryo or fetus ejection is caused by similar administration of the compound during the first or second third of normal gestation or pregnancy.

These compounds are also useful for producing cervical dilatation in pregnant and non-pregnant female mammals for gynecological and obstetric purposes. Cervical enlargement is also observed in the induction of labor caused by these connections and in clinical abortion. In cases of infertility, the cervical enlargement caused by these compounds serves to facilitate sperm movement to the uterus. The cervical enlargement caused by prostaglandins is also useful in surgical gynecology such as D and C (cervical dilation and uterine curettage), where mechanical dilatation can cause uterine perforation, cervical strain, or infection. It is also advantageous in diagnostic procedures where an extension for tissue examination is required. For these purposes, the prostaglandin is administered locally or systemically.

For example, the prostaglandin is administered orally or vaginally in doses of about 5 to 50 mg / treatment to an adult woman, with 1 to 5 treatments per 24 hours. Prostaglandin can also be administered intramuscularly or subcutaneously in doses of approximately 1 to 25 mg / treatment. The exact amounts depend on the age, weight and condition of the patient or animal.

These compounds are also useful in farm animals as an abortion agent (especially for heifers intended for slaughter) and as an aid in determining the heat and for regulating or synchronizing the heat. Farm animals include horses, cattle, sheep and pigs. The regulation or synchronization of the oestrus allows more effective control of conception and contractions and enables the herd owner to give birth to all female animals in short, predetermined periods. This leads to a higher percentage of live births than with a natural course. The prostaglandin is injected or administered in the feed in amounts of 0.1 to 100 mg / animal / day and can be combined with other agents such as steroids. The dosage regimes depend on the animal species treated. For example, mares receive the prostaglandins 5 to 8 days after ovulation and return to heat. Cattle are treated at regular intervals within a 3-week period, so that all animals become hot at the same time.

The PGA compounds, their derivatives and salts increase blood flow in the mammalian kidney, thereby increasing the volume and electrolyte content of the urine. The PGA connections are therefore useful for kidney dysfunction, especially 9

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especially when the kidney vascular layer is blocked. The PGA compounds are useful, for example, to relieve or correct edema resulting from massive surface burns and to treat shocks. For these purposes, the PGA compounds are preferably first injected intravenously in an amount of 10 to 1000 p.g / kg body weight or intravenously infused in an amount of 0.1 to 20 µg / kg body weight per minute until the desired effect is achieved. Subsequent doses can be injected or infused intravenously, intramuscularly or subcutaneously in amounts of 0.05 to 2 mg body weight per day.

The compounds referred to as accelerators of epidermal cell and keratin growth are useful in humans and animals, including farm animals, domestic animals, zoological species, and laboratory animals. The compounds are used to promote and accelerate the healing of damaged skin, for example in the case of burns, wounds, abrasions and after surgical interventions. The compounds are furthermore useful for promoting and accelerating the growth of skin pieces (autografts), in particular small deep (Davis) inserts, which are intended to cover skin-free areas by subsequent growth to the outside, and for delaying rejection of one's own skin (homo-grafts).

For the purposes mentioned, the compounds are preferably applied topically or close to the point at which cell growth or keratin formation is desired, preferably as an aerosol liquid or finely divided powder, spray, as an isoionic solution in the case of moist envelopes or as a lotion, cream or ointment together with conventional ones pharmaceutically acceptable diluents. In some cases, for example in the event of severe fluid loss as a result of extensive burns or skin loss for other reasons, systemic administration is recommended, e.g. by intravenous injection or infusion, alone or in combination with the usual infusion of blood, plasma or blood substitute. Other routes of administration are subcutaneous or intramuscular administration near the site to be treated, oral, sublingual, buccal, recurrent or vaginal administration.

The exact dose depends on the mode of administration, age, weight and condition of the patient. For example, an isotonic aqueous solution with 1 to 500 (ig / ml prostaglandin) is expediently used in a wet envelope for topical use in second and / or third degree burns with areas from 5 to 25 cm 2. 5 In particular when used topically, these prostaglandins are expediently used Antibiotics such as gentamycin, neomycin, polymixin, bacitracin, spectinomycin and oxytetracycline, with other antibacterial agents such as mafenide hydrochloride, sulfadiazine, furazolium chloride and io nitrofurazone and with corticoid steroids, for example hydrocortisone, prednisolone, methyl prednisolone and used in these, with these supplements and used in flightprednisolone, and flightpredisolon, in which these supplements and flight prediction Combination can be used in the usual concentration when used alone.

is Certain PG2-like compounds are known in which the C-13 / C-14 portion consists of a -C = C group. E.g. have been described by Gandolfi C., et al., Il Farmaco, 27, 1125,13,14-didehydro-PGF2a and 13,14-didehydro-PGE2 and their 15-epimers. ZA-PS 73-2329 (Der-20 went Farmdoc CPI54179U) describes 13,14-didehydro-PGF2a, -PGF2ß-, -PGE2- and -PGA2-like compounds with optional C-16-alkyl substitution and optional oxa- or Thia substitution at C-3. The aforementioned ZA-PS also describes the 8β, 12a stereoisomer of the compounds described above 2s; for the disclosure of 13,14-didehydro-PGF2a see also J. Fried, et al., Tetrahedron Letters, 3899 (1963).

Certain 13,14-didehydro-PGi-like compounds are also known, see e.g. J. Fried, et al., Annais of the New York Academy of Science 18.38 (1971), where the 7-oxa-13,14-didehydro-PGFio is disclosed. R. Pappo, et al., Tetrahedron Letters, 2627, 2630 (1972) describe rapidly 13,14-dihydro-l-l-PGEi, and R. Pappo, et al., Annais of the New York Academy of Science 18 , 64 (1971) the 13,14-Didehydro-llß-PGBi. Finally, the following patents describe 13,14-dihydro-PGBi-like compounds, BE-PS 777 022 (Derwent Farmdoc CPI 4379IT), DOS 1925 672 (Derwent Farmdoc CPI 41084) and DOS 2 357 781 (Derwent Farmdoc 42046V).

1 The invention relates to a process for the preparation of new prostaglandin analogs, esters of these analogs and pharmacologically acceptable salts, furthermore of C2-Cs alkanoates of these analogs of the formula

30th

35

40

H.

ch2

c = r

^ CHs-CCHsJg-CHs-COORi

CLXXXII

yl.c_c. (ch2) m-CH3 Mx Li wonn in one of the residues ho ho ho or

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means

Yi is -C = C-,

g is the number 1, 2 or 3 and m is a number from 1 to 5, Mi

or a mixture of and

or

Rs ORô Rs ORö,

Ì14

R 'R4,

10th

where Rs and Rf are hydrogen or methyl, Li

R3

iu, where R3 and R4, which may be the same or different, denote hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only when the other is hydrogen, an alkyl radical having 1 to 12 carbons -

15 atoms, cycloalklyl radical having 3 to 10 carbon atoms, aralkyl radical having 7 to 12 carbon atoms, the phenyl radical, a phenyl radical substituted by 1, 2 or 3 chlorine atoms or alkyl radicals having 1 to 3 carbon atoms or a pharmacologically acceptable potassium.

20 Further compounds which can be prepared according to the invention have the following formula

(ch2.) g-ch2-c00ri yi-c-c- (cha) m-ch3 mj. li

(CLXXXI A)

where J ^) one of the residues

0

V ✓

or

35 out

40

45 exists

(c) PGFß-like compounds when the cyclopentane ring means Li, Mi, Ri, Yi, g and m from the above

To have meaning.

Within the scope of the new prostaglandin analogs which can be produced according to the invention, they are

(a) PGE-like compounds when the cyclopentane ring is off

55

consists,

(d) 8ß, 12a-PGE-like compounds when the cyclo-60 pentane ring is off

0.

65

consists,

(b) PGFa-like compounds when the cyclopentane ring exists,

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(e) 8ß, 12a-PGFa-like compounds when the cyclopentane ring is off

/

ho exists and

(f) 8ß, 12a-PGFit-like compounds when the cyclopentane ring consists of ho ho.

Those prostaglandin analogues which have the group cis-C H = C H-C11> (CIhjg are referred to as PG2 compounds. If g denotes the number 2, it is a "2a-hoino" - or " 2a, 2b-dihomo "compounds, since in this case the carboxyl-terminated side chain has 8 or 9 carbon atoms instead of the 7 carbon atoms of PGEi. These additional carbon atoms are considered to be inserted between positions C-2 and C-3 are therefore numbered C-2a and C-2b, counting from C-2 to C-3.

The new prostaglandin analogs which can be prepared according to the invention have a -C C radical in the C-13 / C-14 position and are called dallerais! 3,14-didehydro compounds.

The new compounds which have the radical - (CH2) m-CH3, where m has the meaning given above, «are referred to as« 19.20-dinor »,« 20-nor »-, • '20 -methyl »Or« 20-ethyl »compounds, if n is the number«, 2.4 or 5 is.

If at least one of the radicals R3 and R4 is not hydrogen carni, apart from the 16-P: i ~ noxy compounds, the 16-methyl compounds are one ;; the residues Rs and R.îis »; Methyl, the 16,16-dimethy-f-e pL, 2 £ te R, and are methyl, the 16-fluoro-gel, one of the radicals Ha and R4 means fluorine, or> if or! Compounds, R3 and R4 both i J Rz and R: different, the corresponding prostagîandin analogue contains an asymmetric carbonate at the C-16. Accordingly, two epimeric configurations are possible, namely «(16S)» and «(16R)». The C-16 epimer mixture “(16RS)” is also suitable for these compounds.

If Rs is the methyl radical, sc the compounds are referred to as i 5-methyl compounds. Ró means the methyl residue. so it is the 15-methyl ether compounds.

According to the invention, the two epimeric configurations of the hydroxyl or methoxy group on C-15 can also be produced. As previously mentioned, PGEi from mammalian tissues on the C-15 has the S configuration. Furthermore, the PGEi from mammalian tissues in the present illustration has the 15-hydroxyl group in the a configuration.

For the 13,14-didehydro derivative of PGEi from mammalian tissues, the S configuration at the C-15 a-hydroxy configuration is when the convention is used according to which the side chains of the new prostaglandin analogs which can be prepared according to the invention have been presented here. Furthermore, (15R) -PGEi has the 15-hydroxy substituent in the β configuration according to the convention used here to prepare the prostaglandins. The corresponding (15R) -13,14-didehydro-PGEi compound also has the 15-hydroxyl group in the β configuration when prepared using the convention used here. Those new prostaglandin analogs whose 15-hydroxyl or 15-methoxy group have the same absolute configuration as (15R) -13, 14-didehydro-PGE 1 at C-15, 15 are therefore referred to as 15-epi compounds. If the preceding “15-epi” is missing, then these are compounds whose configuration of 15-hydroxyl or 15-methoxy group has the same absolute configuration as 15 (S) -13,14-didehydro-PGEi, that is 15a- Hydroxy configuration. 20 As can be seen from the above explanations, the new PG analogs disclosed herein are named after the system of Nelson, N.A., J. Med. Chem. 17,911 (1974).

Examples of alkyl radicals with 1 to 12 carbon atoms 25 are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl radical and their isomeric forms.

Examples of cycloalkyl radicals having 3 to 10 carbon atoms, including alkyl-substituted cycloalkyl radicals 3 ', are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethyl-cyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl -, 3-propylcyclobutyl-, 2,3,4-triethylcyclobutyl-, cyclopentyl-, 2,2-dimethylcyclopentyl-, 2-pentylcyclopentyl-, 3-tert-butylcyclopentyl-, Cyc-35 lohexyl-, 4-tert- Butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclo-nonyl and cyclodecyl.

Examples of aralkyl radicals with 7 to 12 carbon atoms are benzyl, 2-phenethyl, 1-phenylethyl, 2-phenyl-49 propyl, 4-phenylbutyl, 3-phenylbutyl, 2- (l-naphthyl-ethyl) - and l- (2-naphthylmethyl) rest.

Examples of phenyl radicals substituted by 1 to 3 chlorine atoms or alkyl radicals having 1 to 4 carbon atoms are the p-chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-45 trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-

Et'nylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl and 2,4-dichloro-3-methylphenyl.

The prostaglandin analogs which can be prepared according to the invention correspond to the prostaglan-so dynes described above in that they show prostaglandin-like activity.

In particular, the new 8ß, 12a-PGE and PGE compounds are consistent with the PGE compounds described above in that they are useful and the same for any of the purposes described above for which the PGE-55 compounds are used Way how these can be used.

The 8β, 12a-PGF and PGFa-like compounds which can be prepared according to the invention agree with the PGFa compounds described above 69 so that they are usable and in the same way for each of the purposes described above for which the PGFa compounds are used how these can be used.

The 8β, 12a-PGF and PGFß-like compounds obtainable according to the invention agree with the PGF compounds described above in that

that they are useful for any of the purposes described above for which the PGFß compounds are used and can be used in the same way.

13

630897

The prostaglandins described above all cause multiple biological reactions, even at low doses. In numerous applications, the known prostaglandins also show a very short duration of the biological effect. In contrast, the new prostaglandin analogs obtainable according to the invention are much more specific in their action and they have a much longer duration of action. The new prostaglandin analogs are therefore surprisingly more useful for at least one of the above-mentioned pharmacological purposes than the known prostaglandins mentioned, since the new prostaglandin analogs have a different and narrower spectrum of biological activity than the corresponding known prostaglandin and are therefore more specific in their action and produce fewer and fewer undesirable side effects than the corresponding prostaglandin. Furthermore, because of the longer duration of action, fewer and smaller doses of the new prostaglandin analogs are often used to achieve the desired result.

Another advantage of the new prostaglandin analogs that can be produced according to the invention, in particular the preferred PG analogs defined below, compared to the known prostaglandins, is that the new compounds can be administered orally, sublingually, intravaginally, buccally or rectally with success in cases in which to whom the prostaglandin in question is only effective when given intravenously, intramuscularly or subcutaneously by injection or infusion. These additional routes of administration are advantageous because they facilitate the maintenance of uniform levels of the compounds in the body with rarer, shorter or smaller doses and enable self-administration by the patient.

Said new prostaglandin analogs can be administered in different forms for different purposes, e.g. intravenously, intramuscularly, subcutaneously,

oral, intravaginal, rectal, buccal, sublingual, topical and in the form of sterile implants for prolonged action. Sterile aqueous isotonic solutions are usually preferred for intravenous injection or infusion. In these cases, Ri is preferably hydrogen or a pharmacologically acceptable cation because of the increased water solubility. Sterile solutions or suspensions of the acid, a salt or ester in aqueous or non-aqueous media can be used for subcutaneous or intramuscular injection. For oral and sublingual administration, e.g. Tablets, capsules and liquid preparations such as syrups, elixirs and simple solutions that contain the usual pharmaceutical carriers. Suppositories are generally used in a known manner for rectal or vaginal administration. The tissue implants used are e.g. a sterile tablet or silicone rubber capsule or other object that contains or is impregnated with the active ingredient.

The chemical structure of the new 11-deoxy-PGE-like compounds makes them less sensitive to dehydration and rearrangement than the corresponding prostaglandins. These compounds are therefore surprisingly stable and storable.

The new PG analogs obtainable according to the invention can be administered for the purposes described above in the form of the free acid, as esters or pharmacologically acceptable salts. When using the ester form, e.g. those for which Ri corresponds to the above definition. Alkyl esters with 1 to 12 carbon atoms in the alkyl radical are preferred. Among these, the methyl and ethyl esters are particularly preferred because of optimal absorption by the body or the experimental animal system. The straight chain octyl, nonyl, decyl, undecyl

and dodecyl esters are particularly preferred because of their prolonged action in the body.

Pharmacologically acceptable salts of the new prostaglandin analogs which can be prepared according to the invention are those with pharmacologically acceptable metal cations, ammonium, amine or quaternary ammonium cations,

Particularly preferred metal cations are those of the alkali metals such as e.g. Lithium, sodium and potassium and the alkaline earth metals such as e.g. Magnesium and calcium, although also salts with cations of other metals such as Aluminum, zinc and iron fall within the scope of the invention.

Pharmacologically acceptable amine cations are derived in particular from primary, secondary and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclo-hexylamine, benzylamine, dibenzylamine, a-phenylethylamine, ethylamine amine Ethylene diamine, diethylene triamine and 20 similar aliphatic, cycloaliphatic and araliphatic amines up to about 18 carbon atoms, furthermore heterocyclic amines such as Piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl derivatives, for example 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 25 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like, and water-solubilizing or Amines containing hydrophilic groups, such as, for example Mono-, di- and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-l-butanol, 2-amino-2-ethyl-l, 3-propanediol, 30 2-amino-2-methyl-l-propanol , Tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amylphenyl) diethanolamine, galactamine, N-methylgycamine, N-methylglucosamine, ephedrine, phenylephrine, epi-nephrine, procaine and the like. Other useful amine-35 salts are basic amino acid salts, e.g. with lysine and arginine.

Examples of pharmacologically acceptable quaternary ammonium cations are the tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, Phe-40 nyltriethylammonium ion and the like.

The new PG analogs obtainable according to the invention can be used for the purposes described above in the form of the free hydroxyl compound or after conversion of the hydroxyl group into a lower alka-45 noa residue, such as e.g. the acetoxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy radical or a branched chain alkanoyloxy isomer of these radicals. The acetoxy compounds are particularly preferred for the purposes described. The free hydroxyl compounds and the alkanoyloxy compounds are usually used as free acids, as esters and salts.

Certain new compounds are preferred in order to achieve an optimal combination of biological action, specificity, potency and duration of action. The carboxy-terminated side chain preferably contains either 7 or 9 carbon atoms (or carbon and oxygen atoms) and particularly preferably 7 atoms, that is to say it has the natural chain length of the prostaglandins. If the other side chain is the residue - (CH2) m-CH3, then 60 m is preferably the number 3.

In compounds in which at least one of the radicals R3 and R4 is methyl or fluorine, Rs and Rf> are preferably both hydrogen. In compounds in which at least one of the radicals Rs and R6 is methyl, preferably R3 and R4 are both hydrogen.

Furthermore, the 15-hydroxy or 15-methoxy group is preferably not in the 15-epi configuration, that is to say the hydroxy group should have the a configuration if the

630897

14

O 'meln for the new 13,14-Didehydro-PG analogues as shown here.

Those compounds which correspond to one or more of the above preferences are particularly preferred. The above preferences describe the preferred compounds in the context of any general formula of the new prostaglandin analogs described herein. The above preferences thus describe preferred compounds within the scope of any formula of a prostaglandin analog that appears in the schemes below.

The various prostaglandin cyclopentan ring structures used are each representative of a certain “parent structure” that serves to name and categorize the prostaglandin analogues. A formula gives a preferred genus of PG analogs with a

/ C = <

ch2 ch;

single cyclopentane ring structure, then any corresponding genus of PG analogues with the remaining cyclopentane ring structures mentioned here should be equally preferred. For example, for each class of PGFa-like products represented by a specific formula, the corresponding genera of the PGFp and PGE-like products are equally preferred embodiments.

If a subset of PG analogs of any 10 cyclopentane ring structure is described, the corresponding subset of PG analogs with the remaining cyclopentane ring structures are also preferred embodiments of the invention.

The process according to the invention for the preparation of new 15 compounds of the formula

(CHsJg-CHa-COORi.

CLXXXII

Yi-C-C- (CH2) m-CH3 Mi Lx in which the substituents are defined above is characterized in that a compound of the formula ch2- (ch2) n-ch2-c00ri y CLXXXI

■ Y2- | j-C- (CH,) m-CH,

Mi Li in which D, Ri, Li, Mi, g and m are defined above and means in which shark is chlorine, bromine or iodine, deyhdrohalo- ¥ 2 the rest and compounds obtained, in which Ri water-

45 substance is, if necessary, converted into the corresponding salts.

trans -CH = C (Hal) compounds of the formula

/ c = cC

CH2 ch2- (ch2) g-ch2-c00ri.

Yl "n ~ n ~ (CH2) m ~ CH3

M »Li in which the substituents are also defined above, are obtained according to the invention by first preparing, as described above, a compound of the formula CLXXXII and then oxidizing the C-9-hydroxyl group to the oxo group and compounds obtained, in which Ri is hydrogen, optionally converted into the corresponding salts.

The following schemes describe preferred methods by which the new prostaglandin analogs and also the starting compounds of the formula CLXXXI used in the process according to the invention can be prepared.

In the following diagrams, the substituents Ri, Yi, Y2, Mi and Li have the meaning given above, R7

15

630 897

is the group of the formula - (CH2) m-CH3, where m is defined above. Z2 has the same meaning as that defined, and Zi means cis-CH = CH-CH2- (CH2) g- wherein substituent Zi.

g is also defined above. The symbol is too

Scheme A

ho

.CHa-Za-COORi

LXXi

LXXVI

y2-c— c-r7 Aie »II

Ms. Li

1

^ CH2-Z2-COORi

, y2-c — c-r7 rie il H He Li i

'Ys-C-C-r7

Il il

Wed 1 Li

•, CH2-Z2-COOCH3

Y2-C C-R7

IL !,

I.

v

LXX

LXXIII

LXX IV

LXX V

LXX VI

630897

16

Scheme A (continued)

Wed 8

/

Rs

, CH2-Z2-C00RI

Y2-C-C-RT

Hq

10th

R io0

te

LXXVI

Mi L:

HO

\ ^ CH2-Z2-C00RI &

Y2-C-C-Rt

Re II II

Mi Li

Scheme B

0 x a

/ CHO HO '

OH

I.

0

Ri oO

Y-C-C-RT I! H Ms Lt

LXXVI I

CXXI

15

20th

25th

30th

35

40

45

59

Scheme B (continued)

, CH2-Z2-C00RI

Y2-C-C-RT

! j Ii

Mg L i

HO

HÒ

HO

re

, CH2-Z2-C00RI

■ ^ Y2-C-C-R7

iE II

Mi Li

Scheme C

CH2-Zi-COORI

Y3-C-C-RT

!! II

Mg L i

HO

55 \

CXXI 1

CH2-Zi-COORi

60 'Ys • * C— C-Rt

Rs I! II

0 Li

CXXIII

CXXIV

CXXXI

CXXXII

65

V

17th

630897

Scheme C (continued)

9O

, CH2-Zi-COORI

Y3-C-C-R7

II 1!

0 Li

/

/

1 6

V

l @ 0

CH2-Z1-COOR1

cc kY2-C-C-R7

ü II

0 Li

\1/

ReQ

\ .CHa-Zi-COORi

Y2-C-C-Rt

R1 6 II II

Hi Li

HO

re

XH2 -Z1 -COORi

Y2-C-C-Rt

II II

Mi Li

CXXXII

10th

15

20th

CXXX1V

Ms means cxxxv

35

40

45

Scheme D

CH2-Z1-COORi

Y-rrRT

11

Mi Li

*

CH2-Z1-COORi

Yi-C-C-Rt

H II

Mi Li

/ \ H OH,

✓ X

H OH,

/ \

H bCH3.

il OCH3,

or a mixture of

50

CH3 OH

and

55

dH3 OH.

Mó means cxxxvi

60

65

OR10.

H OR10, ^ bCHs, rf OCH3.

CLXXX

CLXXX

CH3 ORio,

630897

or a mixture of and

CH3 ORio, with Rio being a protecting group. M9 means

OH

or

/ \ H OH.

Mn means a mixture of

and

M12 means or

CH3 OH

CftT ^ OH

cfi3 * OH

CH3 OH.

18th

(e) naphthoyl radicals substituted by 1 to 9 alkyl radicals having 1 to 4 carbon atoms, phenylalkyl radicals having 7 to 10 carbon atoms or nitro groups, with the proviso that no more than 2 substituents on each of the fused 5 aromatic rings can be different from alkyl, and that the total number of carbon atoms in the substituents on each fused aromatic ring does not exceed 10, with the further proviso that the substituents may be the same or different, and

10th

(f) alkanoyl residues with 2 to 12 carbon atoms.

/ \

M18 is H ÒH or O

"1" means the hydroxy group, Ri6 means a radical OR9, in which R9 is an acyl protective group as defined below. Ris means the rest -ORio, where Rio has the meaning given below.

R9 represents an acyl protective group. The acyl protective groups R9 preferably include:

(a) the benzoyl radical,

(b) 1 to 5 alkyl radicals having 1 to 4 carbon atoms, phenylalkyl radicals having 7 to 12 carbon atoms or nitro groups, benzoyl radicals, provided that more than 2 substituents are different from alkyl and that the total number of carbon atoms does not exceed 10 in the sub-3 substituents and provided that the substituents can be the same or different,

(c) benzoyl radicals substituted by alkoxycarbonyl having 2 to 5 carbon atoms,

(d) the naphthoyl residue,

In the preparation of these acyl derivatives of compounds containing hydroxyl groups, generally known methods can be used. For example, an aromatic acid of formula R9OH, wherein R9 has the meaning given above, e.g. Benzoic acid, with the compound containing hydroxyl groups in the presence of a dehydrating agent such as sulfuric acid, zinc chloride 20 or phosphoryl chloride or with an aromatic acid anhydride of formula (R9) 20, e.g. with benzoic acid anhydride.

However, the method described in the previous paragraph is preferably carried out with the relevant acyl halide 25 e.g. of the formula R9Hal, in which shark denotes chlorine, bromine or iodine. For example, benzoyl chloride is reacted with the hydroxyl-containing compound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine, triethylamine or the like. The reaction is usually carried out under various conditions using methods known per se. In general, mild conditions are used, namely 20 to 60 ° C and contacting the reactants in a liquid medium (e.g. excess pyridine or an inert solvent such as benzene, toluene or chloroform). The acylating agent can be used either in a stoichiometric amount or in a substantial stoichiometric excess.

The following R9 radicals are available in acids (R9OH), Anhy-40 driden ((R9) 20) or acyl chlorides (R9CI): The benzoyl radical, substituted benzoyl radicals, e.g. (2-, 3- or 4 -) - methylbenzoyl, (2-, 3- or 4-) ethylbenzoyl, (2-, 3- or 4 -) - isopropylbenzoyl, (2-, 3- or 4 -) - tert -Butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimenthylbenzoyl, 2-isopropyltoluyl, 45 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, a-phenyl- (2-, 3- or 4 -) - toluyl, (2- , 3- or 4 -) - phenethylbenzoyl, (2-, 3- or 4 -) - nitrobenzoyl, (2,4-, 2,5- or 2,3 -) - dinitrobenzoyl, 2,3-dimethyl-2- nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 2-so nitro-6-phenethylbenzoyl-, 3-nitro-2-phenethylbenzoyl, monoesterified phthaloyl, isophthaloyl - or terephthaloyl residues, the 1- or 2-naphthoyl residue, substituted naphthoyl residues, for example (2-, 3-, 4-, 5-, 6- or 7 -) - methyl-l-naphthoyl, (2-or 4 -) - ethyl-l-naphthoyl, 2-isopropyl-l-naphthoyl, 4, 5-55 dimethyl-l-naphthoyl, 6-isopropyl-4-methyl-l-naphthoyl, 8-benzyl-l-naphthoyl, (3-, 4-, 5- or 8 -) - nitro-l-naphthoyl, 4 , 5-dinitro-l-naphthoyl, (3-, 4-, 6-, 7- or 8-) methyl-l-naphthoyl, 4-ethyl-2-naphthoyl and (5- or 8-) nitro-2- naphthoyl and the acetyl radical.

60 It is thus possible to use benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride or the like, that is to say compounds R9CI. If the acyl chloride is not available, it can be prepared in a known manner from the acid and phosphorus pentachloride in question. Preferably, the reagent R9OH, (R9) 20 or R9CI should not contain bulky, bulky substituents such as have the tert-butyl radical on the two ring carbon atoms adjacent to the carbonyl group.

19th

630897

The acyl protecting groups R.9 are usually removed by de-acylation. For this purpose, alkali metal carbonates are successfully used at room temperature. Advantageously, e.g. worked with potassium carbonate in methanol at about 25 ° C.

Protective groups Rio are all radicals which replace the hydrogen atom of a hydroxyl group and which are neither attacked by the pending conversions nor are as reactive to the reagents used as the hydroxyl group, and which can subsequently be replaced by hydrogen in the further preparation of the prostaglandin-like compounds. Numerous protecting groups are known, e.g. the tetrahydropyranyl radical and substituted tetrahydropyranyl radicals, compare E.J. Corey, Procee-dings of the Robert A. Welch Foundation Conferences on Chemical Research, 12, Organic Synthesis, pp. 51-79 (1969). The protecting groups that proved to be suitable

belong

(a) the tetrahydropyranyl radical,

(b) the tetrahydrofuranyl residue and

(c) residues of the formula -C (OR11) (R! 2) -CH (Rl3) (Rl4),

in which Rn is an alkyl radical having 1 to 18 carbon atoms, cycloalkyl radical having 3 to 10 carbon atoms, aralkyl radical having 7 to 12 carbon atoms, the phenyl radical or a phenyl radical substituted by 1 to 3 alkyl radicals having 1 to 4 carbon atoms, R12 and R13 alkyl radicals having 1 to 4 carbon atoms, Phenyl radicals or phenyl radicals substituted by 1,2 or 3 alkyl radicals having 1 to 4 carbon atoms or together radicals - (CH2) a- or - (CH2) b-0- (CH2) c, in which a is 3, 4 or 5, b the number 1, 2 or 3 and c is the number 1, 2 or 3, with the proviso that b + c result in 2, 3 or 4, with the further proviso that R12 and R13 may be the same or different, and R14 is hydrogen or represent the phenyl radical.

If the protective group is the tetrahydropyranyl radical, the tetrahydropyranyl ether derivative of any hydroxyl groups of the PG-like intermediates is preferably obtained by reacting the hydroxyl-containing compound with 2,3-dihydropyran in an inert solvent, such as e.g. Methylene chloride, in the presence of an acidic condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. The dihydropyran can be used in a large stoichiometric amount, preferably 4 to 10 times the stoichiometric amount. The reaction is usually complete in less than an hour at 20 to 50 ° C.

If the protective group exists e.g. from the tetrahydrofuranyl radical, the procedure is as described in the previous paragraph, but with 2,3-dihydrofuran instead of 2,3-dihydropyran.

The protective group corresponds to the formula

-C (ORi i) (Rn) -CH (Ri3) (Ri4)

wherein Ri 1, P R13 and R14 have the meaning given above, the reagent in question preferably consists of a vinyl ether, e.g. Isobutyl vinyl ether or a vinyl ether of the formula

C (ORu) (Ri2) = C (Ri3) (Ri4),

or an unsaturated cyclic or heterocyclic

Connection, e.g. 1-Cyclohexen-l-yl methyl ether or 5,6-dihydro-4-methoxy-2H-pyran, see C.B. Reese, et al., Journal of the Chemical Society 89,3366 (1967). The reaction conditions for these vinyl ethers and unsaturated compounds are similar to those for dihydropyran.

The protective groups Rio can be removed by mild acid hydrolysis. For example, the hydrolysis of the protective groups is achieved by reaction with (1) hydrochloric acid in methanol, (2) a mixture of acetic acid, water and tetrahydrofuran or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran at temperatures below 55 ° C.

Scheme A provides a process according to which corresponding 14-halogen PGF compounds which are used as starting compounds in the process according to the invention can be prepared from prostaglandin-like intermediates.

The compound of formula LXXI can be prepared by known methods. The compound of formula LXXII is formed from the compound LXXI by oxidation according to known methods, e.g. using Jones reagent. The compound LXXIII is obtained from the compound LXXI or compound LXXII by hydrolysis of the protective groups. The hydrolysis takes place when the compound is e.g. mixed with water, tetrahydrofuran and acetic acid as described above.

The compound of formula LXXIV is formed from compound LXXIII by converting the residue R i to the methyl ester group using the methods described below. The C-15 epimers are separated from one another to give the compound LXXV.

The compound of the formula LXXVI, which is represented by the formula LXXIII when Ms consists of the individual C-15 epimers, is optionally formed from the compound LXXV by converting the methyl ester into a R 1 radical.

The compound of the formula LXXVII is obtained from the compound LXXVI, in which Mis = 0, by carbonyl reduction, using the methods described below.

Scheme B provides a preferred process for converting the bicyclic lactonaldehyde of formula CXXI to the PGF2a-like intermediate CXXIV, which is used to prepare new 13,14-didehydro-PGF2a-like compound by the procedure of Scheme C.

The compound of the formula CXXI is known. It is available either in one of the two pure enantiomeric forms or as a mixture of the two enantiomers. The compound of the formula CXXII is prepared from the compound CXXI in a known manner. Well-known methods are used. The compound of formula CXXIII is then made from compound CXXII. The compound of formula CXXIV is then formed from compound CXXIII by first hydrolyzing the protecting groups Rio (using the methods described above), then separating the C-15 epimers when Rs is the methyl group. Methods described above are used, e.g. Silica gel chromatography or high pressure liquid chromatography.

As described further above, the PGFct-like compounds produced are converted according to the invention into the relevant PGE-like compounds.

Scheme C provides a process by which a known compound of the formula CXXXI is converted into the corresponding 14-halogen PGF-like compound CXXXVI. The compound of the formula CXXXII is made from the compound CXXXI by selective oxidation of the C-15

5

10th

15

20th

25th

30th

35

40

45

50

55

«0

«5

630 897

20th

Alcohol. The oxidation takes place according to conventional methods, e.g. with 2,3-dichloro-5,6-dicyanobenzo-quinone, activated manganese dioxide or nickel peroxide,

see Fieser, et al., "Reagents for Organic Synthesis" John Wiley and Sons, New York, N.Y. Pp. 215,637 and 731.

The compound of the formula CXXXIII is formed from the compound CXXXII by protecting the free hydroxyl groups with acyl groups R9. The methods described above are used. Optionally, silyl groups of the formula -Si (Gi) 3, in which gl has the meaning given above, can also be used instead of the acyl protective groups. Furthermore, protection by acyl or silyl groups can be omitted if Rs and Re in the remainder Mi of the formula CXXXVI both consist of hydrogen.

The compound of the formula CXXXIV is prepared from the compound CXXXIII by halogenation in the 14-position. This halogenation is carried out by one of several known methods.

A particularly useful reagent for the present reaction is sulfuryl chloride. The product mixtures are broken down in a conventional manner. The compound of the formula CXXXV is then produced from the compound CXXXIV by converting the 15-oxo group into a residue Mi using known methods. Then the compound of formula CXXXVI is prepared from the compound CXXXV with removal of any acyl or silyl protecting groups, following the procedures described above.

Scheme D provides the first method according to the invention. to convert the 14-halogen compounds described into 13,14-didehydro-PG products.

The conversion according to the invention according to scheme D (CLXXXI CLXXXI) is carried out by dehydrohalogenation. According to the preferred method, a mixture of dimethyl sulfoxide or a similar aprotic solvent and methanol in a volume ratio of 5: 1 to 10: 1 serves as the diluent. Then a strong organic base, e.g. Potassium t-butoxide or sodium methylate is added and the reaction is allowed to continue, which usually takes about 24 hours. Reaction temperatures of 0 to 25 ° C. are expediently used.

E.g. If this dehydrohalogenation is applied to PGE or PGA-like compounds or 8β, 12a-PGE or PGA-like compounds, then undesirable dehydration and / or double bond migration takes place. These dehydrohalogenations are therefore carried out on PGF-like compounds, whereupon the 13,14-didehydro-PGF compounds are converted into the relevant 13,14-dide-hydro-PGE or -PGA-like products by the further process according to the invention. According to these processes according to the invention, the 14-halogen PGF compound is thus successively converted into a 13,14-didehydro-PGF compound and then into 13,14-didehydro-PGE compounds.

Following the procedures of the above schemes, optically active PG products are usually obtained from optically active intermediates.

E.g. racemic intermediates used, so you get racemic products. These products can be used in razeine form or broken down into the optically active enantiomers by known methods. You get e.g. a PG-like free acid, the racemic form is broken down into the d- and 1-form by reacting the acid in a known manner with an optically active base (for example brucine or strychnine), a mixture of 2 diastereomers being obtained, which can be disassembled in a known manner (eg by fractional crystallization)

Formation of the diastereomeric salts. The optically active acid can then be recovered from the salt using known methods.

In all of the reactions described, the products can be freed of starting material and impurities in a conventional manner. For example, the products of the various stages are freed from the respective starting materials and impurities by means of silica gel chromatography, which is monitored by thin-layer chromatography.

As already mentioned, the processes lead differently to acids (Ri means hydrogen) or esters or salts.

If an alkyl ester has been obtained while striving for an acid, the saponification can be carried out according to methods known for xs PGF compounds.

In the case of alkyl esters of PGE-like compounds obtained, enzymatic processes for converting the esters into the acids can be used in a known manner if the saponification would cause dehydration of the pro-20 staglandin. The preparation of an esterase is described in U.S. Patent 3,776,156.

If an acid has been produced while an alkyl, cycloalkyl or aralkyl ester is desired, the esterification can expediently be carried out by reacting the acid with the diazohydrocarbon in question. For example, the methyl esters are obtained with diazomethane. Analogously, the use of, for example, diazoethane, diazo-butane, l-diazo-2-ethylhexane, and diazodecane leads to ethyl, butyl, 2-ethylhexyl and decyl esters. Diazocyclohexane and 30 phenyldiazomethane give the cyclohexyl and benzyl esters.

The esterification with diazo hydrocarbons is preferably carried out by mixing a solution of the diazo hydrocarbon in a suitable inert solvent, in particular in diethyl ether, with the acid, which is expediently present in the same or another inert diluent. After the esterification has ended, the solvent is usually evaporated off and the ester is optionally purified in a conventional manner, preferably by chromatography. The contact between the acid and the diazohydrocarbon should not be longer than is necessary for the desired esterification and should preferably be about 1 to 10 minutes in order to avoid undesired molecular changes. Diazo hydrocarbons are known 45 or can be prepared by known methods, see e.g. Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954).

Another preferred method for producing alkyl, cycloalkyl or aralkyl esters is to convert the free acid to the silver salt, which is then reacted with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide, ciclopentyl iodide, benzyl iodide, phenethyl iodide and the like. The silver salts 55 are usually prepared by conventional methods, for example by dissolving the acid in cold dilute aqueous ammonia, evaporating excess ammonia under reduced pressure and adding the stoichiometric amount of silver nitrate.

60 There are several methods available for the production of the phenyl or substituted phenyl esters from the aromatic alcohols and the PG compounds in the form of the free acid, which differ in terms of yield and product purity.

65 According to a preferred method, the PG-like compound is converted into a tertiary amine salt, converted to the mixed acid anhydride with pivaloyl halide and then reacted with the aromatic alcohol. Instead of

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Pivaloyl halide can also be an alkyl or arylsulfonyl halide such as e.g. Use p-toluenesulfonyl chloride, see BE-PS 775 106 and 776 294, Derwent Farmdoc Mos. 33705T and 3901 IT.

Another preferred method uses the coupling agent dicyclohexylcarbodiimide, see Fieser et al., "Reagents for Organic Synthesis", pp. 231-236, John Wiley and Sons, Inc., New York, (1967). The PG compound is usually reacted with 1 to 10 molar equivalents of the aromatic alcohol in the presence of 2 to 10 molar equivalents of dicyclohexylcarbodiimide in pyridine as a solvent.

However, a preferred new process for the preparation of these esters consists of the following stages:

(a) Formation of a mixed anhydride from the PG compound and isobutyl chloroformate in the presence of a tertiary amine and

(b) reaction of the anhydride with the aromatic alcohol.

The mixed anhydride forms easily at temperatures from -40 to + 60 ° C, preferably at -10 to + 10 ° C, where the rate is sufficient but side reactions remain minimal. The isobutyl chloroformate is preferably used in an excess of, for example, 1.2 to 4.0 molar equivalents per mol of the PG compound. The reaction is preferably carried out in a solvent, with acetone being preferred, although other relatively non-polar solvents such as acetonitrile, methylene chloride or chloroform can also be used. The reaction can be carried out in the presence of a tertiary amine, e.g. Triethylamine. Amine hydrochloride formed at the same time usually crystallizes out, but does not have to be removed before the next process step.

The flavored alcohol is preferably used in equivalent amounts or in a substantial stoichiometric excess to ensure that all of the mixed anhydride is converted to the ester. Excess aromatic alcohol can be removed by methods described or known herein, e.g. by crystallizing. The tertiary amine serves not only as a basic esterification catalyst, but also as a convenient solvent. Further examples of suitable tertiary amines are N-methylmorpholine, triethylamine, diisopropylethylamine and dimethylaniline. 2-Methylpyridine and quinoline can also be used, but lead to a slow reaction. A strongly hindered amine such as 2,6-dimethyllutidine, on the other hand, cannot be used, for example, because of the slow reaction rate.

The reaction with the anhydride proceeds particularly smoothly at room temperature (about 20 to 30 ° C.) and can be monitored in a conventional manner by thin layer chromatography.

The reaction mixture is usually worked up on the ester by known methods and the product can be purified, e.g. by silica gel chromatography.

Solid esters can be converted into free-flowing, crystalline form by crystallization from various solvents such as ethyl acetate, tetrahydrofuran, methanol and acetone, by cooling or concentrating a saturated solution of the ester in the solvent or by adding a miscible non-solvent such as diethyl ether, hexane or water. The crystals are then usually collected in a conventional manner, e.g. by filtration or centrifugation, washed with a little solvent and dried under reduced pressure. You can also dry in a stream of warm nitrogen or argon or by heating to about 75 ° C. Although the crystals are sufficiently pure for numerous applications, they can be recrystallized in the same way, with increased purity being achieved after each recrystallization.

The new compounds produced in free sau reform by the processes according to the invention can be converted into pharmacologically acceptable salts by neutralization with suitable amounts of the corresponding inorganic or organic bases, corresponding cations and amines being listed above. This io conversion usually takes place according to various known processes which are generally suitable for the production of inorganic, that is to say metal or ammonium salts. The choice of process depends in part on the solubility properties of the salt to be produced. In the case of inorganic salts, it is usually advisable to dissolve an acid obtained according to the invention in water which contains the stoichiometric amount of a hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. For example, a solution of the sodium salt is achieved with sodium hydroxide, sodium carbonate or sodium bicarbonate. When evaporating the water or adding a water-miscible solvent of moderate polarity, e.g. a lower alkanol or a lower alkanone, the solid inorganic salt 2s is formed if this form is aimed for.

To produce an amine salt, an acid prepared according to the invention can be dissolved in a suitable solvent of moderate or low polarity. Examples of the former are ethanol, acetone and ethyl acetate, for the latter 30 diethyl ether and benzene. Then at least a stoichiometric amount of the amine corresponding to the desired cation is preferably added to the solution. If the resulting salt does not precipitate out, it is usually obtained in solid form by adding a miscible diluent with low polarity or by concentration. If the amine is relatively volatile, an excess can be evaporated off quickly. The use of stoichiometric amounts is recommended for less volatile amines.

Salts whose cation is a quaternary ammonium ion 40 can be prepared by mixing the acid obtained according to the invention with the stoichiometric amount of the quaternary ammonium hydroxide in question in aqueous solution and then evaporating off the water.

According to the invention, the new compounds of the formula CLXXXII are likewise converted into the corresponding C2-C8-alkanoates by the compound containing a free hydroxyl group having a C2-Cs-acylating agent, preferably the anhydride of a corresponding alkane carboxylic acid, that is to say an alkane carbon so acid with 2 to 8 carbon atoms. Acetane hydride, for example, gives the corresponding acetate. The analogous use of propionic anhydride, isobutyric anhydride or hexanoic anhydride leads to the corresponding acylate.

55 The acylation is conveniently carried out by mixing the hydroxyl compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or triethylamine. One works in particular with a substantial excess of anhydride, preferably 60 with about 10 to about 10,000 moles of anhydride per mole of hydroxyl compound. The excess anhydride serves as the reaction diluent and solvent.

An inert organic diluent (e.g. dioxane) can also be added. Sufficient tertiary amine is preferably used to neutralize the carboxylic acid formed in the reaction and any free carboxyl groups present in the hydroxyl compound.

The acylation reaction is preferably at about 0 to

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100 ° C executed. The reaction time depends on factors such as the reaction temperature, the type of anhydride and tertiary amine. With acetic anhydride and pyridine the reaction time is e.g. at 25 ° C for 12 to 24 hours.

The acylated product can be isolated from the reaction mixture by conventional methods. For example, excess anhydride is decomposed with water and the resulting mixture is acidified and then extracted with a solvent such as diethyl ether. The acylate is preferably obtained from the diethyl ether extract by evaporation. It can then be purified in a conventional manner, conveniently by chromatography or crystallization.

In the following examples, the infrared absorption spectra were recorded with a Perkin-Elmer Model 421 spectrophotometer. Unless otherwise specified, undiluted samples were used. The ultraviolet spectra were recorded on a Cary Model 15 spectrophotometer. The nuclear magnetic resonance spectra were recorded with a Varian A-60, A-600 and T-60 spectrophotometer on Deuterochlorofornil solutions, with tetramethyl-silane as the internal standard (downfield). The mass spectra were recorded with a double-focusing high-resolution mass spectrometer CEC model 21-110B or a gas chromatograph / mass spectrometer LKB model 9000. Unless otherwise stated, the trimethylsilyl derivatives were used.

The collection of the chromatographic eluate fractions begins as soon as the front of the eluent reaches the bottom of the column. The solvent system A-IX used in thin layer chromatography

consisted of ethyl acetate / acetic acid / cyclohexane / water (90: 20: 50: 100) after the modification by M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257 (1966). Skelly-solve B means a mixture of isomeric hexanes.

Silica gel chromatography is understood to mean elution, collecting the fractions and combining those fractions which, according to the thin-layer chromatography, contain the pure product, that is to say free of starting material and impurities.

The melting points were determined with a Fisher-Johns or Thomas Hoover melting point apparatus. The specific rotations [a] were determined on solutions of the compound in the specified solvent at room temperature using an automatic polarimeter Perkin-Elmer model 141.

Preparation 1

14-chloro-16,16-dimethyl-PGF2a-methyl ester-11,15-bis-tetrahydropyranyl ether g = 1, R3 and R.4 of Li = methyl,

A

M6 = H OTHP,

Ri = methyl, Ih = hydrogen, R7 = n-butyl,

Ris = tetrahydropyranyloxy,

Y2 = trans-CH = C (Cl) -) or its 15-epimer

A. Sodium hydride (0.40 g, 57% in mineral oil) in 20 ml of dimethyl sulfoxide is added to 1.82 g of 4-carboxybutyltriphenylphosphonium bromide. The reaction mixture is kept under stirring at 20 ° C for 25 minutes, then a solution of 0.38 g of 3a, 5a-dihydroxy-2ß- [2-chloro (3R) -3-hydroxy-4,4-dimethyl-trans -1 -octenyl] -1 a-cyclopentane-acetaldehyde-y-lactol-bis-tetrahydropyranyl ether in 10 ml of toluene. The reaction mixture is at 2 hours

Stirred at room temperature and then diluted with benzene. Then 2.7 g of potassium bisulfate in 30 ml of water are slowly added, the reaction temperature being kept at 10 ° or below. The aqueous phase is extracted with 50 ml of benzene and the organic extracts are washed successively with 50 ml of water and 50 ml of saturated sodium chloride solution and then combined, dried and concentrated. This gives a semi-crystalline residue which is tographed on 100 g of silica gel chroma-10 washed with acid while eluting with 20% ethyl acetate / n-hexane. This gives 0.241 g of the free acid corresponding to the title compound with NMR absorption at 0.65-1.1.1.1-1.4.1.4-1.8.1.8-2.6.2, 8-4.4.4.05.4.4-4.8, 5.2-5.75 and 6.0-6.9 8.

15

B. The reaction product according to Part A, dissolved in 15 ml of diethyl ether, is esterified with diazomethane, using a stoichiometric excess. The crude methyl ester is chromatographed on 100 g of silica gel packed with 2% acetone / methylene chloride 20. Elution with 2 to 12% acetone in methylene chloride gives the title compound.

If the process of this preparation is repeated, but with the (3R) -lactol, the 15-epi-14-chloro-25 PGF2a methyl ester-II, 15-bis-tetrahydropyranyl ether, NMR absorption at 0.7-1 is obtained , 1.1.1-1.4.1.4-1.8.1.8-2.55.3.15-4.2.3.66.4.05.4.5-4.8 , 5.2-5.8 and 5.6 8.

If the process described is also repeated, but using 5-carboxypentyltriphenylphospho-30 nium bromide or 6-carboxyhexyltriphenylphosphonium bromide instead of the 4-carboxybutyltriphenylphosphonium bromide, the 2a homo- or 2a, 2b-dihomo-14-chloro is obtained PGF2a compounds or their 15-epimers.

Furthermore, by the method of preparation 1, 35, however, the 2,2-difluoro-14-chloro-PGF2a-like tetrahydropyranyl ether or its 15 is obtained by replacing the 3-carboxybutyltriphenylphosphoni umbromide with 4,4-difluoro-4-carboxybutyltriphenylphos-phonium bromide -Epimer.

Furthermore, 14-chloro-PGF2a-like products are obtained by replacing the lactol with other lactols and, if appropriate, the Wittig reagent with one of the above reagents by the process of preparation 1 40.

Preparation 2

45 15-methyl-14-chloro-PGF2a methyl ester (formula LXXVI:

R3 and R4 of Li = hydrogen,

Mi = CH3 SOH,

Mis = H NOH,

55

Ri = methyl, R7 = n-butyl, Rs = hydroxy,

Y2 = trans-CH = C (C1) -, Z2 = cis-CH = CH (CH2) 3-) or its 15-epimer.

60 A. A solution of 5.7 g of 3cc-benzoyloxy-5a-hydroxy-2ß- [2-chloro (3S) -3-hydroxy-3-methyl-trans-1-octenyl] -1 a-cyclo-pentanoacetic acid -y-lactone in 150 ml of methanol is deacylated, the 3a, 5a-dihydroxy-2β- [2-chloro (3S) -3-hydroxy-3-methyl-trans-1-octenyl] -1 a- cyclopentane vinegar

65 acid-y-lactone obtained.

A sample of the corresponding (3R) starting material is deacylated analogously, giving the relevant (3R) product.

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B. A solution of 3.65 g of the reaction product according to Part A in 150 ml of tetrahydrofuran is cooled to -60 ° C., then diisobutylaluminum hydride and toluene (85 ml) are added over the course of 23 minutes at -70 ° C. The reaction mixture is stirred for a further 24 minutes, then 100 ml of saturated aqueous ammonium chloride solution are slowly added at -60.degree. The resulting mixture is stirred and allowed to warm to room temperature, whereby a gel forms as a precipitate. This mixture is then diluted with 70 ml of water and 150 ml of ethyl acetate, mixed thoroughly and filtered. The filter cake is washed with water and ethyl acetate, the aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give the lactol corresponding to the starting lactone.

C. Following the procedure of Preparation 1, sodium hydride in dimethyl sulfoxide is combined with 4-carboxybutyltriphenylphosphonium bromide and then with the lactol according to Part B to give the free acid form of the title compound.

The reaction product according to Part C is esterified with diazomethane according to the above procedure, the title compound being obtained.

If steps B to D are repeated, but with the deacylated (3R) lactone, the 15-epi-15-methyl-14-chloro-PGFia-methyl ester is obtained.

The title compound or its 15-epimer can also be prepared by the procedure of Scheme 3. The 3 (RS) -3-methyl-lactone is produced, the chromatographic separation being omitted.

The 3 (RS) -3-methyl-lactol is then produced. Then (15 RS) -15-methyl-14-chloro-PGF2a-bis-tetrahydropyranyl ether methyl ester is formed by methyl esterification of the free acid by the method of preparation 1. The tetrahydropyranyl residues can then be hydrolyzed, whereupon the C-15 epimers are separated by chromatography.

According to the method of preparation 2 or the above alternative method, the 15-epi-15-methyl- or 15-methyl-PGFsa-like compounds are obtained from other corresponding lactols.

Preparation 3

15-methyl-14-chloro-PGF2 «(formula LXXVI: R3 and R4 of Li = hydrogen,

CH3 no

Mis = H <OH,

Ri = hydrogen, R7 = n-butyl, Rs = hydroxy,

Yi = trans-CH = C (Cl) -, Z2 = cis-CH = CH- (CH2) 3-) or its 15-epimer.

A solution of 2.0 g of the reaction product according to preparation 2 or its 15-epimer in 20 ml of methanol is cooled to 0 ° C. 12 ml of a 10% aqueous sodium hydroxide solution are added dropwise to the resulting mixture in a nitrogen atmosphere. The mixture is then allowed to warm to room temperature and stirred for 2 hours. After the methanol has evaporated off under reduced pressure, the residue is diluted with water and extracted with methylene chloride. The aqueous phase is cooled with ice and treated with 24 ml of a 2 molar aqueous sodium bisulfate solution and immediately extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The crude product can then be chromatographed on 150 g silica gel to give the title compound or its 15-epimer.

If the process of preparation 3 is repeated, but with one of the 15-methyl-14-chloro-PGF <x-like methyl esters described, the free acids in question are obtained.

Preparation 4

14-chloro-16,16-dimethyl-PGF2a methyl ester (formula LXXVI: R3 and R4 of Li = methyl,

Mi = rf ^ OH

Mi8 = ^ ^ H,

Ri = methyl, R7 = n-butyl, Rs = hydroxy,

Y2 = trans-CH = C (Cl) -, (Z2 = eis CH = CH- (CH2) 3-) or its 15-epimer. Compare Scheme A. 0.241 g

14-chloro-16,16-dimethyl-PGF2a-bis-tetrahydropyranyl ether are reacted with 20 ml of tetrahydrofuran, water and acetic acid (1: 3: 6) at 40 ° C. for 4 hours. Then the resulting mixture is diluted with 60 ml of water and lyophilized. The residue is esterified with diazomethane, stopping with acetic acid in ether, then washed with sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated to dryness. The residue, when chromatographed while eluting with methylene chloride and acetone (3: 1), gives 0.056 g of pure product with NMR absorption at 0.44.0.98.1.1-1.42.1.42-2.6.2 , 7-3,4,3,7,3,8-4,5,4,04,5,25-5,8 and 5,65 8. The mass spectrum shows peaks at 395,340,331,296 and 281; characteristic ester IR absorptions at 1550, 1577, 1760 and 3450 cm-1.

The 15-epimeric product is obtained from the 15-epimeric starting material in question.

However, if the process of preparation 4 is repeated, replacing the starting material with one of the 11,15-bis-tetrahy-dropyranyl ether, 11-tetrahydropyranyl ether or 15-tetra-hydropyranyl ether described in and following preparation 1, the 14-chlorine in question is obtained -PGF2a-15-methyl ether or 14-chloro-PGF2a compounds.

Preparation 5

15-methyl-14-chloro-PGE2 methyl ester, (formula LXXVI: R3 and R4 of Li and R6 of Mi = hydrogen, Mis = Ri and Rs = methyl, R7 = n-butyl, Rs = hydroxy, Y2 = trans- CH = C (C1), Z2 = cis-CH = CH- (CH2) 3-) or its

15 epimer.

A. A solution of the 15-methyl-14-chloro-PGF2a methyl ester-11.15-bis-tetrahydro-pyranyl ether prepared in the above manner in 60 ml of acetone is cooled to -25 ° C. Then 1.9 ml of Jones reagent are added. The reaction mixture is stirred for 25 minutes at -25 ° C and mixed with 1.9 ml of isopropyl alcohol. After a further 15 minutes at -25 ° C, the mixture is diluted with 200 ml of water at 0 ° C and extracted with diethyl ether. The ether extracts are washed with 75 ml of cold 0.1 N potassium bicarbonate solution and 150 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, the

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15-methyl-14-chloro-PGE2-methyl ester-11,15-bis-tetrahydro-pyranyl ether is obtained.

B. A solution of the crude product according to Part A is reacted with 16 ml of tetrahydrofuran, water and acetic acid (1: 3: 6) and left to stand at 40 ° C. for 4 hours. The resulting mixture is diluted with 120 ml of water and freeze-dried. The residue is dissolved in diethyl ether and the solution is washed with potassium bicarbonate solution and saturated sodium chloride solution, then dried and concentrated to give the crude product. This is chromatographed on silica gel packed in 25 g of 5% acetone in methylene chloride while eluting with 5 to 40% acetone in methylene chloride. The pure product is obtained.

If the above procedure is repeated, but with the 15-epimer starting material, the 15-epimer product is obtained.

The procedure of preparation 5 is also repeated, but with the different 15-methyl-14-chloro-PGFa-methyl-ester-11,15-bis-tetrahydropyranyl ether or -15-tetrahydro-pyranyl ether described in or following preparation 1 , 14-methyl-14-chloro-PGE products are obtained.

Preparation 6

14-chloro-PGFia methyl ester or its 15-epimer.

A solution of 4.8 g of 14-chloro-PGF2a methyl ester in 90 ml of acetone and 60 ml of benzene, which contains 0.75 g of tris (triphenylphosphine) rhodium (I) chloride, is made from hydrogen at room temperature 1 to 3 atmospheres shaken for 3 Vi hours. Then the solvent is evaporated off and the residue is chromatographed on 400 g of silica gel packed in methylene chloride while eluting with 1 to 6% methanol in methylene chloride. This gives 0.90 g of impure product. It is purified to pure product by silica gel chromatography.

If the above procedure is repeated, but with the 15-epi-14-chloro-PGF2 «methyl ester, the 15-epi-14-chloro-PGFia-methyl ester is obtained.

If the process of preparation 6 is repeated, but with replacement of the starting material by one of the PGF2a compounds described in or following preparation 1, the PGFia-like products in question are obtained.

Preparation 7

i 4-chloro-16,16-dimethyl-PGF2ß, sodium salt.

A solution of 100 mg of 14-chloro-16,16-dimethyl-PGF2a in 50 ml of water and ethanol (1: 1) is cooled to 5 ° C. and neutralized with the equivalent amount of 0.1 N aqueous sodium hydroxide solution. The neutral solution is concentrated to a residue from the title compound.

If the process of Example 24 is repeated using potassium hydroxide, calcium hydroxide, tetramethylammonium hydroxide or benzyltrimethylammonium hydroxide instead of the sodium hydroxide, the corresponding salts of 14-chloro-16,16-dimethyl-PGF2 are obtained. Similarly, following the procedure of Example 24, the various other prostaglandin-like acids described above are converted to their sodium, potassium, calcium, trimethylammonium or benzyltrimethylammonium salts.

example 1

Î 5-methyl-l 3,14-didehydro-PGF2o-methyl ester (formula CLXXXII: Ri and Rs = methyl, R3 and R4 of Li and Rs of Mi = hydrogen, R? = N-butyl, Yi = -C = C -, Zi = cis-CH = CH- (CH2) 3-,

ho

3- CC

ho ').

Compare schemes C and D

A. 14.4 g of 15-keto-PGF2a methyl ester of the formula CXXXII in 35 ml of pyridine are treated with 10.5 ml of benzoyl chloride and the reaction is allowed to proceed for 2 hours. The resulting mixture is then diluted with ice water, cooled and diluted with ice-cold 10% sulfuric acid and methylene chloride. The phases are separated and the organic phase is dried and concentrated to give 24.18 g of crude product of the formula CXXXIII (Rie = benzoyloxy). Chromatographic purification of 15.8 g of this crude product on 600 g of silica gel gives 13.6 g of pure compound while eluting with 15% ethyl acetate in hexane.

B. 5.0 g of the reaction product according to Part A in 35 ml of carbon tetrachloride are cooled to freeze and 1.38 g of bromine are added dropwise. The reaction mixture is then diluted with methylene chloride, washed with sodium bicarbonate solution, dried and concentrated to give 5.6 g of crude 13,14-dibromo product. This crude dibromo compound is heated to 90 to 95 ° C. in 25 ml of pyridine for 1 hour. The mixture is left to stand at room temperature for 24 hours and then diluted with methylene chloride. The resulting dark colored solution is then distributed with ice-cold 5% sulfuric acid. The organic extract is washed with saturated sodium chloride solution and sodium bicarbonate solution, dried and concentrated to give 5 g of crude product of the formula CXXXIV. Chromatographic purification on 320 g of silica gel gives 2.13 g of product when eluted with 5% ethyl acetate in benzene.

C. Excess methylmagnesium bromide in ether is added dropwise to a solution of 6.32 g of the reaction product according to part B in 45 ml of tetrahydrofuran at -78 ° C. The reaction runs for 5 minutes and is then stopped by adding aqueous potassium bisulfate solution. The reaction mixture is diluted with diethyl ether, washed with saturated sodium chloride solution, dried and concentrated to give 6.5 g of crude compound CXXXV. The crude product is purified on 315 g of silica gel while eluting with 7.5% ethyl acetate in benzene. 4.28 g of the compound CXXXV are obtained as a mixture of the C-15 epimers.

D. A solution of 4.28 g of the reaction product according to Part C in 45 ml of methanol is treated with 1.5 g of potassium carbonate at room temperature for 72 hours. The resulting solution is concentrated under reduced pressure, then diluted with 5% sodium chloride solution and extracted with methylene chloride. The aqueous phase is cooled, acidified with 0.2 molar potassium bisulfate solution and extracted successively with methylene chloride and ethyl acetate. The fraction containing the carboxylic acid is washed with saturated sodium chloride solution, dried and concentrated to give 3.2 g of the compound CXXXVI (Ri = hydrogen) as an epimer mixture. This mixture of epimers is esterified with excess diazomethane

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2.32 g of the methyl ester is obtained. High pressure liquid chromatography of the methyl ester mixture on 512 g silica gel gives 0.75 g 15-epi-15-methyl-14-bromo-PGF2a-methyl ester and 0.21 g of 15-methyl-14-bromo-PGF2a-methyl ester. Further chromatographic separations yield 0.26 g of the (15S) compound.

The reaction product according to Part A shows NMR absorption at 0.89, 1.3-1.5, 3.61, 5.25-5.75, 6.3, 6.8-7.25, 7, 25-7.7 and 7.75-8.25; IR absorptions at 1250, 1575, 1594, 1625, 1680 and 1740 cm- '.

The reaction product according to Part B shows NMR absorption at 0.70-1.1, 1.1-3.05, 3.63, 5.25-5.8, 7.17 and 7.2-8, 25S; Peaks in the mass spectrum at 652, 530,451,408, 328,497 and 105; characteristic IR absorptions at 1720, 1610 and 1270 cm-1.

The (15RS) epimer mixture from stage C shows NMR absorptions at 0.8-1.1, 1.1-3.4, 1.48, 3.62, 3.9-5.8, 6.15, 6.06 and 7.10-8.28.

For the 15-methyl-14-bromo-PGF2a methyl ester, NMR absorptions at 0.7-1.1, 1.1-1.3, 1.49, 3.68, 3.85-4.4, 5.2-5.6 and 5.905 observed. The mass spectrum shows a basic peak at 604.2587 and further peaks at 586.571.533.525.507.347 and 217. For the 15-epi-15-methyl-14-bromo-PGF2a methyl ester, NMR absorptions were found at 0.7-1.1, 1.1 -3.4, 1.47, 3.8-4.4, 4.25-5.6 and 5.938 observed; Base peak in the mass spectrum at 504.2615 and further peaks at 586.573.571.533.525.514, 507.496.437 and 217.

E. A solution of 0.19 g of the 15-epi compound according to Part D in 9 ml of dimethyl sulfoxide is treated with 0.5 molar potassium tert-butoxide in dimethyl sulfoxide (0.9 ml). To follow the course of the reaction, thin-layer chromatography with silica gel impregnated with silver nitrate is used. After 2 hours the reaction is complete and the reaction mixture is diluted with diethyl ether, washed with ice-cold potassium bisulfate solution, 5% sodium chloride solution and 5% sodium bicarbonate solution, dried and freed from the solvent, giving 0.126 g of the crude (15R) title compound.

The 15-epimer is prepared according to the above procedure or by saponifying the methyl ester of the compound CXXXVI, dehydrohalogenation of the saponified product and finally methyl esterification of the dehydrohalogenated product. In this procedure, a solution of 0.55 g of the reaction product according to Part D in 30 ml of methanol is treated with 5 ml of 2N sodium hydroxide solution for 18 hours. Then the reaction mixture is diluted with benzene and 0.2 M potassium bisulfate solution. The organic phase is washed with 5% sodium chloride solution, dried and concentrated to give 0.49 g of 15-epi-15-methyl-14-bromo-PGF2a; NMR absorptions at 0.7-1.1, 1.1-3.4, 3.7-4.4, 5.1-5.75 and 5.955; characteristic IR absorptions at 3300.2600 and 1725 cm1. The dehydrohalogenation is carried out by treating 0.49 g of the free acid in 10% methanolic dimethyl sulfoxide (7 ml) with 4.43 millimoles of sodium methylate in 10.2 ml of 10% methanolic dimethyl sulfoxide and allowing the mixture to react for 20 hours. Then the reaction mixture is diluted with benzene and washed with ethyl acetate and benzene (1: 1). The combined organic extracts are washed with saturated sodium chloride solution, dried and concentrated to give 0.31 g of crude 15-epi-15-methyl-13,14-dide-hydro-PGF2a. This crude product is then esterified with excess diazomethane in a nitrogen atmosphere, and 2.8 g of the crude methyl ester are obtained on concentration. Purification on 25 g of silica gel while eluting with methylene chloride in acetone gives 0.211 g of pure 15-epi-15-

Methyl 13,14-didehydro-PGF2a methyl ester. NMR absorptions at 0.7-1.1, 1.1-3.2, 1.45,

4.0-4.5 and 5.4-6.05 observed; characteristic IR absorptions at 3200 to 3400.2600 to 2700.2220 and 1710 cm-1. NMR absorptions were observed for the methyl ester at 0.8-1.1.1.1-3.2.1.46.4.0-4.5.5.3-5.65.

The 15-methyl-13,14-didehydro-PGF2a-methyl ester is also obtained by the alternative process for the preparation of 15-epi-15-methyl-13,14-didehydro-PGF2a-methyl ester. A solution of 0.41 g of 15-methyl-14-bromo-PGF2a-methyl ester in 25 ml of methanol is treated with 6 ml of 10% aqueous sodium hydroxide solution and the reaction is allowed to proceed overnight at room temperature. The acid is isolated as described in the case of the 15-epimer, the yield is 0.34 g of crude product.

Without further purification, 0.32 g of the crude acid in a mixture of dimethyl sulfoxide and methanol (9: 1, 10 ml) with 0.43 m sodium methylate in a mixture of dimethyl sulfoxide and methanol (9: 1.6.6 ml) treated.

After 20 hours, the resulting solution is distributed by adding ice-cold 0.2 M potassium bisulfate in benzene. The aqueous phase is extracted with a 1: 1 mixture of benzene and ethyl acetate and the combined extracts are washed with saturated sodium chloride solution, dried and concentrated to give 0.180 g of crude 15-methyl-13,14-didehydro-PGF2a. After esterification with diazomethane (see procedure above), the crude title compound is obtained, which is chromatographed on 25 g of silica gel while eluting with acetone and methylene chloride (4: 1). 0.109 g of pure 15-methyl-13,14-didehydro-PGF2a methyl ester are obtained, NMR absorptions at 0.7-1.1,

1.1-3.5, 1.46, 3.69, 4.0-4.5 and 5.3-5.75. The mass spectrum shows a basic peak at 581.3508 and further peaks at 596.525.506.491.435.416.345.255 and 217, characteristic IR absorptions at 3350.2900.2220 and 1740 cm1.

If the process of Example 1 is repeated, but with the replacement of the 15-keto-PGF2a methyl ester by the various 15-keto-PGF compounds known or easily prepared by known methods, the corresponding 13,14-didehydro-PGF- Products. Thus, each of the 13,14-didehydro-PGFa-like compounds described herein is made by the method of Example 1 by choosing the appropriate PGFa starting material.

Example 2

15-methyl-13,14-didehydro-PGE2 methyl ester (formula CLXXXII: Ri and Rs = methyl, R3 and R4 from Li and R «from Mi = hydrogen, R7 = n-butyl, Rs = hydroxy, Yi = -C = C-, Zi = cis-CH = CH- (CH2) 3-) or its 15-epimer. Compare Scheme D.

A. A solution of 0.142 g of 15-methyl-13,14-didehydro-PGF2 "methyl ester (see Example 1) in 18 ml of acetone at -45 ° C is treated with 0.6 ml of trimethylsilyldiethylamine. After 2Vi hours, 2.1 ml of additional reagent is added and the reaction is continued for 5 hours. The resulting mixture is then diluted with pre-cooled diethyl ether and distributed with aqueous sodium bicarbonate solution. The organic phase is dried and concentrated to a yellow oil (15-methyl-13,14-didehydro-PGF2a-methyl ester-11 - (trimethylsilyl ether).

B. The oil obtained in Part A is dissolved in 10 ml of methylene chloride and the solution is added to a solution of 0.26 g of chromium trioxide in 20 ml of methylene chloride and 0.4 ml of pyridine at 0 ° C. This oxidation mixture is then at 0 ° C for 5 minutes and at room temperature

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Stir vigorously for 10 minutes. The resulting suspension is filtered through silica gel, the methylene chloride is evaporated off and 0.103 g of 15-methyl-13,14-dide-hydro-PGE2-methyl ester of the formula CLXXIII is obtained.

C. The crude reaction product according to Part B in 20 ml of methanol is treated with 10 ml of water and 1 ml of acetic acid and reacted for 5 minutes at 0 ° C. and then for 10 minutes at room temperature. The reaction mixture is diluted with diethyl ether and distributed with 0.2 m sodium bisulfate solution. The organic phase is washed with sodium chloride solution and sodium bicarbonate solution, dried and concentrated to give 0.082 g of crude title compound.

The 15-epimer is also obtained by the above procedure.

For the 15-methyl-13,14-didehydro-PGE2 methyl ester, the mass spectrum shows a basic peak at 407.2981 and further peaks at 522.491.451.432.361.307.277 and 187. NMR absorptions were found for the 15-epimer at 0.8-1.1, 1.1-3.2, 1.48, 3.68, 4.1-4.7 and 5.3-5.65 observed; the mass spectrum shows peaks at 507.2981.522, 491.451.432.361.307.277 and 187; characteristic IR absorptions at 3300.2257 and 1740 cm-1.

Following the procedure of Example 2, the various 13,14-dide-hydro-PGF-like compounds described in Example 1 are converted into the corresponding 13,14-didehydro-PGE compounds.

Example 3

15-methyl-13,14-didehydro-PGFia methyl ester or its 15-epimer. Compare schemes C and D.

A. A solution of 8.5 g of PGFia methyl ester in 60 ml of dioxane is treated with 6.8 g of 2,3-dichloro-5,6-dicyan-1,4-benzo-quinone. The reaction runs for 21 hours, then the suspension is filtered and the filter cake is washed with dioxane. The filtrate and washing solution are concentrated under reduced pressure, the residue is triturated with methylene chloride and filtered off, the filtrate is freed from the solvent, 11.6 g of crude 15-keto-PGFia methyl ester being obtained. The crude product is chromatographed on 450 g of silica gel while eluting with hexane and ethyl acetate (1: 1), 7.04 g of pure compound being obtained; NMR absorptions at 0.89.1.05-2.05.25.05-2.75, 3.20-3.8.3, 67.6.13 and 6.765.

B. A solution of 7.07 g of the reaction product according to Part A in 40 ml of pyridine is treated with 6.3 ml of benzoyl chloride and the reaction is carried out at room temperature

Allow to run for 3 hours. The resulting mixture is then diluted with ice water and extracted with methylene chloride. The methylene chloride extract is washed with ice cold dilute sulfuric acid, sodium bicarbonate solution and sodium chloride solution, dried and concentrated to give 11.4 g of a viscous oil. This is chromatographed on 200 g of silica gel while eluting with hexane in ethyl acetate (85:15). This gives 10.76 g of pure 15-keto-9, ll-dibenzoyl-PGFia methyl ester; NMR absorptions at 0.89, 1.5-1.80, 2.0-2.3, 2.3-2.7, 3.63, 5.1-5.65, 6.26, 6, 92, 7.2-7.7 and 7.8-8.25.

C. A solution of 8.3 millimoles of bromine in 30 ml of tetrachloroethane is added dropwise to a solution of 4.77 g of the reaction product according to Part B in 20 ml of carbon tetrachloride. The color disappears after 10 minutes. The solvent is concentrated under reduced pressure and 5.0 g of 13,14-dibromo-9, l-dibenzoyl-15-keto-PGFia methyl ester are obtained; NMR absorptions at 0.9, 1.10-2.0,

2.0-3.3, 3.65, 4.4-4.95, 5.08, 5.45-5.85, 7.10-7.8 and

7.9-8.25.

D. 2.56 g of the reaction product according to Part C in 18 ml of pyridine are heated to 90 to 95 ° C. for 1 hour. The resulting dark green solution is then diluted with methylene chloride, washed with ice-cold 10% sulfuric acid, 5% sodium bicarbonate solution and 5% sodium chloride solution, dried and concentrated. This process is repeated two more times and 9.0 g of crude product are obtained. The crude product is chromatographed on 210 g of silica gel while eluting with hexane and ethyl acetate (85:15). 5.5 greiner 14-bromo-9, ll-dibenzoyl-15-keto-PGFia methyl ester are obtained, NMR absorptions at 0.92, is 1.1-2.0, 2.0-2.6, 2.6-3.1, 3.64, 5.1-5.7, 7.12, 7.2-7.7 and 7.8-8.75.

E. A solution of 0.43 g of the reaction product according to Part D in 15 ml of tetrahydrofuran is cooled to -78 ° C

20 and treated with 1.6 ml of ethereal methyl magnesium bromide in 10 ml of tetrahydrofuran. After 3 hours, the reaction mixture is poured into a cold mixture of diethyl ether and saturated ammonium chloride solution with stirring. The combined ether extracts are washed with sodium chloride solution, dried and concentrated and give 0.43 g of crude (15RS) -15-methyl-14-bromo-9.11 -diben-zoyl-PGFia-methyl ester. Chromatography on 25 g of silica gel while eluting with benzene in acetone (97: 3) gives 0.280 g of pure product, NMR absorptions at 0.83, so 1.0-2.0, 1.47, 2.0-3 , 4, 3.63, 5.0-5.8, 6.13, 7.2-7.7 and 7.8-8.25.

F. A solution of 0.28 g of the reaction product according to Part E in 15 ml of methanol is mixed with 0.1 g of potassium carbonate

35 treated. The solution is stirred for 24 hours and then concentrated under reduced pressure, diluted with sodium chloride solution and extracted with ethyl acetate. This gives 0.197 g of crude deaeylated product. 0.19 g of this crude product is chromatographed on 25 g of silica gel while eluting 40 with methylene chloride in acetone (85:15), 43 mg

14-bromo-15-methyl-PGFia-methyl ester and 40 mg of 15-epi-14-bromo-15-methyl-PGFia-methyl ester can be obtained. For the (15S) product, NMR absorptions at 0.88,

1.10-2.1.1.45.2.1-2.7.3.67.3.7-4.4 and 5.925 observed; 45 peaks in the mass spectrum at 426,395 and 372. For the

15-epimeric compound had NMR absorptions at 0.88, 1.10-2.1, 1.45, 2.1-2.5, 2.5-3.3, 3.67, 3.8-4 , 4 and 5.975 observed; Peaks in the mass spectrum at 408 and 329.

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G. A solution of 0.37 g of potassium tert-butoxide in 15 ml of tert-butanol is treated with 0.36 g of the reaction product according to Part F. After 3 Vi hours, the reaction mixture is diluted with diethyl ether and 1% aqueous potassium bisulfate solution is added. The aqueous phase is extracted with diethyl ether and benzene solutions and the combined organic extracts are washed with saturated sodium chloride solution, dried and concentrated to give 0.35 g of crude product. The crude product 60 is purified on silica gel, eluting with 40% ethyl acetate in benzene, to give 78 mg of 15-methyl-13,14-dide-hydro-PGF2a.

When the product is esterified according to the preceding section with diazomethane, 38 mg of the pure title compound of F. 50 ° C., peaks in the mass spectrum at 598,583,527,508,469, 411,217 and 187, are obtained characteristically after chromato-65 graphing on silica gel while eluting with 12% acetone in methylene chloride IR absorption at

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1740 and 2220 cm- '. Following the procedure of Part G, 0.362 g of 15-epi-15-methyl-14-bromo-PGFia methyl ester is reacted to 30 mg of the 15-epimeric title compound, NMR absorptions at 0.9, 1.45, 2.1-2 , 4, 3.67 and 4.0-4.48, peaks in the mass spectrum at 598,583,508,493,477,469, 411,217 and 187; characteristic IR absorptions at 1740 and 2240 cnr '.

Example 4

13,14-Didehydro-PGFia methyl ester or its 15-epimer.

A. 0.44 g of sodium borohydride in 30 ml of methanol at -35 ° C. are treated with a solution of 5.04 g of the reaction product according to Example 28, Part D and methanol. The solution is stirred for 20 minutes, then 20 ml of acetic acid are added, it is diluted with diethyl ether and then ice-cold 0.2 M sulfuric acid is added. The combined organic extracts are washed with sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated. The crude residue from 5.0 g

14-bromo- (15RS) -9.11 -dibenzoyl PGFi a-methyl ester is used without further purification; NMR absorptions at 0.7-1.0, 1.0-1.9, 1.9-2.3, 2.3-3.3, 3.63, 3.9-4.3,

5.0-5.6, 6.02, 7.2-7.7 and 7.2-8.25.

B. A solution of 5.0 g of the reaction product according to Part A in 35 ml of methanol is mixed with 1.5 g of potassium carbonate and agitated for 20 hours. The resulting suspension is concentrated under reduced pressure, diluted with water! and extracted with ethyl acetate. After drying and evaporation of the solvent, 4.52 g of the crude, epimer-mixed deacylated product are obtained. The above aqueous phase is acidified and extracted with ethyl acetate to give 0.45 g of the free acid of the epimer mixed acylated product. These acids are esterified with excess diazomethane in ether and the combined methyl ester fractions are chromatographed together on silica gel while eluting with methylene chloride and acetone (7: 3), 1.38 g of 14-bromo-PGFia methyl ester and 1.23 g of 15-epi -14-Bromo-PGFia methyl ester can be obtained. For the (15S) compound, NMR absorptions at 0.7-1.1, 1.1-2.0, 2.0-2.6, 2.6-3.5, 3.68, 3, 75, 4.4 and 5.855 observed. The mass spectrum shows peaks at 414, 412, 360, 358, 351, 333, 279 and 278.

For the 15-epimer product, NMR absorptions were found at 0.7-1.10.1.1-2.0.2.0-2.5.2.5-3.5.3.68.3.8-4 , 5 and 5,885, the mass spectrum of this compound shows peaks at 360; 258,333,279 and 278.

C. A suspension of 50% sodium hydride (0.7 g) in

10 ml of dimethyl sulfoxide is treated with 1.3 ml of tert-butanol and stirred until the foaming stops. Then a solution of 1.38 g of the reaction product according to Part B in 15 ml of dimethyl sulfoxide is added. After 20 hours, the reaction mixture is diluted with benzene and diethyl ether (1: 1) and mixed with ice-cold potassium bisulfate solution in water, then the phases are separated, the organic extracts are washed with sodium chloride solution, dried and concentrated, and the residue is esterified with diazomethane. The resulting crude ester (1.13 g) is chromatographed on silica gel eluting with methylene chloride in acetone (7: 3). This gives 0.61 g of the pure title compound of F. 68 ° C, NMR absorptions at 0.90,

1.1-2.0, 2.0-3.0, 3.0-3.9, 3.68 and 4.0-4.455; characteristic IR absorptions at 1740,2250 and 3200 bis

3600 cm-1; Mass spectrum peaks at 322,319,306,297, 295,294,279,278,276,250 and 222.

Following the procedure of Example 4, 1.23 g of 15-epi

14-bromo-PGFia-methyl ester converted into 0.53 g of 15-epi-13,14-dide-hydro-PGFia-methyl ester, NMR absorptions at 0.90, 1.1-2.0, 2.0-3, 4, 3.68 and 3.9-4.75; characteristic IR absorptions at 1740,2250 and 3450; Mass spectrum peaks at 350,337,332,319,306,297,295,294,279,278, 276,250 and 222.

Example 5

13,14-Didehydro-PGEi methyl ester or its

15 epimer.

A. A solution of 0.22 g of 13,14-didehydro-PGFia methyl ester (see Example 4) in 18 ml of acetone at -45 ° C is treated with 0.8 ml of trimethylsilyldiethylamine and the resulting mixture is stirred for 3½ hours . Then another 0.8 ml of silylating agent is added. After 45 minutes, sodium bicarbonate solution is added and the mixture is extracted with diethyl ether. After drying and evaporation of the solvent, 0.34 g of crude 13,14-didehydro-PGFia methyl ester-1,15-bis (-trimethylsilyl ether) is obtained.

B. 0.6 g of the reaction product according to Part A in 25 ml of methylene chloride at 0 ° C are treated with 0.5 g of chromium trioxide, 40 ml of methylene chloride and 0.8 m 'pyridine. Oxidation conditions (0 ° C) are maintained for 5 minutes, then allowed to warm to room temperature for an additional 10 minutes. The resulting mixture is diluted with methylene chloride and filtered through silica gel. The eluate is concentrated and gives 0.41 large 13,14-didehydro-PGE1 a-methyl ester-11,15-bis (trimethylsilyl ether).

C. The product according to Part B is combined with a mixture of methanol, water and acetic acid (20: 10: 1.31 ml). The reaction is allowed to proceed for 5 minutes at 0 ° C and then for 15 minutes at room temperature. This results in '] «; The mixture is diluted with water and extracted with diethyl ether. The combined ether extracts are washed with sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated to give 0.33 g of the crude title compound. This crude product is then chromatographed on 25 g of silica gel while eluting with methylene chloride in acetone (9: 1), 80 mg of pure 13,14-didehydro-PGEia methyl ester having a melting point of 46 ° C. being obtained. NMR absorption at 0.9.1.1-2.05.25.05-3.4.3.67 and 4.0-4.65. Peaks in the mass spectrum at 348,320,319, 295,292 and 263. The IR spectrum shows characteristic absorptions at 1675,1740,2220 and 3400 cm- '.

Following the procedure of Example 5, Parts A, B and C, 130 mg of 15-epi-13,14-didehydro-PGFia methyl ester are converted into 26.5 mg of the 15-epi title compound; characteristic IR absorptions at 1740.2225 and 3450 cm-1, peaks in the mass spectrum at 348.320.319.317.295.292 and 263.

Example 6

13,14-Didehydro-PGFia or its 15-epimer.

6.79 g of potassium tert-butoxide in 45 ml of tert-butanol and 8 ml of methanol are reacted with 3.02 g of 14-bromo-PGFi (see Example 4) for 25 hours. The resulting reaction mixture is diluted with diethyl ether and washed with ice-cold 8% phosphoric acid, whereupon the phases are separated. The aqueous phase is extracted with benzene and then with ethyl acetate. The combined organic extracts are washed with sodium chloride solution, dried and concentrated, whereby 2.86 g of the title compound of 74 to 75 ° C. are obtained. The mass spectrum shows a basic peak at 642.3961 and further peaks at 627.571.552,

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537,481 and 436; characteristic IR absorptions at 3150 to 3525, 2700, 2220, 1710 and 1680 cm-1.

According to the procedure in the previous section, 1.46 g of 15-epi-14-bromo-PGFio as starting material gives 1.46 g of 15-epi-13,14-didehydro-PGFi «from 95 ° C to 96 ° C .; NMR absorptions at 0.8-1.1, 1.1-1.9, 2.0-2.8 and 3.9-4.75, basic peak in the mass spectrum at 642.4021 and further peaks at 627.571.552.537.481 and 217 ; the infrared spectrum shows characteristic absorptions at 3150 to 3300, 2700, 2220, 1725 and 1700 cm-1.

Example 7

13,14-Didehydro-16,16-dimethyl-PGF2 methyl ester. Compare Scheme D

A solution of the reaction product of preparation 4 in 10 ml of dimethyl sulfoxide is reacted with 40 mg of potassium tert-butoxide at room temperature for 28 hours. The resulting one

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Solution is diluted with diethyl ether and then poured into a mixture of ice-cold potassium bisulfate solution and diethyl ether. The mixture is distributed with benzene, washed with sodium chloride solution, dried and concentrated, s The residue is esterified with excess diazomethane in ether. The crude methyl ester is chromatographed on 10 g of silica gel while eluting with methylene chloride and acetone (75:35). This gives 0.016 g of the title compound, in which a characteristic IR absorption io (-C = C-) is observed at 2250 cm-1; Mass spectrum peaks at 327,320,304,303,295,284,263,247,245,235, 227 and 57.

All of the 14-halogen PGFa compounds described above are converted into the relevant 13,14-dihydro PGFa products by the process of Example 7.

Furthermore, the various 13,14-didehydro-PGFa-like products are converted to the 13,14-didehydro PGE products according to the procedure of the above examples.

B

Claims (4)

o30 897 PATENT CLAIMS ì. Process for the preparation of new prostaglandin analogs of the formula H \ / H / C = C \ CH2 ^ CH2- (CH2) q-CH2-COORi Yl-C-C- (CH2) m "CH3 Mi Li CLXXXII where inD one of the remnants ho <x ho ho means Yi is -C = C-, g is the number 1, 2 or 3 and m is a number from 1 to 5, Wed or Rs ORe Rs ORe, means where Rs and Rô are hydrogen or methyl, Li R3 Ì14, R3 "\ 4, ho \ / j or V-s ho ' or a mixture of 30th and "ÌU R3 means 35 wherein R3 and R4, which may be the same or different, are hydrogen, methyl or fluorine, provided that one of the radicals R3 and R4 is fluorine only if the other is hydrogen or fluorine, and R 1 is hydrogen, an alkyl radical having 1 to 12 carbon atoms, cycloalkyl radical having 3 to 10 carbon atoms, aralkyl radical having 7 to 12 carbon atoms, the phenyl radical, a phenyl radical substituted by 1, 2 or 3 chlorine atoms or alkyl radicals having 1 to 3 carbon atoms, or represents a pharmacologically acceptable cation, characterized in that a compound of the formula : c = r ch2 * ch2- (ch2) g-ch2-c'00ri CLXXXI y2-c-c- (ch2) m-ch3 Mx Li . beforehand D, Ri, Li, Mi, g and m are defined above and 60 2. A method according to claim 1, characterized in that Y2 the rest that compounds obtained, which are present as acid, are converted into the corresponding esters. trans -CH-C (Hal) 3. The method according to claim 1, characterized in that compounds obtained which are present as esters means in which shark is chlorine, bromine or iodine, 65 saponified to free acid. dehydrohalogenated and obtained compounds in which Ri is hydrogen, optionally in the corresponding 4th process for the preparation of C2-C8 alkanoates from Salts transferred. new prostaglandin analogue of the formula 3rd 630897 c = c H "ch2- (ch2) -cha-coori y CLXXXII wherein D one of the remnants ho Yi-jj-jj- <CHa) m-CH, Mi Li HO ho HO or means Yi-OC-is g is the number 1, 2 or 3 and m is a number from 1 to 5, 25 or a mixture of and Wed or RI ^ R4, Rs ORe Rs ORe, means where Rs and R & are hydrogen or methyl, Li R3 R4, R3 R4, 30 means wherein R3 and R4, which may be the same or different, are hydrogen, methyl or fluorine, provided that one of R3 and R4 is fluorine only when the other is hydrogen or fluorine, and Ri is hydrogen, 35 an alkyl group 1 to 12 carbon atoms, cycloalkyl radical having 3 to 10 carbon atoms, aralkyl radical having 7 to 12 carbon atoms, the phenyl radical, a phenyl radical substituted by 1, 2 or 3 chlorine atoms or alkyl radicals having 1 to 3 carbon atoms or a pharmacologically acceptable cation , characterized in that a compound CLXXXII is prepared in the process according to claim 1 and this is reacted with a Cî-Cs acylating agent. 5. Process for the preparation of new prostaglandin-45 analogs of the formula c = c * * ch2- (ch2) g-ch2-c00ri CLXXXII; A Y.-jj-Ç-tCH,) «-», Mi Li where one of the remains .0 or ho means 60 Yi-C = C-is g is the number 1, 2 or 3 and m is a number from 1 to 5, Wed 65 or R5 \> R6 r1 ) RÔ, 630897 means where Rs and R.6 are hydrogen or methyl, Li R3 Ìl4, K3 R4, / \ R3 R4, / \ R3 R4, c00h or a mixture of and means wherein R3 and R4, which may be the same or different, are hydrogen, methyl or fluorine, provided that one of R3 and R4 is fluorine only when the other is hydrogen or fluorine, and Ri is hydrogen, an alkyl group with 1 up to 12 carbon atoms, cycloalkyl radical with 3 to 10 carbon atoms, aralkyl radical with 7 to 12 carbon atoms, the phenyl radical, a phenyl radical substituted by 1,2 or 3 chlorine atoms or alkyl radicals with 1 to 3 carbon atoms or a pharmacologically acceptable cation, characterized in that that a compound of the formula CLXXXII is prepared by the process according to claim 1 and then the C-9-hydroxyl group is oxidized to the oxo group and compounds obtained, in which R 1 is hydrogen, are optionally converted into the corresponding salts. 6. The method according to claim 5, characterized in that obtained compounds, which are present as free acid, are converted into the corresponding esters. 7. The method according to claim 5, characterized in that saponified compounds which are present as esters, saponified to free acid. compare e.g. Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and literature references there. The systematic name for prostanoic acid is 7 - [(2ß-octyl) -cyclopent-la-yl] -10 heptanoic acid. The prostaglandins mentioned have the following formulas: 15 PGEi: 20th 25th PGE2: 30th 35 PGE3! 40 c00h