IL33226A - Omega-nor and omega-homo pgf2beta derivatives and process for their preparation - Google Patents

Description

ω-HOR AND j^HOMO PgFgg DERIVATIVES AND PROCESS FOR THEIR PREPARATION ABSTRACT OF THE DISCLOSURE The invention is jbbwc<; group^ of organic compounds of the fbrmu la/: wherein Ri is hydrogen, al kyl of one to 8 carbon atoms, inclusive, or a pharmacological l y acceptable cation, R2 and R3 are hydrogen or alkanoyl of one to 8 carbon atoms, inclusive.. with the proviso that when R3 is alkanoyl , R2 is also alkanoyl , m is zero or 2 , p is 5 or 5J and Z is -CH2CHa- or cis-CH=CH-.

These compounds have prostaglandin Ρβ-type biological properties , and are useful for the same pharmacological uses as prostaglandin Ρβ compounds .

DESCRIPTION- OF THE INVENTION This Invention relates to novel compositions of matter and to methods for producing them. In particular, this Invention relates to novel compounds of the formula: wherein Ri is hydrogen, alkyl of one to 8 carbon atoms, inclusive, or a pharmacological ly acceptable cation, R2 and R3 are hydrogen or alkanoyi of one to 8 carbon atoms, Inclusive, with the proviso that when R3 is alkanoyi, R2 Is also alkanoyi, m is zero or 2, and Z Is -CH2CH2- or cls-CHBCH- . are both alkanoyi, those can be the same or different. ethyl , propyl , butyl ,., pentyl, hexyl, heptyl, octyl, and; isomeric forms thereof.

Examples of alkanoyl of one to 8 carbon atoms, inclusive, are formyl acetyl, propionyl> butyryl, valeryl , hexanoyl , heptanoy 1 , octanoyl , and isomeric forms thereof . .

Pharmacological ly acceptable cations within the scope of i in formulas I , -I I - and I I K are quaternary ammonium ions or the cationic form of a metal , ammonia, or an amine.

Especially preferred metal cations are those derived from the alkal i metals, e.g., l ithium, sodium, and: potass ium, and from the a 1 ka 1 i ne ea rth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations within the scope Ri in formulas I, -I I , and I I \ are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, d i methyl am i ne, tr imethyl ami ne, ethylamine, dibutyl-amine, t r i i sopropy 1 ami ne, N-methyl hexyl am i ne, decylamine, dodecy 1 am i ne, allylamine, crotylamine, cyclopentyl ami ne, d icyclohexylami ne, benzylamine, d | i benzyl am i ne, -phenyl ethyl -amine, β-pheriylethyl ami ne, ethyl ened iami ne, d i ethyl enet r i am i ne, and l ike al iphatic, cycloal iphatic, and aral iphatic amines containing up to and including about 18 carbon atoms, as wel l as heterocycl ic amines, e.g., piperidine, morphol ine, pyrrol i-dine, piperazine, and lower-alkyl derivatives thereof, e.g., 1- methy 1 p i per i d i ne, -ethylmorphol i ne, 1- i sopropyl pyrrol id i ne, 2- methyl pyrrol idine, 1,4-d imethyl p i per.az i ne, 2-methylpiperidine, and the l ike, as we-lU as amines conta i n ing water-sol ub i l i z i ng or hydrophil ic groups, e.g., mono-, d i - , and t r i ethano 1 am i ne, ethy 1 d i ethariol ami ne, N-bu tyl ethanol ami ne-, 2-am i no- 1-butano 1 , ' ' t r is (hydroxymethyl )ami nomethane, N-phenylethanolamlne, N- (p-tert-amyl phenyl }diethano1amlne, galactamlne, N-methyl glucami ne, N-methyl glucosami ne, ephedrlne, phenylephrine, epinephrine, procaine, and the l ike.

Examples of suitable pharmacolog ical 1 y acceptab 1 e quaternary ammonium cations within the scope of i In formulas I , Ί I , ond' I I I are tet ramethy 1 ammon ium, tet raethyl ammon i urn, benzyl-trimeth.yl ammonium, phenyl triethyl ammonium, and the l ike.

The novel compounds of formulas I , •=4^==aw i=W†- are somewhat simi lar to certain of the known prostaglandins. The latter are cons idered to be derivatives of prostanoic acid which has the fol lowing structure: The known prostanoic acid derivative, prostaglandin F2p (PGF has the fol lowing structure.

The compound of formula I wherein Ri , R2, and R3 are hydrogen, and Z is -CHaCH2-, has the same structure as PGF2p except that this novel formula I compound has one less carbon atom in the hyd roxy-conta i n i ng s ide chain (ω-nor) when m Is zero, and one more carbon atom in the same chain (ω-homo) when m is 2. The other compounds encompassed by formula I , I .e., when Z is cis-CH=CH-, are simi larly related to the known prostanoic acid derivative PGF3p. Th« rnmpnnnrt nf formula I I whsrftin R1 Rg , hydrogen has one less carbon atom — (ω-inor) than jbhe known d'l hydro- ΡθΓχβ when p is 3, and une mum arbori atom (to-homo ) when p is These novel ω-nor and < -homo PGFp compounds of formulas I, -11 / and I I ore extremely potent In . causing various b iological responses of the general type caused by the known PGFp compounds. For that reason, these , novel formula I , j 1 , and I I I compounds are useful for pharmacological pu poses. Examples of those biological responses are pressor activity as measured, for example, in anesthetized (pentobarbital sodium) pentol tnium-treated rats with Indwel l ing aortic and right heart cannulas; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig Ileum,: rabbit duodenum, or gerbl l colon; activity on the central nervous, system; Inhibition of gastric secretion as shown in dogs with secretion stimulated by food or histamine Infusion; decrease of blood platelet adhesiveness as shown by plateleftp-glass adhesiveness, and Inhibition of bipod platelet aggregation and thrombus formation Induced by various phys leal stimul 1,, e.g., arterial injury, and various biochemical stimul i, e.g., ADP, ATP, serotonin, thrombin, and collagen.

Because of these biological responses, these novel formula I , I I , and I I I prostaglandins are useful to study, prevent, control, or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals, Including humans, useful domestic animals, pets, and zoological specimens, and in laboratory animals, for example, mice, rats, rabbits, and monkeys.

For example, these novel formula I , H , diiU I I I compounds are useful in place of oxytocin to induce labor in pregnant or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is preferably infused intravenously at a dose 0.01 to 50 μς., ρβτ kg. of body weight per minute unti 1 or near the termination of the second stage of labor, e.; expulsion of the fetus . These compounds are especial 1 y useful when the female Is one or more weeks post-mature and natural labor has not started, or 12 to 6o hours after the membranes have ruptured and natural labor has not yet started.

The novel formula I , I > ond I 11 ^compounds of this . .. I invention are useful in mammals, including man, as nasal decongestants. For this purpose* the compounds are used in a dose range of about 10 μ$. to about 10 mg. per ml . of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical ,appl i cat ion.

The novel formula 1 , -11, and I I I compounds not only are potent in causing smooth muscle stimulation, but also are highly active in potentiating other known smooth muscle stimulators, for example, oxytocin, vasopressin, and the various ergot alkaloids including derivatives and analogs thereof. For this reason, these novel compounds are useful in place of or in comb I nat ion wi th less than the usual amounts of these known smooth muscle stimulators, for example, to rel ieve the symptoms of paral yt ic ileus , to control or prevent atonic uterine bleeding after abortion or delivery, to aid In the expulsion of the placenta, and during the puerperium. For these purposes, these novel formula 1 , 11, and I I I compounds are preferably first administered by intravenous infusion at a dose in the range about 0.01 to about 50 pg. per kg. of body weight per mi ute until the desi red effect is obtained. Subsequent doses are or infus ion in the range 0.01 to 2 mg. per kg. of body weight per day.

These novel formula I ; I \., and I I I compounds are also useful for control l ing the reproductive cycle in ovulating female mammals, including humans and animals such: as monkeys , rats, rabbits, dogs, cattle, and the like. For that purpose, the compounds are administered siystemical 1 y at a dose level in the range about 0.01 mg. to about 20 mg. per kg. of body, weight of the female mammal , advantageously during a span of time starting approximately at the time of ovulation and end 1 ng approxlmatel y at the time of menses or just prior to menses, thus insuring a non-pregnant cycle notwithstanding ovulation and contact with a f ert i 1 e ma 1 e .

These novel formula I , I , and I I I compounds are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are preferably administered by Intravenous infus ion at the rate about 0.01 to about 50 μg. per kg. of body weight per minute, or in s ingle or multiple doses of about 25 to 500 g per kg. of body weight total per day.

These novel formula I , -I I , and I I I -compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excess ive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, I accelerating the healing of such ulcers al ready present in j the gastrointestinal tract. For this purpose, the compounds are r injected or infused intravenously, subcutaneous 1 y, or intramuscularly in an infusion dose range about 0.1 pg. to about ,50 μ$. per kg. of body weight per minute, or in a total dai l y dose by injection or infusion in the range about 0,1 to about These novel formula I , ι ι , anH ι ι ι r.nm nimHs are useful whenever it is desired to inhibit platelet aggregation to reduce the adhesive character of platelets , and to remove or prevent the. format ion of thrombi in mammals, including man, rabb i ts , and' rats For example, these compounds, are usefu l, i n the treatment and prevent ion of myocardial infarcts, to treat and prevent .post-operative thrombosis, to promote patency of vascular grafts fol lowing surgery, and to treat conditions such as atherosclerosis, arteriosclerosis blood clotting defects due to lipemia, and other cl inical conditions In which the underlying etiology is associated with l ipid imbalance or hyper-l ipidemia. For these purposes, these compounds are administered s ys tern j ca 11 y, e^g. , intravenous 1 y, subcutaneous 1 y, .intrar muscularly, and in the form, of" 's ter i le implants for prolonged action. For rapid response, especially Vn emergency situations, the .intravenous route of administration is preferred, Doses in the range, about 0.005 to about 20 mg. per kg. of body weight per day are prefe red,.: These novel formula V , I I, and — M — compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids .which": are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., l imbs and organs , whether attached to the or i g i na 1 body , detached and being preserved or . prepared for transplant, or. attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and ; portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradual 1 y or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the or to two or all of those at a total steady state dose of about .001 to 10 mg. per l iter of circulating fluid. It Is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to 5 develop new methods and techniques for organ and l imb transplants. r These novel formula I , I I j and I I I compounds and also the other known PGFp compounds increase the flow of blood in the mammalian kidney, thereby increasing volume and electrolyte 0 content of the urine. Therefore, these compounds are useful in managing cases of renal disfunction, especial 1 y those involving blockage of the renal vascular bed. Illustratively, the compounds are useful to al leviate and correct cases of edema resulting, for example, f rom mass I ve su rface burns, and in the ,5 management of shock. For these purposes, the compounds are preferably first administered by Intravenous injection at a dose In the range 10 to 1000 g. per kg. of body weight or by intravenous infusion at a doie in the range 0.1 to 20 μ . per kg. of body weight per minute until, the desired effect Is obtained. 0 Subsequent doses are given by Intravenous, intramuscular, or . subcutaneous injection or infusion in the range 0.05 to 2 mg. per kg. of body weight per day.

In spite of the apparent similarities of structure between the novel compounds of formulas I, I I , dnd I I Γ, and the known 5 PGFp compounds, i .e., dlhydro-PGF^, PGF^, PG>Fz$t and PGF3p, the novel formula I, 1-1 , ond — h-H- compounds are surpris Ingl y and quite unexpected 1 y more us efu 1 for one or more of the above illustrative purposes than the known PGFp compounds . The known PGFp compounds uniformly cause multiple responses even at low 0 doses. For example, PGF^ causes smooth muscle stimulation and increase nasal patency. In stri king contrast, the novel formula I >■ .11 , and I I I- compounds each are more specific In causing PGFg-type biological responses. Each of these novel compounds is therefore surprisingly and unexpectedly more useful for. the pharmacological purposes indicated above because each has a different and narrower spectrum of biological activity than the natural GF^ compounds, caus i ng smal ler and fewer undesi red side effects than the natural compounds.

For the above purposes, the novel formula I , I I , and -J-compounds of this invention are administered in various ways. For. example, as mentioned above, topical administration is the preferred route when the compound is used to promote nasal patency in cases of nasal congestion. Systemic administration, e.g.. Intravenous, subcutaneous, Intramuscular, oral, rectal, vaginal , buccal , subl ingual, and as sterile Implants for prolonged action, are preferred for the other pharmacological purposes mentioned above.

For intravenous injection or infusion, steri le aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solub i 1 i ty that i in the formula I, I I , or — l-H — compound be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspens ions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and 1 iqu id preparations such as syrups, el ixirs, and s imple. solutions, with the usual pharmaceutical carriers, are used for oral, buccal, or subl ingual administration. For rectal or vaginal administration, suppositories or powders prepared as known in the art are used. For tissue implants, a steri le tablet or sil icone rubber capsule containing the The novel compounds of formula I are prepared by reduc the carbonyl group of the corresponding compounds of the f o rmu 1 a : defined above, and R4 is hydrogen or alkyl of one to 8 carbon atoms , i nclus ί ve.

These formula VI , vi I s and I I I ^'•""ft intermediates are known in the art or are prepared by methods known in the art. See Beerthuis et al ., Rec . Trav. Chim. 87 6l. (1968)- for the zero or 2, and Z is -CH2CH2- , and for the compound of formula VI I wherein 2 and R4 are hydrogen.

The formula VI compounds wherein R2 and R4 are hydrogen, m is zero or 2, and Z is cis-CH=CH-, are prepared from ,8,11,14,17-nonadecapentaenoic acid (m.-θ) and 5,8,11,14,17- heneicosapentaeno ic acid (m = 2) as described by Struijk et al ., Rec, Trav. Chim. 85, 1233 (1966), for the production of PGE3 from 5, 8, 11, 14, 17-ei cosapentaeno i c ac id . These C-19 and C-21 pentaenoic acids are prepared by saponification of the corres- ponding methyl esters which are prepared as described by the combination of Van der Steen et al ., Rec. Trav. Chim. 82, 1015 (1963) and Pabon et al ., Rec. Trav. Chim. 84, 1319 (1965), using in place of the initial reactant of Pabon et al ., i .e., of this invention wherein Ri is alkyl are prepared by carbonyl reduction of the corresponding alkyl esters of the formula prepared by es ter i f i cat ion of the corresponding formula VI , VI I /-or VI I I . ketone intermediates wherein R4 is hydrogen.

Alternatively, the formula I , I I , or — M-l — a-lkyl esters are prepared by es ter i f i cat i on of the corresponding formula Λ , ++, or — HH- acids, i .e. , wherein Ri is hydrogen.

The novel formula I , -formul o — I I , and formu 1 a — H~l compounds of this invention wherein i is a pharmacological ly acceptable cation are preferably prepared by transformation of the corresponding formula I , l-l , or 11-1, f ree acid (Ri = H) to' the . des i red salt.

The novel formula I , formula l l j and formula I I I compounds of this invention wherein both R2 are alkanoyl are prepared by carbonyl reduction of the correspond ing a 1 kanoyl derivatives of the formula VI , l-l or VI I I ketone intermediates wherein both R2 are alkanoyl . This produces a formula I , I I or I I I ■ dial kanoyl compound wherein R3 is hydrogen. These dial kanoyl formula VI , VI I , ond VI I i- ketone intermediates are prepared by acylation of the corresponding formula VI , -VI I , or V 4-I- ketone intermediate wherein both R2 are hydrogen.

When it is desi red that R3 in the novel formula I , formu l.a. Γ, -oi — o rmu Va — H- compounds of this invention be alkanoyl , the formu 1 a I , . \A , OF — W- — compound wherein R3 is hydrogen is acylated. When both R2 in the formula I , -l l j or M l — compound are alkanoyl , the R3 alkanoyl introduced can be the same or different as the R2 alkanoyls . When both R2 in the formula I , H , or I l-l compound are hydrogen, acylation changes al l three hydroxy .groups to the same alkanoyloxy group.

In a formula I , ■f o rmu 1 a — M , or f o rmu 1 a Λ compound, when Ri is to be alkyl and R3 and/or R2 are to be alkanoyl , either or both the alkyl and the alkanoyls are added before or after the R3 is hydrogen is carried out by reacting the corresponding keto intermediates of formulas VI , VI I , 6hd VI M with any carbonyl reducing agent which does not react with the ester group or the carbon-carbon double bonds. Examples of such reducing agents are sodium or potassium borohydride and l ithium aluminum (tr i - tert-bu toxy)hydr ide.

These carbonyl reductions are carried out by methods known in the art for comparable reductions of prostanoic acid derivatives. See, for example, Bergstrom et al ., Acta Chem. Scand. 16, 969 (1962) and Anggard et al ., J. Biol . Chem. 239, 4101 (1964). Lower al kanol s , e.g., methanol and ethanol , are preferred as reaction solvents, although other solvents, e.g., dioxane and diethylene glycol dimethyl ether are also used, especially in combination ith the lower alkanol .

Although 0.25 molecular equivalent of the borohydride or l ithium aluminum (tri-tert-butoxy)hydr ide reducing agent is sufficient to reduce one molecular equivalent of the formula VI, "formula VI I , ur formula VI I I- ketone reactant, it is preferred to use an excess of the reducing agent, preferably about 1 to about 15 molecular equivalents of reducing agent per molecular equivalent of the ketone reactant. It is preferred to add a solution or suspension of the reducing agent to the ketone reactant, although the reverse order can also be used. A ° ° usually satisfactory. At about 25° C, the desired reaction is usual ly complete in about 0.5 to 2 hours. The resulting complex compound is then transformed to the desired product in the usual manner by treatment with aqueous acid, advantageously di lute hydrochloric acid.

The desired formula I , fo mu la I I , or formu 1o I I I reduction product is isolated by conventional techniques, for example, evaporation qf the reaction solvent and extraction of the residual aqueous mixture with a water- immiscible solvent, for example, diethyl ether. Evaporation of the latter solvent then gives the des i red product .

These borohydride or l ithium aluminum (trl-tert-butoxy)-hydride reductions of the formu la VI , VI I , and VI I I — keto reactants each produce a mixture of a beta-hydroxy compound and an isomeric (epimeric) al pha-hydroxy compound. The beta and alpha components of these mixtures of isomeric hydroxy compounds are separated from each other by methods known In the art for the separation of analogous pairs of isomeric prostanoic acid derivatives. See, for example, Bergstrom et al ., cited above, Granstrom et al ., J. Biol . Chem. 240, 457 (1965), and Green et al ,, J. Lipid Research 5, 117 (1964). Especial ly preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, thin layer chromatography, and countercu r rent distribution procedures. c a'rbon - ca rbon doTrb~Te~~ brrnndB~l"n~rh¾~vaTTOcrs— u-ns¾tu-re^©d— i-n-t-er---- For catalytic hydrogenat ion, palladium catalysts, especially on a carbon carrier, are preferred. It Is also preferred that the hyd rogenat ion be carried out in the presence dioxane, ethyl acetate, and the l ike. Hydrogenat ion pressures ranging from about atmospheric to about 50 p.s. I ., and hydrogenat ion temperatures ranging from about 10° to about 100° C. are preferred. The reduced formula M l acid or ester is isolated from the hydrogenation reaction mixture by conventional methods, for example, removal of the catalyst by fi ltration or centrifugation, fol lowed by evaporation of the solvent. The desired hydrogenation product is purified by conventional techniques., advantageously by methods known to be useful for purification of the prostaglandins, especially thin layer chromatography. See, for example, Green et al . , cited above.

For di imide reduction, the general procedure described by van Tame 1 en et al ., J. Am. Chem. Soc, 83, 3726 (1961) Is used. See also F!eser et al ., "Topics In Organic Chemistry," elnhold Publishing Corp., New York, pp. 432-434 (1963) and references cited therein for useful general procedures. The unsaturated acid or ester reactant Is mixed with a salt of azodiformlc acid, preferably an alkal i metal salt such as the dlsod!um or dipotassium salt, in the presence of an inert diluent, pre-ferably a lower alkanol such as methanol or ethanol, and preferably in the absence of substantial amounts of water. At least one molecular equivalent of the azodiformlc acid salt is used for each molecular equivalent of the reactant. The resulting suspension is then stirred, preferably with exclusion of oxygen, and the mixture is made acid, advantageously with a carboxyl ic acid such as acetic acid. When an acid reactant is used, that acid also serves to acidify an equivalent amount of the azodi formic acid salt. A reaction temperature in the range about 10° to about 40° C. is usual 1 y su I table. Within that temperatu re "range, the reaction is usually complete within isolated by conventional methods, for example, evaporation of the diluent, followed by separation from inorganic materials by solvent extraction, The product is purified, if desired, as described above.

Esterif ication of the formula I, I I , or I l acids or any of the other acid reactants is carried out by Interaction of the acid with the appropriate diazohydrocarbon. For example, when d iazomethane is used, the methyl esters are produced. Similar use of dlazoethane, dlazobutane, and 1-d 1 azo-2-ethyl hexane, for example, gives the ethyl, butyl, and 2-ethylhexyl esters, respectively.

Esterif ication with d iazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon In a suitable Inert solvent, preferably diethyl ether, with the acid reactant, advantageously In the same or a different Inert diluent. After the esterif ication reaction is complete, the solvent. is removed by evaporation, and the ester purified If desi red by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired es teri f i cat ion, preferably about one to about ten minutes, to avoid undesired molecular changes. D i azohyd rocarbons are known in the art or are prepared by methods known in the art. See, for example, Organic Reactions, John Wi ley & Sons, Inc., New York, N.Y., Vol . 8, pp. 389-39 (195^).

An alternative method for esterif Ication comprises transformation of the free acid to the corresponding silver salt, fol lowed by interaction of that salt with an alkyl Iodide.

Examples of suitable iodides are methyl iodide, ethyl Iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, and the l ike. example, by dissolving the acid in cold dilute aqueous ammonia, evaporating the excess ammonia at reduced pressure, and then adding the stoichiometric amount of s i 1 ver n i trate.

Carboxyacylat ion of the hydroxy moieties in the keto reactants or in the formula I , I I , or I I I — hydroxy compounds is accompl ished by interaction of the hydroxy compound with a carboxyacyl at ί ng agent, preferably the anhydride of an alkanoic a'cid of one to 8 carbon atoms, inclusive. For example, use of acetic anhydride gives the corresponding diacetate. Similar use of propionic anhydride, isobutyric anhydride, and hexanoic acid anhydride gives the corresponding carboxyacyl ates .

The carboxyacylat ion is advantageously carried out by mixing the hydroxy compound and the acid anhydride, preferably in the presence of a tertiary amine such as pyridine or t r i ethyl -amine. A substantial excess of the anhydride should be used> preferably about 10 to about 10,000 moles of anhydride per mole of the hydroxy compound reactant. The excess anhydride serves as a reaction di luent and solvent. An inert organic diluent, for example, dioxane, can also be added. It is preferred to use enough of the tertiary amine to neutral ize the carboxyl ic acid produced by the reaction, as well as any free carboxyl groups present in the hydroxy compound reactant.

The carboxyacyl at ion reaction is preferably carried out in the range about 0° to about 100° C. The necessary reaction time will depend on such factors as the reaction temperature, and the nature of the anhydride and tertiary amine reactants. With acetic anhydride, pyridine, and a 25° C. reaction temperature, a 12 to 24- hour reaction time is used.

The carboxyacyl ated product is isolated from the reaction mixture by conventional methods'. For example, the excess acidi ied and then extracted with a solvent such as diethyl ether. The desi red carboxyacyl ate is recovered from the diethyl ether extract by evaporation. The carboxyacyl ate is then purif ied by conventional methods, advantageously by chrpma-tography.

The formula I , f'\-\ , or — (-4-1 — a^ids ( i = hydrogen) are transformed to: pharmacological 1 y acceptable salts by neutral ization with appropriate amounts of the co responding inorganic or organic base, examples of which correspond to the cations and amines l isted above. These transformations are carried out' by a variety of procedures known in the art to be general ly useful for the preparation of . morgan i c, i .e. , metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts . The choice of procedure depends in part upon the solubi l ity characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usual ly suitable to dissolve the formula I , I I , or — H-+ acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt des i red. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the sol id inorganic salt if that form is desi red.

To produce an amine salt, the formula I , J--I , or I I I- ac i d is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol , acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corres If the resulting salt does not precipitate, it is usual ly obta i ned in so 1 i d form by add i t ion of a mi sc ib.l e d i luent of . low polarity or by evaporation. If the amine is relatively volati le> any excess is easi ly removed by evaporation. It is preferred to use stoichiometric amounts of the less volati le amines.

Salts wherein the cation is quaternary ammonium are produced by mixing the formula I , I I , or — l-W — acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, fol lowed by evaporation of the water .

The invention is more ful ly understood by the fol lowing examp 1 es .

Example 1 i»rnor-PGF;^ (formula I : Ri, R2, and R3 = H, m e 0, Z = -CH2CH2~).

A suspension of sodium borohydride (900 mg. ) in 100 ml . of methanol at about 5° to 10° is added gradual ly with sti rring during 2 minutes to a solution of wnor-PGF2 (500 mg. ) in 30 ml . of methanol at about 0° to 5° C. Sti rring is continued at 0° to 5° C. for 20 minutes . The reaction mixture is then al lowed to warm to 25° C., and is sti rred at that temperature for one hour. The resu 1 t i ng m i xtu re is then concentrated by evaporation to 2/3 of its original volume, mixed with 25 ml . of water, and evaporated further to remove the methanol . The aqueous solution which results is acidified with di lute hydrochloric acid and extracted three times with diethyl- ether. The diethyl ether extracts are combined, washed with water, dried, and evaporated to give a mixture of the beta and alpha epimers of ornor-PGF2.

The mixture of epimeric acids is subjected to reversed phase partition chromatography on s i lanized diatomaceous earth (Gas Col lege, Pa. j, using methanol -water (516 ml . -684 ml . ) as the mobi le phase and ' isooctanol -ch loroform (6o ml .-6o ml . ) as the stationary phase. The column support (500 g. ) is mixed with 5 ml . of stationary phase, and is then packed into column form as a slurry with mobi le phase. The mixture of epimeric ornor- PGF2 acids is dissolved in 15 ml . of stationary phase and mixed with an additional 12 g. of the column support. The resulting slurry is poured onto the column. The column is then eluted with mobi le phase, 50-ml . fractions of eluate being col lected. The eluate fractions containing the beta epimer., as shown by smooth muscle assays, are combined and evaporated to give Fol lowing the procedure of Example 1, but us ing in place of the w-nor-PGE2, t-r nor-»PGE aj"nor-d i hydro- PGEi , ω-nor- PGCg-, -ω- homo- PGE i , -irhomo-PGE2, -homo-d i hydro* PGEi ? or homo -PGC3, the methyl esters of each of those and also of o-nor-,PGE2, the diacetates of each of those and also of arnor-PGE2, and the methyl ester diacetates of each of those and also of rnor-PGE2, there are obtained o-nor-PGFi , -t)-.homo - PGF ιβ, or homo - PG F 2 β , -aj-boroo-d i h yd ro " PG F. ι-β , the methyl esters of each of tho&e PGFp analogues and- also of Ornor-PGF^, the diacetates nf Parh nf fhngp. ^β analogue anrj al-so of ωτ no r- GFg-β-, and the methyl ester diacetates of" each of those PGFβ analogues and also of or nor-PGF2 , respectivel y.

Example 2 rnor-PGF2 methyl ester (formula I : Ri = methyl , R2 and R3 = H, m = 0, Z = -CH2CH2- ) . io-nor-PGF^ (10 mg . ) is dissolved in a mixture of methanol and diethyl ether (l : 1 . A diethyl ether solution of diazo- methane (l g. ) is added, and the mixture is al lowed to stand at about 25° for 5 minutes. The reaction mixture is then Fol lowing the procedure of Example 2 but using in place of d i azomethane, dlazoethane, dlazobutane, and 1-d lazo-2-ethyl -hexane, there are obtained the ethyl , butyl , and 2-ethylhexyl esters, respectively.

Also fol lowing the procedure of Example 2, ω-nor-PGF ιβ, ω-nor-dl hydro-PGFip, ω ηοι·-Ρ6Γ3β, ωΊιοπιο-ΡΘΓΐ -, arhomo-PGFap, ω-homo-dl hydro<-PGF^, ω-Ιιοιτιο-Ρ0Ρ3β, the diacetates and tri-acetates of each of those and also of ω-nor-PGF^, arnor-PGE2, arhomo-PGE2, wr homond 1 hyd ro-PGEi , ^homo- ft £-3, and the diacetates of each of those, are each transformed to the correspond i ng methyl , ethyl , butyl , and 2-ethylhexyl esters . Example 3 arnor-PGF^ t iacetate (formula I : Ri » H, Re and R3 = acetyl , m ■ 0, Z ■ -CH2CH2-). urnor-PGF^ (10 mg. ) is mixed with acetic anhydride (3 ml . ) and pyridine (3 ml . ), and the mixture Is al lowed to stand at 25° C. for 18 hours. The reaction mixture Is then cooled with ice, di luted with water, and acidified with di lute hydrochloric acid to pH 1. The mixture Is then extracted three times with diethyl ether. The diethyl ether extracts are combined, and washed successivel y with di lute hydrochloric acid, di lute aqueous sodium bicarbonate solution, and water. The diethyl ether is then evaporated to give arnor-PGF^ triacetate.

Fol lowing the procedure of Example 3, but replacing the acetic anhydride with propionic anhydride, Isobutyric anhydride, and hexanolc acid anhydride, the corresponding t icarboxyacyl derivatives of arnor-PGF^ were obtained.

Also fol lowing the procedure of Example 3, or nor-PGF ιβ, u)rnor-dl hydro-PGFt , bnomPGFapj co-homo-PGF ιβ,- co-homo- ΡΰΡ2β, ω-homn-d i hydro- PGFifi, i-homo-PGFafi-y and the methyl esters of the corresponding t ri acetates , , t r i prop ionates, tr i isobutyrates , arid tri hexanoates .

Also fol lowing the procedure of Example j5, ω-nor-d i hyd ro- FGEjLj Also fol lowing the procedure of Example 3 the diacetates of co-nor-PGF ιβ, ω-nor-d i hyd ro- PGF ιβ, oo-nor-PGF2 , ui-nor- PGFafi, , and o- homo- P F0p arp each transformed to the corresponding triacetates, prop.ionate-d i acetates , butyrate-d i acetates , and hexanoate- di acetates.

Exampl e 4 ω-nor-PGF^ sodium salt (Formula I : R_ = Na+, 2 and R3 = H, m = 0, Z = -CH2CH2-). ω-nor-PGF Ζβ (lO mg. ) is dissolved in 10 ml . of water- ethanol (l.-l). The solution is cooled to about 10° C , and is neutral ized with an equivalent amount of' 0.1 N aqueous sodium hydroxide solution. . Evaporation to dryness gives u>-nor-PGF2p sod i urn sal t .

Fol lowing the procedure of Example 4 but us i ng. potass i urn hydroxide, calcium hydroxide, tet ramethy 1 amnion i urn hydroxide, and benzyl tr imethylammonium hydroxide, in place of sodium hydroxide there are obtained the corresponding salts of co-nor-PGF2 .

Also fol lowing the procedure of Example 4, each of the other PGF analogues and the diacyl and triacyl PGFg, analogues mentioned above are transformed to the corresponding sodium, potas.sium, calcium, tet ramethyl ammon i urn, and benzyl trimethyl - . ammon i urn sa 1 ts .

Example 5fx. - -w-homo-PGFgp (for ■mula I t · : · R ■2 ∞d R3 * H» m * 2, Z « -CBgCHg-) Sodium borohydride (l¾0 mg. ) le added gradually with stirring during 3 minutes to a solution of co-homo-PGEg (270 mg. ) in 10 ml. of methanol at -20°C. The resulting mixture is stirred 50 minutes at -20°C. ' Then, 10 ml. of water is added* and the mixture is concentrated under reduced pressure to remove the methanol. Water (20 ml.) and ethyl acetate (50 ml.) are added with stirring to the concentrate, and the mixture is acidified with 3 ml. of 3 M potassium hydrogen sulfate. Sodium chladde is then added to saturate the aqueous phase. The layers are separated, and the aqueous layer is extracted twice with 5 ml. of ethyl acetate. The e»hyl acetate layer and the ethyl acetate extracts are combined,, dried with anhydrous sodium sulfate, and evaporated under reduced pressure.

The residue is chromato raphed over 100 g. of acid-washed silica gel, elutlng successively with * )0 ml. ethyl acetati Skellyeolve B} (60-4o) , ¾00 ml. ethyl acetate-Skellysolve B (80-20), *»00 ml. ethyl acetate, 1000 ml. ethyl aoetate con taining 1$ methanol, 1000 ml. ethyl aoetate containing 2$ methanol, 1000 ml. ethyl acetate containing 2$ methanol and 1$ acetic acid, and 1000 ml. ethyl containing 4$ methanol and 2# acetic acid, collecting 200-ml. fractions. Fractions 21-2*1 are combined and evaporated under reduced pressure. The residue is dissolved in 6 ml. of acetone. Skellyeolve B (10 ml. ) is added and the cloudy solution is Skellyeolve B( 13 ml.) is added, and the mixture is maintained at -20° C. fo about 15 hours to give ¾ rag. of w- omo-PGP2p in the form of a crystalline solldt m.p. 88.0-89.3°C , infrared absorption at 3210, 2700, 2250, 17 5. 1315i 1305» 1195. 1,0*0, 1005 and 97 cm"1.

The blood pressure depreesion is about y> of i?GE1 and PG 2p - 25$ of ,PG¾? Antifertllity (Hametor) yi-hbmo-PGFgp active at 0.25 mg. /hamster, P Fgp - inactive at 0.25 m&, hamster. l¾e compound tWg can therefore be used to control fertility without simul aneously decreasing the blood pressure to any significant degree*

Claims (1)

1. 2514 WHAT IS CLAIMED IS: ·■ 1 - A compound of the formu la : wherein Ri is hydrogen, al kyl of one to 8 carbon atoms , i nclus ive , or a pharmacological l y acceptab le cation, R2 and R3 are hydrogen or al kanoyl of one to 8 carbon atoms , inclus ive, wi th the proviso that when R3 is al kanoyl , Rs is also al kanoyl , m is zero or 2, and Z is -CH2CH2- or cis-CH=CH- . - 2 - 33226/2 r 7 -