FI59791B - ANALOGIFICATION OF FARMING AGAINST PHARMACOLOGICAL ANALYSIS E2 ANALOG OF AV PROSTAGLAND - Google Patents

Description

[Β] (11) ANNOUNCEMENT cQ7gi

Ma 11 '' utlAggningsskrift o-7 / yic Patent r: .yr: n:; c · tt-y 12 10 1931 # ^ 5v§ 4S ^ Patent eoJ Elat ^ ^ (51) Kv.ik? / Inca3C 07 C 177 / 00 ENGLISH —Fl N LAN D (21) Ptttnttlhikemui - Pitunaroäknlng 773810 (22) Hak «ml * cloud —An * eknlngfdaf l6.12.77 ^ ^ (23) Alkupttvi — Glltlghutadag 11. OU. 72 (41) Tullut Julkteakal - Bllvlt offantllf l6.12.77

National Board of Patents and Registration N «ht» Vlk,., »Non |. kuLjulkabun pm * -, 4 patents * och registerstyrelsen AnaSkan utlagd och utl-ikrlften publkarad 30.06.81 (32) (33) (31) Pyydetty atuolkau * —Begird priori * · * .12.0U. 71 USA (US) 1333 ^ 2 (71) The Upjohn Company, 301 Henrietta Street, Kalamazoo, Michigan, USA (US) (72) Barnley John Magerlein, Portage, Michigan, USA (US) (74) Berggren Oy Ab (5U ) Analog method for the preparation of pharmacologically useful prostaglandin E2 analogues

This invention relates to an analogous process for the preparation of new pharmacologically useful analogues of prostaglandin E2 (PGE2).

Prostanoic acid has the following structure and numbering: rSX 2 o

The systematic designation of prostanoic acid is 7 - [(2-octyl) cyclopent-1-yl] -heptanoic acid.

PGE2 has the following structure:

O

'^ - = / X / ^ (: ooh ho' '"2 59791

The prostaglandin formula shown above has several asyiranetriak.es. The formula represents a particularly optically active form of prostaglandin obtained from the tissues of certain mammals, e.g. the sheep bladder glands, the porcine lung and human semen, or by reducing or removing water from the prostaglandin thus obtained. See, e.g., Bergström et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. The mirror image of the formula represents the molecule of this enantiomer of prostaglandin. The racemic form of prostaglandin contains an equal number of two types of molecules, one of which corresponds to one of the above formulas and the other to a mirror image of this formula.

Thus, both formulas are needed to determine racemic prostaglandin. See Nature 212, 38 (1966) for the stereochemistry of prostaglandins.

In the above and following formulas, the dashed bond to the cyclopentane ring means that the substituents are in the alpha configuration, i. below the level of the cyclopentane ring. The thick dark lines emanating from the cyclopentane ring indicate that the substituents are in the beta configuration, i. above the level of the cyclopentane ring. The side chain hydroxy group on carbon atom C-15 above is in the alpha configuration.

It is therefore an object of the present invention to provide novel pharmacologically useful prostaglandin Έ> 2 analogs, or pharmaceutically acceptable salts thereof, having the formula

XX

/ R 1, OH OH 1 wherein and R 2 represent hydrogen, methyl or ethyl, and in which at most one of these is hydrogen.

In the process of the invention for an optically active or racemic compound of formula »357979

O

γΛ

<At R2 (ID

/! * i

0H OH

wherein and R 1 are as defined above, the following reactions are carried out sequentially: a) the hydroxyl hydrogens are replaced by tetrahydropyranyl groups; b) the lactone oxo group is reduced to a hydroxy group; c) Wittig alkylation is performed using a compound of formula Hal- (CH 2) 2 -COOH 2 wherein Hal is bromine or chlorine; d) the 9-hydroxy group is oxidized to an oxo group; and e) converting the tetrahydropyranyloxy groups to hydroxy groups.

All of the novel prostanoic acid analogs of this invention have one or two methyl or ethyl substituents on the C-16 carbon atom, i. at the carbon atom adjacent to the hydroxyl-substituted C-15 carbon atom. Thus, these novel prostanoic acid analogs may be conveniently referred to as 16-methylprostaglandins, 16-ethylprostaglandins, 16,16-dimethyl-prostaglandins, 16,16-diethylprostaglandins or 16-methyl-16-ethylprostaglandins, e.g. 16-methyl-P2, 16-methyl -ethyl-PGE2, 16,16-dimethyl-PGE2, 16,16-diethyl-PGE2, 16-methyl-16-ethyl-PGE2 and so on.

As with the natural prostaglandins described above, these new 16- or 16,16-di-substituted prostaglandin analogs have several centers of asymmetry. In addition to those observed in natural prostaglandins, a center of asymmetry occurs on the C-16 carbon atom when this carbon atom is monosubstituted as in 16-methyl or 16-ethyl-PG compounds. The compound 16-methyl-PGE2 therefore has two C-16 epimers, each with the same configuration in other centers of asymmetry as the natural compound PGE2, i. for the alpha side chain at C-8 and for the alpha hydroxyls at C-11 and C-15.

The compound PGE2 and its pharmacologically acceptable salts are very effective in producing various biological effects.

* 4 59791 Therefore, these compounds are useful for pharmacological purposes. See, e.g., Bergström et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. Some of these biological effects include smooth muscle stimulation, as evidenced, e.g., by tests performed on strips of guinea pig ileum, rabbit duodenum, or gerbo rodent colon; enhancement of other smooth muscle stimulants; as an anti-fat cleavage effect in contrast to epinephrine-induced mobilization of free fatty acids or to prevent spontaneous release of glycerin from isolated fat pads in rats; as a prevention of gastric secretion which occurs in dogs whose gastric secretion has been stimulated by food or histamine injection; as an activity in the central nervous system; decreased platelet adhesion as manifested by platelet adhesion to glass, and platelet aggregation caused by various physical stimuli, e.g., arterial injury and various biochemical stimuli, e.g., ADP, STP, serotonin, thrombin, and collagen; and as an induction of skin regrowth and cornea that occurs upon addition to the culture of fetal chickens and skin fractions of rats.

Due to these biological effects, known prostaglandins are useful in the study, prevention, control or alleviation of a very large number of diseases and undesirable physiological conditions in birds and mammals, including humans, beneficial domestic animals, pets and zoos, and laboratory species, as well as .

The PGE compounds are useful in mammals, including humans, as nasal sprays. For this purpose, the compounds are used in doses of about 10 μg to 10 mg per ml of a pharmacologically acceptable liquid excipient or as an aerosol spray, for both external use. In this application and the following, a lower limit dose is preferred for humans and a higher limit for domestic animals, e.g., horses and cows.

The PGEs are useful in mammals, including humans, and certain useful animals, e.g., dogs and pigs, to reduce and regulate excessive gastric acid secretion, to reduce or avoid gastrointestinal wound formation, and to accelerate the healing of ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected intravenously, subcutaneously or intramuscularly at an injection dose of between about 0.1 μg and about 500 μg per kg of body weight per minute or as a total daily dose as a spray of between about 0.1 μg and about 20 μg. per kg body weight per day, the exact dose depending on the age, weight and condition of the patient or animal and the frequency and route of administration.

The PGEs are useful at any time when it is desired to prevent platelet formation, reduce platelet infectivity, and eliminate or prevent the formation of thrombosis from the team in mammals, including humans, rabbits, and rats. These compounds are useful in e.g. the cause of the disease is associated with lipoid imbalance or blood obesity. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and for sustained release as sterile grafts. For rapid effect, especially in the event of an accident, intravenous administration is preferred. Doses ranging from about 0.005 to about 20 mg per kg of carcass weight per day are used, depending on the age, weight and condition of the animal or patient, and the frequency and route of administration.

PGEs are particularly useful as additives for blood, blood products, blood substitutes, and other fluids used in the artificial external circulation and lavage of isolated parts of the body, such as limbs and organs, whether or not they are still attached to, separated from, or stored in the original body. for transplantation or whether they have already been transplanted into a new body. During these cycles and flushing, adherent platelets tend to clog blood vessels and parts of the recycling equipment. The presence of these compounds 6 59791 prevents this clogging. For this purpose, the compound is added gradually or in one or more doses to the circulating blood, the blood of the donating animal, the perfused body part attached or detached, to the recipient, or to two or all of them in a constant total dose of about 0.001 to 10 mg per liter of circulating fluid. These compounds are particularly preferably used in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes to develop new methods and procedures for organ and limb transplants.

PGEs are particularly potent smooth muscle stimulants and are also very effective in enhancing other known smooth muscle stimulants, e.g., contraceptives. e.g., oxytocin and various ergot alkaloids, including derivatives and analogs thereof. Therefore, e.g.

PGE2 is useful to replace or be used in combination with a smaller amount of these known smooth muscle stimulants, e.g., to alleviate intestinal paralysis or to regulate or prevent flaccid uterine bleeding after abortion or childbirth, to assist in placental prolapse, and in childbirth. For the latter purpose, the PGE compound is administered by intravenous injection immediately after abortion or delivery at a dose of between about 0.01 and about 50 ug per kg of body weight per minute until the desired effect is obtained. Subsequent doses are administered intravenously, subcutaneously, or intramuscularly during infancy in an injection dose of between 0.01 and 2 mg per kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

Instead of an oxytokine, the PGEs are useful for inducing pushing in or near pregnant female animals, including humans, cows, sheep, and pigs, or in pregnant animals in which the fetus has died in utero from about 20 weeks to time. For this purpose, the compound is injected intravenously from 0.01 to 50 μg per kg of body weight per minute until the second stage of labor is complete or nearing completion, i. fetal squeezing. These compounds are particularly useful when the female is one or two weeks late and natural labor has not yet begun, or 12-60 hours after 7 59791 when the membranes have ruptured and natural labor has not yet begun. An alternative route of administration is oral.

The PGEs are useful in regulating 1 reproductive cycle in ovum-producing mammals, including humans, and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. By ovum-producing female mammals is meant animals that are mature enough to produce eggs but are not so old that regular ovum production has ended.

As mentioned above, PGEs are potent antibodies to epinephrine-induced free fatty acid mobilization.

To this end, these compounds are useful in experimental medicine for both in vivo and in vitro studies in mammals, including humans, rabbits and rats, aimed at understanding, preventing, alleviating and ameliorating diseases associated with abnormal lipid mobilization and high levels of free fatty acids. , e.g., diabetes, vascular disease, and hyperthyroidism.

The PGE compounds promote and accelerate the growth of skin cells and cornea in animals, including humans, beneficial domestic animals, pets, zoo varieties, and laboratory animals. Therefore, these compounds are useful in promoting and accelerating the healing of damaged skin, e.g., from burns, wounds, and bruises, and after surgery. These compounds are also useful in promoting and accelerating the adhesion and growth of skin self-transplants, especially small deep (Davis) grafts, which are intended to cover skinless areas with subsequent outward growth rather than immediately and to slow coagulation of the same tissue.

For these purposes, these compounds are preferably administered externally at a site close to where the cell is desired to grow or form a horn, preferably as an aerosol or very fine powder spray, as a co-tension aqueous solution in the case of wet dressings or as a washing liquid, as an ointment or foam. with pharmaceutically acceptable diluents. In some cases, for example when significant amounts of fluid have been lost, such as from extensive burns or skin loss due to other causes, systemic administration is preferred, e.g., by intravenous injection alone or in combination with conventional injections of blood, plasma or these substitutes. Alternative routes of administration are subcutaneous or intramuscularly close to the space, orally, sublingually, buccally, rectally, or vaginally. The exact dosage will depend on such factors as the route of administration and the age, weight and condition of the subject. These prostaglandins are particularly useful for topical use in combination with antibiotics such as gentamicin, neomycin, polymyxin B, bacitricin, spectinomycin and oxytetracycline in combination with other antibacterial agents, e.g. · With hydrocortisone, prednisolone, methylprednisolone and fluprednisolone, each used in combination at the usual concentration suitable for its use alone.

The novel 16- and 16,16-disubstituted PGE2-type compounds of formula I each provide the biological effects described above for PGEs, and each of these novel compounds is therefore useful for the corresponding purposes described above and is used for these purposes in the same manner as described above. .

Known PGE compounds uniformly produce many biological effects even at low doses. For example, PGE1 and PGE2 each cause vascular paralysis and smooth muscle arousal while having an antilipolytic effect. These known prostaglandins also have an unusually short biological duration of action for many purposes. The novel prostaglandin analogs of formula I, on the other hand, are substantially much more specific in their ability to produce prostaglandin-like biological effects and have a substantially longer biological duration. Thus, each of these new prostaglandin analogs is a useful substitute for one of the corresponding known prostaglandins mentioned above for at least one of the pharmacological purposes mentioned above, which is surprisingly and unexpectedly much more useful for this purpose because of its different and much narrower biological range. than the known prostaglandin and is therefore much more specific in its effect and causes fewer and smaller undesirable side effects than the known prostaglandin. In addition, due to its prolonged effect, fewer and lower doses of a new prostaglandin analog can be used to achieve the desired result.

Another advantage of the novel compounds of this invention, especially the preferred compounds defined above over known prostaglandins, is that these novel compounds can be effectively administered orally, sublingually, vaginally, buccally or rectally in addition to conventional intravenous, intramuscular or subcutaneous injections. mentioned in connection with known prostaglandins. These properties are advantageous because they allow the levels of these compounds to be kept constant in the body at fewer, shorter and lower doses and allow the patient to take the drug himself.

The 16- and 16,16-disubstituted PGE2-type compounds of the formula I are used for the purposes described above in the form of the free acid or in the form of a pharmacologically acceptable salt.

Pharmacologically acceptable salts of these compounds of formula I useful for the purposes described above are formed with pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations.

Particularly preferred metal cations are alkali metals, for example lithium, sodium and potassium, and alkaline earth metals, e.g. magnesium and calcium, although cationic forms of other metals, e.g. aluminum, zinc and iron, are included within the scope of the invention.

«

Pharmacologically acceptable amine cations include primary, secondary and tertiary amines. Examples of suitable amines include methylamine, dimethylamine, trimethylamine, ethyl; 59791 10 amine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine ethylenethylamine-ethylenethylamine, α-phenylethylamine, α-phenylethylamine, , cycloaliphatic and araliphatic amines having up to about 18 atoms, as well as heterocyclic amines, for example piperidine, morpholine, pyrrolidine, piperazine and their lower alkyl derivatives, for example 1-methylpiperidine, 4-ethyl-morpholine, 1-ethyl-morpholine, , 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like, as well as amines containing water-soluble or hydrophilic groups, for example, mono-, di- and triethanolamine, ethyl-diethanolamine, N-butylethanolamine, 2 -amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amine-2-methyl-1-pro panol, tri (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amylphenyl) diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations include tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like. As described above, the compounds of formulas I-VI are administered in various ways for various purposes, for example intravenously, intramuscularly, subcutaneously, orally, vaginally, rectally, buccally, sublingually, topically and as sterile grafts for long-term action.

Sterile aqueous solutions of the same voltage are preferred for intravenous injection. For subcutaneous or intramuscular injection, sterile solutions or suspensions of acid or salt in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, and simple solutions with conventional pharmaceutical carriers are used for oral sublingual administration. For rectal or vaginal administration, suppositories prepared in a manner known in the art are used.

11 59791

For tissue grafts, a sterile tablet or silicone rubber capsule or other article containing or impregnated with a substance is used.

The 16- and 16,16-disubstituted PGE2-type compounds of formula I are prepared by the reactions and methods described below.

The novel 16-alkyl and 16,16-dialkyl-PGE2-type acids of formula I are prepared by the reaction steps shown in Reaction Schemes A and B. In reaction formulas A and B, and R 2 represent hydrogen, methyl or ethyl, provided that at least one of the groups R.

O 1 and R 2 are not hydrogen; R3 is (1) .. n- (t) s ** in C \ / '^ T is 1-4 carbon-

atom-containing alkyl, 7 to 10 carbon atoms phenylalkyl or nitro and s is 0 to 5, provided that no more than two T groups represent other than alkyl and that the total number of carbon atoms in the groups T does not exceed 10 carbon atoms; NRF ~ JL ~ ^ C0OR

“C 4’ wherein R 4 is alkyl containing 1 to 4 carbon atoms; ^ (T) s wherein T and s are as defined above, or (4) acetyl; R 1 is hydrogen, THP is tetrahydropyranyl and represents the bonding of the hydroxyl group in the alpha or beta configuration.

12 59791

REACTION FORMULA

/ ° / 0 '/); «Λ" Λ r \ -) XX—} ex-> r ^ CHnOCHg /> CH2OCH3, \) HaOCH3 OH OR OR 3

III IV V

Λ K

X - * ä, - *

T> ch2oh / CHO

// OR j OR3

VI VII

.0, 0: ° Λ ->? Λ ->

'0' OH

OR3 OR,

VIII IX

? Λ

OH OH

II

13 59791

REACTION FORMULA B

Λ - '; 1 ', ° ι

() H OH C / T H P OTUF

X

II

J "

Q \ HO

CU ^ CGr ^ V ”/: Ki /: Ki

OTHP OTHP OTHP OTHP

XI XII

O.

^^ v ^^ COQh

. OTHP OTHP

XIII

\ / VC ~ ^ cooh oh 'oij XIV (= 1) 14 59791

Reaction formula A shows the steps required for the preparation of intermediates of formulas III-IX and thus of the bicyclic lactone diol of formula II.

The intermediate bicyclic lacton diol of formula r <

n C5Hl L

• 1

OH CH

the preparation has been previously described by E.J. By Corey in J.Am.Chem.Soc. 91, 5675 (1969), and later shown in optically active form by E.J. Corey'n et al. by J.Am.Chem.Soc. 92, 397 (1970). The reaction of this intermediate to PGE2, in either racemic or optically active form, is described in these publications.

The iodolactone of formula III in Reaction Formula A is known in the art (see Corey et al., Supra). It is available in either racemic or optically active (+ or -) form. For racemic products, the racemic form is used. For prostaglandins with a natural configuration, the left-turning form (-) is used.

The compound of formula IV (Reaction Formula A) has an R 2 O group in the 4-position, wherein R 2 is as defined above. In preparing a compound of formula IV by replacing the hydrogen of the hydroxyl group in the 4-position with an acyl group R 1, methods known per se in the art are used. Thus, an aromatic acid of formula R 1 OH, wherein R 1 is as defined above, for example benzoic acid, is reacted with a compound of formula III with a dehydrating agent, e.g. sulfuric acid, zinc chloride or phosphoryl chloride; or an anhydride of an aromatic acid of the formula (R 10) is used, e.g. benzoic anhydride.

Preferably, however, the acyl halide, e.g. R 1 Cl, for example benzoyl chloride, is reacted with a compound of formula III in the presence of a hydrogen chloride rinsing agent, e.g. a tertiary amine such as pyridine, triethylamine and the like. The reaction is carried out under varying conditions using methods known per se in the art. Generally, gentle conditions are used, e.g., 20-60 ° C, whereby the reactants are contacted in a liquid medium, e.g., excess pyridine, or in an inert solvent such as benzene, toluene, or chloroform. The acylating agent is used either in a stoichiometric amount or in excess.

Examples of the group are the following available as acids (R 2 OH), anhydrides (R 2 O) or acyl chlorides (R 2 Cl): benzoyl; substituted benzoyl, e.g. (2-, 3- or 4-) methylbenzoyl, (2 -, 3- or 4-) ethylbenzoyl, (2-, 3- or 4-) isopropylbenzyl, (2-, 3- or 4-) tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, α-phenyl- (2-, 3- or 4-) toluyl), (2-, 3- or 4-) phenethylbenzoyl, (2-, 3- or 4-) nitrobenzoyl, (2,4-, 2,5- or 3,5-) dinitrobenzoyl, 3,4-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6 -phenylbenzoyl, 3-nitro-2-phenethylbenzoyl; monoesterified 0 0 9

"” C — O — C H

phthaloyl, e.g. "9f" ° "CH3 'isophthaloyl, e.g. 0 2 5 ^

O KJ

w or terephthaloyl, e.g. -C-r> -C-O-C4Hg; (1- or 2-) naphthoyl; substituted naphthoyl, e.g. (2-, 3-, 4-, 5-, 6- or 7-) methyl-1-naphthoyl, (2- or 4-) ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl -1,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5- or 8-) nitro-1- naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or 8-) methyl-1-naphthoyl, 4-ethyl-2-naphthoyl and (5- or 8-) nitro-2 naphtoyl; and acetyl.

Therefore, benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl chloride and the like can be used, i.e. R 1 -Cl compounds corresponding to the R 1 groups mentioned above. If acyl chloride is not available, it is prepared from the corresponding acid and phosphorus pentachloride, as is known in the art. The reagent R 1 OH, R 3 OH 2 ° or R 3 C '* L preferably does not contain large inhibitory substituents, e.g. tert-butyl on both of the ring carbon atoms adjacent to the carbonyl binding site.

16 59791

The compound of formula V is then obtained by removing iodine from the compound of formula IV using a reagent which does not react with the lactone ring or OR 1 group, e.g. zinc dust, sodium hydride, hydrazine palladium, hydrogen and Raney nickel or platinum and the like. Particularly preferred is tributyltin hydride in benzene at about 25 ° C using 2,2'-azobis- (2-methylpropionitrile) as the initiator.

The compound of formula VI is obtained by demethylating a reagent of formula V which does not affect the OR 2 group, for example with boron tribromide or trichloride. The reaction is preferably carried out in an inert solvent at about 0-5 ° C.

The compound of formula VII is obtained by oxidizing a group of formula VI to a CH2OH group -CHO and avoiding cleavage of the lactone ring. Useful for this purpose include dichromate sulfuric acid, Jones reagent, lead tetraacetate and the like. Particularly preferred is Collins' reagent (pyridine-CrO 2) at about 0-10 ° C.

A compound of formula VIII is obtained by Wittig alkylation of a compound of formula VII using a sodium derivative of dimethyl 2-oxoheptylphosphonate. Trans-enonyl lactone is obtained stereospecifically (see D.H. Wadsworth et al., J.Org.Chem.Vol. 30, p. 680 (1965)).

The compound of formula IX is obtained as a mixture of alpha and beta isomers by reduction of the compound of formula VIII. For this reduction, a known ketone carbonyl reducing agent is used which does not reduce ester or acid groups or carbon-carbon double bonds when the latter is not desirable. Examples of these are metal borohydrides, in particular sodium, potassium and zinc borohydrides, lithium (tri-tert-butoxy) aluminum hydride, metal trialoxyborohydrides, e.g. sodium trimethoxyborohydride, lithium borohydride, diisobutylaluminum hydride and problem, boranes, e.g., disiamylborane.

To prepare PG-type compounds of natural configuration, the desired alpha form of formula IX is separated from the beta isomer by silica gel chromatography.

17 59791

The compound of formula II is then obtained by deacylation of the compound of formula IX with an alkali metal carbonate, e.g. potassium carbonate in methanol at about 25 ° C.

Reaction Scheme B shows the reaction of compounds of formula II to PGE2-type compounds of formula XIV.

Bis (tetrahydropyranyl) ether X is obtained by reacting a diol of formula II with a dihydropyran in an inert solvent, e.g. dichloromethane in the presence of an acidic condensing agent such as p-toluenesulfonic acid. Dihydropyran is used in excess, preferably 4-10 times the theoretical amount. The reaction is usually complete in 15-30 minutes at 20-30 ° C.

Lactol XI is obtained by reducing the lactone of formula X without reducing the 13,14-ethylene group. For this purpose, diisobutylaluminum hydride is prepared. The reduction is preferably carried out at a temperature between -60 and -70 ° C.

The compound of formula XII is obtained by the Wittig reaction using a Wittig reagent derived from 4-carboxybutyltriphenylphosphonium bromide and sodium dimethylsulfylurea, together with the lactol of formula XI at about 25 ° C. This compound of formula XII is an intermediate in the preparation of a PGE2-type product.

To prepare PGE2-type compounds of formula XIV, the bis (tetrahydropyranyl) ether of PGF2 (formula XII) is oxidized at the 9-hydroxy position, preferably with Jones reagent. Finally, the tetrahydropyranyl groups are replaced by hydrogen hydrolysis.

When the Wittig reagent used to prepare the compound of formula XII is a carboxylic acid ester, i. the phosphonium halide has the formula Br (C 9 H 11) (CH 2) 4 COOR 7, wherein R 1 represents alkyl having 1 to 8 carbon atoms.

Ιβ 59791

The final compounds of formula XIV prepared by the process of the invention are reacted into pharmacologically acceptable salts by neutralizing them with appropriate amounts of the corresponding inorganic or organic base, e.g. corresponding to the cations and amines mentioned above. These reactions are carried out by one of the numerous methods known in the art for the use of inorganic, i. for the preparation of metal or ammonium salts, amino acid addition salts and quaternary ammonium salts. The choice of method depends in part on the solubility properties of the particular salt to be prepared. In the case of inorganic salts, it is usually preferable to dissolve the acid in water containing a stoichiometric amount of hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. Thus, using e.g. sodium hydroxide, sodium carbonate or sodium bicarbonate, a solution of the sodium salt is obtained. Evaporation of water or the addition of a water-miscible solvent of reasonable polarity, e.g. the addition of a lower alkanol or lower alkanone, gives a solid inorganic salt if this form is desired.

To prepare the amine salt, the acid of formula XIV is dissolved in a suitable solvent of either moderate or low polarity. Examples of the above are ethanol, acetone and ethyl acetate. Examples of the latter are ethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to this solution. If the desired salt does not precipitate, it is usually obtained in solid form by adding a low polarity miscible solvent or by evaporation. If the amine is relatively volatile, the excess can be easily removed by evaporation. These volatile amines are preferably used in stoichiometric amounts.

Salts in which the cation is quaternary ammonium are prepared by mixing the acid with a stoichiometric amount of the corresponding quaternary ammonium hydroxide in aqueous solution, after which the water is evaporated.

The invention is described in more detail below by means of examples.

All temperatures are in degrees Celsius.

19 59791

Infrared absorption spectra were measured on a Model 421 Perkin-Elmer infrared spectrophotometer. Undiluted samples have been used unless otherwise stated.

NMR spectra were measured on a Varian A-60 spectrophotometer in deuterochloroform solutions using tetramethylsilane as an internal standard (downfield).

Mass spectral values were obtained from Consolidated Electrodynamic Corporation1 by preparing a model 21-110 B with a High Resolution mass spectrometer.

As used herein, saline means a saturated aqueous solution of sodium chloride.

Preparation 1 3α-Benzoyloxy-5α-hydroxy-4-iodo-2g-methoxymethylcyclopentaneacetic acid γ-lactone (Formula IV: R 2 is benzoyl)

Reference is made to Reaction Scheme A. A mixture of optically active levorotatory (-) iodolactone III (EJ Corey et al., J.Am.Chem.Soc.Vol. 92, p. 397 (1970), 75 g) in 135 ml of dry pyridine under a nitrogen atmosphere is added 30.4 ml of benzoyl chloride under cooling to maintain the temperature at about 20-40 ° C. Stirring is continued for another 30 min. About 250 ml of toluene are added and the mixture is concentrated under reduced pressure. The residue is dissolved in one liter of ethyl acetate, washed with 10% sulfuric acid, brine, saturated aqueous sodium bicarbonate and brine. The ethyl acetate solution is dried over sodium sulfate and concentrated under reduced pressure to give 95 g of an oil.

Crystallization of the oil gives the title compound, mp 84-86 ° C; [α] 7 D + 7 ° (CHCl 3), infrared spectrum absorptions at 1768, 1722, 1600, 1570, 1490, 1275, 1265, 1180, 1125, 1090, 1060, 1030 and 710 cm and NMR peaks (nuclear magnetic resonance) at 2.1- 3.45, 3.3, 3.58, 4.38, 5.12, 5.51, 7.18-7.58 and 7.83-8.05 5.

Following the procedure of Preparation 1, an optically active iodilactone of formula III is reacted to give a compound of formula IV using R 1 Cl instead of benzoyl chloride, wherein R 1 is substituted benzoyl, 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, 20 59791 3,5-dimethylbenzoyl, 2 -isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, α-phenyl- (2-, 3- or 4-) toluyl, 2-, 3- or 4-phenethylbenzoyl, 2-, 3- or 4 -Nitrobenzoyl, (2,4-, 2,5- or 3,5-) dinitrobenzoyl, 3,4-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethyl -benzoyl, 3-nitro-2-phenethylbenzoyl; monoesterified phthaloyl, 899 e.g. f-O-CH3, isophthaloyl, e.g. C-O-C2H5 or terephthalo-O-O-loyl, e.g. C-O-C2H5? (1- or 2-) naphthoyl; substituted naphthoyl, e.g. (2-, 3-, 4-, 5-, 6- or 7-) methyl-1-naphthoyl, (2- or 4-) ethyl-1-naphthoyl, 2-isopropyl-1 -naphthoyl, 4,5-dimethyl-1-naphthoyl, 6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5- or 8-) nitro-1- naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7- or 8-) methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-) nitro-2-naphthoyl? as well as acetyl.

Following the procedure of Preparation 1, but replacing the optically active iodolactone of formula III with a racemic compound of this formula and a mirror image thereof, and using either benzoyl chloride or each of the R 1 Cl reagents described above, the corresponding racemic compound of formula IV is obtained.

Preparation 2 3α-Benzoyloxy-5α-hydroxy-2β-methoxymethylcyclopentanoic acid γ-lactone (Formula V; is benzoyl)

Referring to Reaction Scheme A. To a solution of the optically active benzoxy compound of Formula IV (Preparation 1, 60 g) in 240 mL of dry benzene is added about 60 mg of 2,2'-azobis- (2-methylpropionitrile). The mixture is cooled to 15 ° C and a solution of 75 g of tributyltin hydride in 600 ml of ether is added with stirring and at such a rate that a continuous reaction is obtained at about 25 ° C. When the reaction is complete by thin layer chromatography, the mixture is concentrated under reduced pressure to an oil, the oil is mixed with 600 ml of Skellysolve B (isomeric hexanes) and 600 ml of water and stirred for 30 min. The aqueous layer containing the product is separated and 450 ml of ethyl acetate and sufficient solid sodium chloride are added to saturate the aqueous phase. The ethyl acetate layer, which now contains the product, is separated, dried over magnesium sulfate and concentrated under reduced pressure to an oil, 39 g of the title compound. Analytical sample gives /? Ct7D -99 ° (CHCl.j); infrared absorptions at 1775, 1715, 1600, 1585, 1490, 1315, 1275, 1180, 1110, 1070, 1055, 1025 and 715 cm-1? NMR peaks at 2.15-3.0, 3.25, 3.34, 4.84-5.17, 5.17-5.4, 7.1-7.5 and 7.8-8, 05 6; and mass spectral peaks at 290, 168, 105, and 77.

Following the procedure of Preparation 2, each optically active or racemic compound of formula IV following Preparation 1 is reacted to the corresponding optically active or racemic compound of formula V.

Preparation 3 3α-Benzoyloxy-5α-hydroxy-2g-hydroxymethylcyclopentanoic acid γ-lactone (Formula VI; is benzoyl).

Referring to Reaction Scheme A. To a cold (0-5 ° C) solution of lactone V (Preparation 2, 20 g) in 320 mL of methylene chloride under a nitrogen atmosphere is added a solution of 24.8 mL of boron tribromide in 320 mL of dichloromethane. , dropwise and with vigorous stirring over 50 min at 0-5 ° C. Stirring and cooling are continued for one hour. When the reaction is completed by thin layer chromatography, a solution of sodium carbonate (78 g of monohydrate) in 200 ml of water is carefully added. The mixture is stirred at 0-5 ° C for 10-15 min, saturated with sodium chloride and the ethyl acetate layer is separated. Further extracts of the aqueous layer with ethyl acetate are combined with the main ethyl acetate solution. The combined solutions are purified by brine, dried over sodium sulfate and concentrated under reduced pressure to an oil, 18.1 g of the title compound. The m.p. is 116-118 ° C; 80 ° (CHCl 3), infrared spectral absorptions at 3460, 1735, 1708, 1600, 1580, 1490, 1325, 1315, 1280, 1205, 1115, 1090, 1070, 1035, 1025, 730 and 720; and NMR peaks at 2.1-3.0, 3.58, 4.83-5.12, 5.2-5.45, 7.15-7.55 and 7.8-8.0 δ.

Following the procedure of Preparation 3, each optically active or racemic compound of formula V following Preparation 2 is reacted to the corresponding optically active or racemic hydroxymethyl compound of formula VI.

22 59791

Preparation 4 3α-Benzoyloxy-2β-carboxaldehyde-5α-hydroxy-cyclopentanoic acid γ-lactone (Formula VII; R 3 is benzoyl)

Reference is made to Reaction Scheme A. A mixture of 150 ml of dry dichloromethane and Collins' reagent (JC Collins et al., Tetrahedron Lett. 3363 (1968), 28 g) at about 10 ° C under a nitrogen atmosphere is added with vigorous stirring. (10 ° C) solution of optically active hydroxymethyl lactone VI (Preparation 3, 5.0 g) in 150 ml of dichloromethane. After further stirring for 5 minutes, about 100 ml of dry benzene are added, the mixture is filtered and the solution is concentrated under reduced pressure. Make up to about 150 ml with benzene. A solution of the title compound of formula VII is used directly.

Concentration of the benzene solution under reduced pressure gives a similar run-off oil which, when triturated with ether, gives crystals of the optically active compound of formula VII, m.p. 115 ° C (decomposes); NMR peaks at 1.8-3.7, 4.9-5.2, 5.54-5.77, 7.2-7.6, 7.7-8.0 and 9.8 <5.

By proceeding as in Preparation 4, each optically active or racemic hydroxymethyl compound of formula VI 'following Preparation 3 is reacted to give the corresponding optically active or racemic aldehyde of formula VII, wherein R 1 is an R 1 group listed after Preparation 1, e.g. 2-methylbenzoyl, pentamethyl. -libenzoyl, 2,5-dinitrobenzoyl, monomethylphthaloyl, 1-naphthoyl, acetyl or the like.

Preparation 5

Dimethyl 2-oxo-3-methylheptylphosphonate, CH 3 (CH 2) 3 -CH (CH 3) -N-CH 2 -P (OCH 3) 2 n-Butyllithium (150 mL) is slowly added to a solution of dimethyl methylphosphonate (25 mL). , 6 g) in 475 ml of tetrahydrofuran (THF) at about -65 ° C. A solution of racemic ethyl 2-methylhexanoate (18.4 g) in 50 ml of THF is added to the mixture, and the resulting mixture is stirred at -70 ° C for 2 hours. 16 ml of acetic acid are then added and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml) and water (about 50 ml), shaken and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation gives 16.7 g of the title compound, b.p. 126-12900 / 1 mm.

By proceeding as in the method of Preparation 5, but replacing racemic ethyl 2-methylhexanoate with ethyl esters of the (+) and (-) isomers of 2-methylhexanoic acid (see PA Levene et al., J. Biol. Chem. 70, 211 (1926) and 84, 571 (1929)) gives the corresponding optically active (+) and (-) title compounds.

By proceeding in the same manner as in the process of Preparation 5, but substituting optically active or racemic ethyl 2-ethylhexanoate for ethyl 2-methylhexanoate, the corresponding compounds of formula

0 Q

Optically active or racemic phosphonates according to CH3 (CH2) 2-CH (C2H5) -C-CH2-P (OCH-j) 2, i.e. homologues of the title compound in which the 3-methyl group has been replaced by a 3-ethyl group.

Preparation 6 3α-Benzoyloxy-5α-hydroxy-28- (3-oxo-4-methyl-trans-1-octenyl) 1α-cyclopentaneacetic acid γ-lactone (Formula VIII; R 2 is hydrogen, R 1 is methyl and R 3 is benzoyl)

Referring to Reaction Scheme A. A solution of racemic dimethyl 2-oxo-3-methylheptylphosphonate (Preparation 5.9, 7.9 g) in 36 mL of THF is added with stirring to a cold (5 ° C) suspension of sodium hydride (55%, 1.62 g) in 180 ml of THF. The reaction mixture is then stirred at about 25 ° C for 2.5 hours and cooled to -10 ° C. A benzene solution of optically active aldehyde VII (Preparation 4, 108 ml) is added to the mixture. After 1.5 hours, 1.8 ml of acetic acid are added and the THF is distilled off in vacuo. The residue is dissolved in ethyl acetate, and the solution is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel using 25-30% ethyl acetate in Skellysolv B (isomeric hexanes) for elution affords the C-16 epimers of the title compound of formula VIII separated.

By proceeding as in the method of Preparation 5, using the optically active aldehyde VII, but replacing the racemic phosphonate with each of the optically active (+) and (-) phosphonates following Preparation 5, the corresponding optically active compounds of formula VIII are obtained.

24 59791

Following the procedure of Preparation 6, but substituting both optically active or racemic aldehydes of formula VII described after Preparation 4 for aldehyde VII and using either optically active or racemic phosphonates following Preparation 5, the corresponding compounds of formula VIII wherein R 1 corresponds to R ^ in the aldehyde of formula VII. Thus, as in Preparation 6, each optically active aldehyde of formula VIII i reacts with a racemic phosphonate to give a pair of diastereoisomers, i. 16-epimers of formula VIII which can be separated by methods known to those skilled in the art, e.g. by silica gel chromatography. When reacted with an optically active phosphonate, each optically active aldehyde gives the corresponding optically active compound VIII. When reacted with a racemic phosphonate, each racemic aldehyde of formula VII gives two pairs of racemates of formula VIII which can be separated into separate pairs of racemic compounds by methods known per se, e.g. by silica gel chromatography. When reacted with an optically active phosphonate, each racemic aldehyde gives a pair of diastereoisomers that are separable, e.g., by silica gel chromatography.

Similarly, following the procedure of Preparation 6, but replacing the dimethyl 2-oxo-3-methylheptylphosphonate with the optically active or racemic dimethyl 2-oxo-3-ethylheptylphosphonate described after Preparation 5 and reacting these phosphonates with the optically active or racemic compounds described after Preparation 4. with aldehydes of formula VII, the corresponding optically active or racemic compounds of formula VIII are obtained in which R 1 is hydrogen, is ethyl and R 2 is the same as the R 2 group in the intermediate aldehyde.

Preparation 7 3α-Benzoyloxy-5α-hydroxy-2β- (3α-hydroxy-4-methyl-trans-1-octenyl) -1α-cyclopentanoic acid γ-lactone (Formula IX; R 2 is hydrogen, R 1 is methyl, is benzoyl and means alpha)

Referring to Reaction Scheme A. A solution of 16-epimers of ketone VIII (Preparation 6, 2.75 g) in 14 mL of 1,2-dimethoxyethane is added to a mixture of zinc chloride (anhydrous, 4.94 g) and sodium borohydride (1 , 12 g) of the prepared zinc borohydride in 48 ml of dry 1,2-dimethoxyethane, with stirring and cooling to -10 ° C. Stirring is continued for 2 hours at 0 [deg.] C. and water (7.8 ml) is carefully added, followed by 52 ml of ethyl acetate. The mixture is filtered and the filtrate is separated. The ethyl acetate solution is washed with brine, dried over sodium sulfate and concentrated under reduced pressure to a mixture of the corresponding 15-alpha and 15-beta isomers of formula IX. The compounds are subjected to chromatography on a silica gel column, eluting with ethyl acetate to separate the 15-alpha (less polar) and 15-beta isomers of the title compounds of formula IX.

According to the method of Preparation 7, optically active or racemic ketones of formula VIII derived from the optically active or racemic phosphonates described after Preparation 6, wherein R 1 is benzoyl, are reacted to the corresponding optically active or racemic hydroxy compounds of formula IX.

Likewise, according to Preparation 7, each optically active or racemic ketone of formula VIII described after Preparation 6 other than benzoyl is reacted to the corresponding 3'α and 3'β hydroxy compounds of formula IX while retaining the R 1 group of the ketone of formula VIII.

Similarly, according to the method of Preparation 7, each optically active or racemic 4'-ethyl ketone of formula VIII described after Preparation 6 is reacted to the corresponding 4'-ethylhydroxy compounds of formula IX.

Preparation 8 3α, 5α-Dihydroxy-2β- (3α-hydroxy-4-methyl-trans-1-octenyl) -1α-cyclopentanoic acid γ-lactone (Formula II; R 2 is hydrogen and R 2 is methyl)

Reference is made to Reaction Scheme A. Potassium carbonate (0.79 g) is added to a solution of C-16 alpha- and beta-epimeric alpha-hydroxy compounds of Formula IX (Preparation 7, 2.2 g) in 25 mL of methanol and the mixture is stirred for one hour at about 25 ° C: in. 80 ml of chloroform are then added and the mixture is filtered and the organic fraction is concentrated under reduced pressure. The residue is taken up in dichloromethane and the solution is washed with brine. Concentration of the organic phase gives a residue which is triturated with Skellysolve B, then concentrated to the corresponding mixed C-16 alpha and beta epimeric compounds of formula XIV, the title 15-alpha compounds, 1.2 g.

26 59791

According to the method of Preparation 8, each optically active or racemic hydroxy compound of formula IX having benzoyl described after Example 3 is reacted to give the corresponding optically active or racemic title compound of formula II.

Similarly, according to the method of Preparation 8, but substituting each of the optically active or racemic compounds of formula IX other than benzoyl described after Preparation 7, said compounds are reacted to the corresponding optically active or racemic title compounds of formula II.

Similarly, according to the method of Preparation 8, but using the 4'-ethylhydroxy compounds of formula IX, i. wherein R 2 is ethyl, the corresponding optically active or racemic title compounds of formula II are obtained in which R 2 is hydrogen and R 2 is ethyl.

Preparation 9 3a, 5a-Dihydroxy-2g- (3a-hydroxy-4-methyl-trans-1-octenyl) -1g-cyclopentaneacetic acid γ-lactone, 3,3'-bis (tetrahydropyranyl) ether (Formula X; R2 is hydrogen and R1 is methyl)

Referring to Reaction Scheme B. A solution of diols of formula II (Preparation 8, 1.3 g), 4.25 mL of dihydropyran, and 0.019 g of p-toluenesulfonic acid in 35 mL of dichloromethane is stirred at about 25 ° C for 30 min. The solution is washed with potassium bicarbonate solution, dried and concentrated under reduced pressure to give the title compounds of formula X, 2.7 g.

According to the method of Preparation 9, each optically active or racemic compound of formula II described after Preparation 8 is reacted to the corresponding optically active or racemic compound of formula X, e.g. those in which R 2 is hydrogen and is either methyl or ethyl.

Preparation 10 3g, 5g-Dihydroxy-2g- (3g-hydroxy-4-methyl-trans-1-octenyl) -1g-cyclopentaneacetaldehyde γ-lactol, 3,3'-bis (tetrahydropyranyl) ether (Formula XI: R 2 is hydrogen, is methyl and (is alpha or beta)

Referring to Reaction Scheme B. Diisobutylaluminum hydride (2.6 mL) in 27 mL of 25 mL of toluene is added dropwise to a stirred solution of tetrahydropyranyl ethers of formula X (Preparation 9, 2.7 g) in 30 mL of toluene, cooled to -70 °. C. Stirring is continued at -70 ° C for 30 min, after which a solution of 12 ml of THF and 6 ml of water is carefully added. The mixture is filtered and the filtrate is washed with brine, dried and concentrated to a mixture of the alpha and beta hydroxy isomers of the title compounds of formula XI, 2.4 g, which show no lactone absorption by infrared.

According to the method of Preparation 10, after Preparation 9, each doped optically active or racemic compound of formula X is reacted to the corresponding optically active or racemic compound of formula XI.

Preparation 11 16-Methyl-PGF 2a, 11,15-bis (tetrahydropyranyl) ether (Formula XII: R 2 represents hydrogen and is methyl

Referring to Reaction Scheme B. 4-Carboxybutyltriphenylphosphonium bromide (5.94 g) is added to a solution of sodium hydride (60%, 0.90 g) and 19 mL of dimethylsulfoxide (DMSO) in sodium dimethylsulfinylcarbanide and the mixture is stirred for about 20 ° C. :in. To this reagent is added dropwise the lactols of formula XI (Preparation 10, 2.4 g) in 4 ml of DMSO. The mixture is stirred at about 25 ° C for 16 hours, then diluted with about 30 ml of benzene. To this is added dropwise a solution of potassium hydrogen sulfate (3.64 g) in 30 ml of water under cooling and stirring. The organic layer is separated, washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on silica gel using a mixture of chloroform and methanol (10: 1) to elute to give 1.5 g of compounds of formula XII.

According to the method of Preparation 11, each optically active or racemic compound of formula XI described after Preparation 10 is reacted to the corresponding optically active or racemic compound of formula XII.

Similarly according to the method of Preparation 11, but substituting other 4-carboxybibyltriphenylphosphonium bromide of formula

Compounds of formula Br (C 9 H 8) (CH 2) 2 COOR 4 wherein R 1 represents not only hydrogen but also alkyl of 1 to 8 carbon atoms, as defined herein, provide the corresponding compounds of formula XII wherein R 8 is 1- Alkyl of 8 carbon atoms.

Preparation 12 * 16-methyl-PGE2, 11,15-bis (tetrahydropyranyl) ether (formula XIII, R2 represents hydrogen and R1 is methyl

Referring to Reaction Scheme B. To a solution of 16-methyl-PGF 2α bis (tetrahydropyranyl ether) of Formula XII (Preparation 11, 0.9 g) in 13 mL of acetone at -20 ° C is added dropwise 1.0 Jones. reagent (2.1 g chromic anhydride, 6 ml water and 1.7 ml concentrated sulfuric acid). After stirring for 15 minutes, 1 ml of 2-propanol is added, more is stirred and then 35 ml of water are added. The solution is shaken with three portions of dichloromethane, the organic extracts are combined, dried and concentrated under reduced pressure. The residue is chromatographed on silica gel to give a fraction which, according to thin layer chromatography, contains 0.5 g of the title compounds of formula XIII.

According to the method of Preparation 12, each of the optically active or racemic compounds of formula XII described in the residue of Preparation 11 is reacted to the corresponding optically active or racemic compound of formula XIII. Thus, for example, 11,15-bis (tetrahydropyranyl) ether of the compound 16-methyl-PGE2, methyl ester, i.e. formula XIII wherein R 2 is hydrogen and R 1 and R 2 represent methyl. Similarly, 11,15-bis (tetrahydropyranyl) ether of 16-ethyl-PGE2 is obtained, i.e. formula XIII wherein R 2 and R 2 are hydrogen and R 2 is ethyl.

Example 1 16-methyl-PGE2 (Formula XIV: R 2 represents hydrogen and R 1 is methyl)

Reference is made to Reaction Scheme B. A solution prepared from the diethyl ether of Formula XIII (Example 9, 0.5 g) in 2 mL of THF and 20 mL of 67% (aqueous) acetic acid is maintained at 40 ° C for 2 hours. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel using a mixture of chloroform and methanol (10: 1) for elution. The fractions containing the desired product by thin layer chromatography are combined and concentrated to give the title compound of formula xiv, 0.17 g. High resolution mass spectrum of the TMS derivative: M + -c, Hno / 497.2582.

o 1J

* 29 59791

According to the method of Example 1, each optically active or racemic compound of formula XIII described after Preparation 12 is reacted to the corresponding optically active or racemic compounds of formula XIV. Thus, for example, 16-methyl-PGE2, methyl ester, i. formula XIV wherein R 2 is hydrogen and and R 1 represents methyl. 16-ethyl-PGE2, i.e. formula XIV wherein R 2 and R 2 are hydrogen and R 2 is ethyl.

Preparation 13

Dimethyl 2-oxo-3,3-dimethylheptylphosphonate, 999 ch3 (ch2) 3-c (ch3) 2-c-ch2-p (och3) 2 n-Butyllithium (400 ml) is slowly added to a solution of dimethylmethylphosphonate ( 73.7 g) in 1.3 liters of THF at about -66 ° C. A solution of ethyl 2,2-dimethylhexanoate (53 g) in 150 ml of THF is added to the mixture and the resulting mixture is stirred at -70 ° C for 2 hours. 46 ml of acetic acid are then added and the mixture is concentrated under reduced pressure. The residue is mixed with portions of dichloromethane (about 1.2 L) and water (about 150 mL), shaken and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation gives the title compound 41.6 g, b.p. 117-120 ° C / 1 mm.

According to the method of Preparation 13, but substituting ethyl 2,2-diethylhexanoate or ethyl 2-ethyl-2-methylhexanoate for ethyl 2,2-dimethylhexanoate, the corresponding phosphonates are obtained, i. dimethyl 2-oxo-3,3-diethylheptylphosphonate and dimethyl 2-oxo-3-methyl-3-ethylheptylphosphonate.

Preparation 14 3α-Benzoyloxy-5α-hydroxy-25 (3-oxo-4,4-dimethyl-trans-1-octenyl) -1α-cyclopentanoic acid γ-lactone (Formula VIII: R 1 and represent methyl and R 3 is benzoyl)

Referring to Reaction Scheme A. A solution of dimethyl 2-oxo-3,3-dimethylheptylphosphonate (Preparation 13, 11.0 g) in 50 mL of THF is added to a cold (5 ° C) suspension of sodium hydride (55%,

2.26 g) in 250 ml of THF and with stirring. The reaction mixture is then stirred at about 25 ° C for 2.5 hours and cooled to -10 ° C. The mixture is added with optically active aldehyde VII

30 59791 (Preparation 4, 150 ml) in benzene solution. After 1.5 hours, 2 ml of acetic acid are added and the THF is distilled off in vacuo.

The residue is dissolved in ethyl acetate and the solution is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel using 25-30% ethyl acetate in Skellysolv B to elute gives the corresponding optically active title compound, 0.6 g, m.p. 82-3 ° C.

According to the method of Preparation 12, but replacing the aldehyde VII with each of the optically active racemic aldehydes of formula VII following Preparation 4, the corresponding optically active or racemic compound of formula VIII is obtained wherein R 1 corresponds to the R 1 group in the aldehyde of formula VII.

Similarly according to the method of Preparation 14, but substituting dimethyl 2-oxo-3-diethylheptylphosphonate or dimethyl-2-oxo-3-ethyl-3-methylheptylphosphonate for the dimethyl 2-oxo-3,3-dimethylheptylphosphonate described in Preparation 13. after, the corresponding optically active or racemic compound of formula VII is obtained, wherein R 1 and R 2 each represent ethyl or wherein one is ethyl and the other methyl.

Preparation 15 3g-Benzoyloxy-5q-hydroxy-28- (3-hydroxy-4,4-dimethyl-trans-1-octenyl) -1α-cyclopentanoic acid γ-lactone (Formula IX: R 1 and R 2 represent methyl, R 2 is benzoyl and λ, is alpha or beta)

Referring to Reaction Scheme A. To a solution of ketone VIII (Preparation 14, 4.65 g) in 30 mL of 1,2-dimethoxyethane is added zinc borohydride prepared from zinc chloride (anhydrous, 7.95 g) and sodium borohydride (1, 75 g) to a mixture in 71 ml of dry 1,2-dimethoxyethane with stirring and cooling to -10 ° C. Stirring is continued for 2 hours at 0 ° C and water (12 ml) is carefully added, followed by 25 ml of ethyl acetate. The mixture is filtered and the filtrate is separated. The ethyl acetate solution is washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give a mixture of isomers of formula IX. The alpha and beta isomeric title compounds are separated by chromatography on a silica gel column, eluting with ethyl acetate, to give 2.1 g of the alpha isomer and 0.4 g of the beta isomer of the optically active title compounds.

31 59791

According to the method of Preparation 15, each optically active or racemic ketone of formula VIII described after Preparation 14 is reacted to the corresponding hydroxy compounds of formula IX, retaining the R 2 group of the ketone of formula VIII. Thus, hydroxy compounds of formula IX are obtained in which and R 2 each represent methyl or ethyl or in which one is ethyl and the other methyl.

Preparation 16 3g, 5c-Dihydroxy-2g- (3-hydroxy-4,4-dimethyl-trans-1-octenyl) -1g-cyclopentanoic acid γ-lactone (Formula II; R1 and R2 represent methyl)

Reference is made to Reaction Scheme A. Potassium carbonate (0.72 g) is added to a solution of the optically active alpha-hydroxy compound of formula IX (Preparation 16, 2.1 g) in 35 ml of methanol and the mixture is stirred for one hour at about 25 ° C. 75 ml of chloroform are then added, the mixture is filtered and the organic phase is concentrated under reduced pressure. The residue is taken up in dichloromethane and the solution is washed with brine. Concentration of the organic phase gives 1.4 g of a residue which is triturated with Skellysolve B and then concentrated to the corresponding optically active title compound of formula II.

According to the method of Preparation 16, but substituting each optically active or racemic compound of formula IX described after Preparation 7, wherein R 3 does not represent benzoyl, the corresponding optically active or racemic title compound of formula II is also obtained. Thus, compounds of formula II are obtained in which R 1 and R 2 each represent methyl or ethyl or in which one is ethyl and the other methyl.

Preparation 17 3g, 5g-Dihydroxy-2g - (3g-hydroxy-4,4-dimethyl-trans-1-octenyl) -1a-cyclopentanoic acid γ-lactone, 3,3'-bis (tetrahydropyranyl) ether (Formula X: R 1 and R 2 represent methyl)

Referring to Reaction Scheme B. A solution of the optically active diol of Formula II (Preparation 16, 1.4 g ·), 4.3 mL of dihydropyran, and 0.023 g of p-toluenesulfonic acid in 30 mL of dichloromethane is stirred at about 25 ° C for 30 min. . The solution is washed with potassium bicarbonate solution, dried and concentrated under reduced pressure to give the corresponding optically active title compound of formula X, 3.0 g.

32 59791

According to the method of Preparation 17, the optically active or racemic compound of formula VII described after Preparation 16 is reacted to the corresponding optically active or racemic compounds of formula X. Thus, compounds of formula X are obtained in which R 1 and R 2 each represent methyl or ethyl or in which one is ethyl and the other methyl.

Preparation 18 3 cif 5α-Dihydroxy-2β- (3α-hydroxy-4,4-dimethyl-trans-1-octenyl) -1α-cyclopentaneacetaldehyde γ-lactol, 3,3'-bis (tetrahydropyranyl) ether (Formula XI; R. [and R 2, mean methyl and R 2 is alpha or beta)

Referring to Reaction Scheme B. Diisobutylaluminum hydride (2.5 mL) in 16 mL of toluene is added dropwise to a stirred solution of optically active tetrahydropyranyl ether of Formula X (Preparation 18, 3.0 g) in 25 mL of toluene, cooled to -70 ° C. : C. Stirring is continued at -70 ° C for 30 min, after which a solution of 9 ml of THF and 4.6 ml of water is carefully added. The mixture is filtered and the filtrate is washed with brine, dried and concentrated to the alpha- and beta-hydroxy isomers of the corresponding optically active title compound of formula VII, 2.8 g, which have no lactone absorption in the infrared spectrum.

According to the method of Preparation 18, the optically active or racemic compounds of formula X described after Preparation 17 are reacted to the corresponding optically active or racemic compounds of formula XI.

Preparation 19 16,16-Dimethyl-PGF 2,11,15-bis (tetrahydropyranyl) ether (Formula C 1 -C 3 - - - - - - - XII; R 1 and R 2 represent methyl and R 2 is hydrogen)

Reference is made to Reaction Scheme B. 4-Carboxybutyltriphenylphosphonium bromide (10.5 g) is added to a solution of sodium dimethylsulfinylcarbamide prepared from sodium hydride (60%, 2.0 g) and 50 mL of DMSO and the mixture is stirred for 20 min at about 25 ° C: in. To this reagent is added dropwise optically active lactol of formula XI (Preparation 18, 2.8 g) in 9 ml of DMSO. The mixture is stirred at about 25 ° C for 2 hours, then diluted with about 30 ml of benzene. To this is added dropwise a solution of potassium hydrogen sulfate (6.4 g) in 30 ml of water, cooling and stirring. The organic layer was separated, washed with water, dried and concentrated under reduced pressure. The residue is chromatographed on silica gel using a mixture of chloroform and methanol (10: 1) for elution to give 1.6 g of the corresponding optically active compound of formula XII.

According to the method of Preparation 19, the optically active racemic compounds of formula XI described after Preparation 18 are reacted to the corresponding optically active or racemic compounds of formula XII.

Preparation 20 16,16-Dimethyl-PGE? 11,15-bis (tetrahydropyranyl) ether (Formula XIII: and R 2 represents methyl and is hydrogen)

Referring to Reaction Scheme B. To a solution of 16,16-dimethyl-PGF 2a α optically active ether of formula XII bis (tetrahydropyranyl) ether (Preparation 19, 0.8 g) in 13 mL of acetone at -20 ° C is added dropwise 0.88 ml of Jones reagent (2.1 g of chromic anhydride, 6 ml of water and 1.7 ml of concentrated sulfuric acid). After stirring for 15 minutes, 1 ml of 2-propanol is added, the mixture is stirred further and then 35 ml of water are added. The solution is shaken with three portions of dichloromethane, the organic extracts are combined, dried and concentrated under reduced pressure. The residue is chromatographed on silica gel to give a fraction which, according to thin layer chromatography, contains the corresponding optically active title compound of formula XIII, 0.7 g.

According to the methods of Preparation 30, the optically active or racemic compounds of formula XII are reacted to the corresponding optically active or racemic compounds of formula XIII. Thus, 16,16-diethyl and 16-ethyl-16-methyl-PGE2 derivatives of formula XIII are obtained in which R and R2 each represent methyl or ethyl or in which one is ethyl and the other methyl.

Example 2 16,16-Dimethyl-PGE 2 (Formula XIV: R 1 and R 2 represent methyl and R 2 is hydrogen)

Reference is made to reaction formula B. A solution of the optically active diethyl ether of formula XIII (Preparation 20, 0.7 g) in 5 ml of THF and 18 ml of 67% (aqueous) acetic acid is kept at 40 DEG C. at 2 hours. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel using a mixture of chloroform and methanol (10: 1) for elution. The fractions containing the desired product by thin layer chromatography are combined and concentrated to give the optically active title compound of formula XIV, 0.37 g, high resolution of the TMS derivative mass spectrum: M + -C7H15, 497.2521.

According to the method of Example 2, the optically active or racemic compounds of formula XIII described after Preparation 2 are reacted to the corresponding optically active or racemic compounds of formula XIV. Thus, the corresponding 16,16-diethyl-PGE2- and 16-ethyl-16-methyl-PGF2a- compounds are obtained.

Example 3 Sodium salt of 16-methyl-PGE2

A solution of 16-methyl-PGE 2 (Example 1, 100 mg) in 50 ml of a water-ethanol mixture (1: 1) is cooled to 5 ° C and neutralized with an equal volume of 0.1 N aqueous sodium hydroxide solution. The neutral solution is evaporated to give the title compound.

According to the methods of Preparation 6, each pair of diastereoisomers described in Preparation 6 and Example 1 and thereafter is separated, i. C-16 epimers, by methods known per se, e.g. by silica gel chromatography. The products with the highest biological activity in the biological screening test, e.g., the smooth muscle strip test and the anti-secretory living organism tests referred to above, are most useful for the purposes described herein.

The solvent systems used in this thin layer chromatography include: A IX Ethyl acetate-acetic acid-2,2,4-trimethylpentane water (90: 20: 50: 100).

A IX 'Ethyl acetate, acetic acid, Skellysolve B (isomeric hexanes) water (90: 20: 50: 100).

See M. Hamberg and B Samuelsson, J. Biol. Chem. 241, 257 (1966).

Claims (1)

An analogous method for the preparation of pharmacologically useful prostaglandin analogues of the formula 0 V. "X-COOH / | R2 (I) / I R1 OH1 OH wherein R1 and R2 represent hydrogen, methyl or ethyl, provided that at least one of the groups R 1 and R 2 do not represent hydrogen, and for the preparation of these pharmaceutically acceptable salts, characterized in that for an optically active or racemic compound of formula 0, ° Λ? 2 y (11); same as above, the following reactions are carried out successively a) hydroxyl hydrogens are replaced by tetrahydropyranyl groups, b) the lactone oxo group is reduced to a hydroxy group, c) Wittig alkylation is performed using a compound of formula Hai- (CH2) ^ -COOH4, wherein Hal is bromine or chlorine; the hydroxy group is oxidized to the oxo group, and (e) the tetrahydropyranyloxy groups are converted into hydroxy groups. the prostaglandin of formula 0 V. - ^ X- / V / ^ COOH; Ri ° H OH