Claims
- 1. A racemic compound of the formula: ##EQU32## wherein R.sub.1 is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive; wherein R.sub.2 is --(CH.sub.2).sub.a --CH.sub.3 wherein a is 2, 3, 4, 5, or 6, or --(CH.sub.2).sub.d --X wherein d is zero, one, 2, 3, or 4 and X is isobutyl, tert-butyl, 3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl; wherein R.sub.3 and R.sub.4 are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein A is trimethylene or --CH.sub.2 --Z-- wherein Z is ethylene substituted with one or 2 fluoro, methyl, or ethyl; and pharmacologically acceptable salts thereof when R.sub.1 is hydrogen.
- 2. A racemic compound according to claim 1 wherein R.sub.1 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or a pharmacologically acceptable cation.
- 3. A racemic compound according to claim 2 wherein R.sub.2 is --(CH.sub.2).sub.a --CH.sub.3 wherein a is 2, 3, 4, 5, or 6.
- 4. A racemic compound according to claim 2 wherein R.sub.2 is pentyl.
- 5. A racemic compound according to claim 3 wherein A is trimethylene.
- 6. A racemic compound according to claim 4 wherein A is trimethylene.
- 7. A racemic compound according to claim 3 wherein A is --CH.sub.2 Z-- wherein Z is ethylene substituted with 2 fluoro on the carbon adjacent to the carboxylate moiety.
- 8. A racemic compound according to claim 4 wherein A is --CH.sub.2 Z-- wherein Z is ethylene substituted with 2 fluoro on the carbon adjacent to the carboxylate moiety.
- 9. A racemic compound according to claim 5 wherein R.sub.3 and R.sub.4 are hydrogen.
- 10. A racemic compound according to claim 6 wherein R.sub.3 and R.sub.4 are hydrogen.
- 11. A racemic compound accoding to claim 7 wherein R.sub.3 and R.sub.4 are hydrogen.
- 12. A racemic compound according to claim 8 wherein R.sub.3 and R.sub.4 are hydrogen.
CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation-in-part of copending application Ser. No. 807,405, filed Mar. 14, 1969 now abandoned.
This invention relates to compositions of matter, and to methods and intermediates for producing them. In particular, the several aspects of this invention relate to racemic prostaglandin E.sub.2 (PGE.sub.2), racemic prostaglandin F.sub.2 (PGF.sub.2.sub..alpha. and PGF.sub.2.sub..beta.), racemic prostaglandin A.sub.2 (PGA.sub.2), racemic prostaglandin B.sub.2 (PGB.sub.2), to the corresponding acetylenic prostaglandins, 5,6-dehydro-PGE.sub. 2, 5,6-dehydro-PGF.sub.2.sub..alpha., 5,6-dehydro-PGF.sub.2.sub..beta., 5,6-dehydro-PGA.sub.2, and 5,6-dehydro-PGB.sub.2 ; to analogs of those prostaglandins and 5,6-dehydro-prostaglandins; to processes for producing racemic PGE.sub.2, PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., PGA.sub.2, PGB.sub.2, the corresponding 5,6-dehydro-prostaglandins, and the analogs thereof; and to chemical intermediates useful in those methods.
Optically active PGE.sub.2, PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., PGA.sub.2, and PGB.sub.2 are known substances. All of those except PGF.sub.2.sub..beta. have been obtained in very small quantities from certain mammalian tissues, for example, sheep vesicular glands, swine lung, and human seminal plasma. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. Optically active PGE.sub.2 and PGF.sub.2.sub..alpha. have also been obtained in small amounts by enzymatic cyclization of arachidonic acid, for example, with certain of the enzymes of sheep vesicular glands. See, for example, U.S. Pat. No. 3,296,091. Similar enzymatic cyclizations of other unsaturated long-chain acids have been used to produce a limited group of optically active PGE.sub.2 analogs. See, for example, Struijk et al., Rec. Trav. Chim. 85, 1233 (1966) and Beerthuis et al., Rec. Trav. Chim. 87, 461 (1968). Optically active PGA.sub.2 and PGB.sub.2 have been obtained by dehydration of PGE.sub.2, and optically active PGF.sub.2.sub..alpha. and PGF.sub.2.sub..beta. have been obtained by carbonyl reduction of PGE.sub.2. In each case, the PGE.sub.2 used was necessarily obtained as described above. See, for example, Bergstrom et al., Arkiv Kemi, 19, 563 (1963) and Pike et al., Proc. Nobel Symposium II Stockholm (1966); Interscience Publishers, New York, p. 161 (1967).
The above-mentioned methods for producing prostaglandins are costly and difficult, the necessary biological materials are limited, and the methods are not adaptable to production of a wide variety of prostaglandin intermediates.
It is the purpose of this invention to provide processes for the production of compounds with prostaglandin-like activity in substantial amounts and at reasonable cost. The useful compounds produced according to the processes of this invention comprise racemic PGE.sub.2, racemic PGF.sub.2.sub..alpha., racemic PGF.sub.2.sub..beta., racemic PGA.sub.2, racemic PGB.sub.2, the corresponding 5,6-dehydroprostaglandins, and other hitherto unavailable racemic and optically active analogs thereof.
PGE.sub.2 has the following structure: ##SPC1##
PGF.sub.2.sub..alpha. has the following structure: ##SPC2##
PGF.sub.2.sub..beta. has the following structure: ##SPC3##
PGA.sub.2 has the following structure: ##SPC4##
PGB.sub.2 has the following structure: ##SPC5##
In formulas I, II, III, IV, and V, as well as in the formulas given hereinafter, broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e., above the plane of the cyclopentane ring.
PGE.sub.2, PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., PGA.sub.2, and PGB.sub.2 are derivatives of prostanoic acid which has the following structure and atom numbering: ##SPC6##
Compounds similar to formula VI but with carboxyl-terminated side chains attached to the cyclopentane ring in beta configuration are designated 8-iso-prostanoic acids, and have the following formula: ##SPC7##
Racemic prostaglandin E.sub.2 and its analogs produced according to 7 processes of this invention are represented by the formula: ##EQU1## wherein R.sub.1 is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the .beta.-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo; wherein R.sub.2 is hydrogen or alkyl of one to 10 carbon atoms, inclusive, substituted with zero to 3 fluoro; wherein R.sub.3 and R.sub.4 are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein A is alkylene of one to 10 carbon atoms, inclusive, substituted with zero to 2 fluoro, and with one to 5 carbon atoms, inclusive, between --COOR.sub.1 and ##EQU2## and wherein .about. indicates attachment of the ##EQU3## moiety to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when R.sub.1 is hydrogen.
Racemic prostaglandin F.sub.2 and its analogs produced according to the processes of this invention are represented by the formula: ##EQU4## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are as defined above for formula VIII, and .about. indicates attachment of the hydroxy and
Racemic prostaglandin A.sub.2 and its analogs produced according to the processes of this invention are represented by the formulas: ##EQU5## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are as defined above for formula VIII, and .about. indicates attachment of the
Racemic prostaglandin B.sub.2 and its analogs produced according to the processes of this invention are represented by the formula: ##EQU6## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are defined above for formula VIII, and pharmacologically acceptable salts thereof wherein R.sub.1 is hydrogen.
The acetylenic prostaglandin, 5,6-dehydro-PGE.sub.2, and its analogs produced according to the processes of this invention are represented by the formula: ##EQU7## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are as defined above for formula VIII, and .about. indicates attachment of the --CH.sub.2 --C.tbd.C--A--COOR.sub.1 moiety to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when R.sub.1 is hydrogen.
The acetylenic prostaglandin, 5,6-dehydro-PGF.sub.2, and its analogs produced according to the processes of this invention are represented by the formula: ##EQU8## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are as defined above for formula VIII, and .about. indicates attachment of the hydroxy and --CH.sub.2 --C.tbd.C--A--COOR.sub.1 moieties to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when R.sub.1 is hydrogen. Included in formula XIII are compounds wherein the configuration of the hydroxy and --CH.sub.2 --C.tbd.C--A--COOR.sub.1 moieties are, respectively .alpha.,.alpha., .alpha.,.beta., .beta.,.alpha., and .beta.,.beta..
The acetylenic prostaglandin, 5,6-dehydro-PGA.sub.2, and its analogs produced according to the processes of this invention are represented by the formula: ##EQU9## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are as defined above for formula VIII, and .about. indicates attachment of the --CH.sub.2 --C.tbd.C--A--COOR.sub.1 moiety to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when R.sub.1 is hydrogen.
The acetylenic prostaglandin, 5,6-dehydro-PGB.sub.2, and its analogs produced according to the processes of this invention are represented by the formula: ##EQU10## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, and A are as defined above for formula VIII, and pharmacologically acceptable salts thereof when R.sub.1 is hydrogen.
Also included in formulas VIII, IX, X, XI, XII, XIII, XIV, and XV are separate isomers wherein the side chain hydroxy is in R or S configuration. All of the compounds encompassed by those formulas have the trans --CH=CR.sub.4 --CR.sub.2 R.sub.3 OH side chain attached in beta configuration.
Formulas VIII, IX, X, XI, XII, XIII, XIV, and XV represent PGE.sub.2, PGF.sub.2, PGA.sub.2, PGB.sub. 2, 5,6-dehydro-PGE.sub.2, 5,6-dehydro-PGF.sub.2, 5,6-dehydro-PGA.sub.2, and 5,6-dehydro-PGB.sub.2, respectively, when in these formulas R.sub.1, R.sub.3, and R.sub.4 are each hydrogen, R.sub.2 is pentyl, A is trimethylene, the attachment of --CH.sub.2 --CH=CH--A--COOR.sub.1 or --CH.sub.2 --C.tbd.C--A--COOR.sub.1 to the cyclopentane ring is in alpha configuration, and the configuration of the side chain hydroxy is S.
With regard to formulas VIII to XV, inclusive, examples of alkyl of one to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomeric forms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive, are those given above, and pentyl, hexyl, heptyl, octyl, and isomeric forms thereof. Examples of alkyl of one to 10 carbon atoms, inclusive, are those given above, and nonyl, decyl, and isomeric forms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and 1-(2-naphthylmethyl). Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and 2,4-dichloro-3-methylphenyl.
Examples of alkylene of one to 10 carbon atoms, inclusive, are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, and decamethylene, and isomeric branched chain forms thereof.
Examples of alkyl of one to 10 carbon atoms, inclusive, substituted with one to 3 fluoro, are 2-fluoroethyl, 2-fluorobutyl, 3-fluorobutyl, 4-fluorobutyl, 5-fluoropentyl, 4-fluoro4-methylpentyl, 3-fluoroisoheptyl, 8-fluorooctyl, 3,4-difluorobutyl, 4,4-difluoropentyl, 5,5-difluoropentyl, 5,5,5-trifluoropentyl, and 10,10,10-trifluorodecyl.
Examples of alkylene of one to 10 carbon atoms, inclusive, substituted with one or 2 fluoro, have the formulas --CH.sub.2 CHF--, --CH.sub.2 CF.sub.2 --, --CH.sub.2 CH.sub.2 CHFCH.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 CF.sub.2 --, ##EQU11## --CH.sub.2 CH.sub.2 CH.sub.2 CHFCHF--, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CHF--, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CF.sub.2 --, --CH.sub.2 CH.sub.2 CH.sub.2 CF.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --, and --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CF.sub.2 --.
PGE.sub.2, PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., PGA.sub.2, and PGB.sub.2, and their esters and pharmacologically acceptable salts, are extemely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (168), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of PGE.sub.2, PGF.sub.2 .sub..beta., and PGA.sub.2 as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for PGF.sub.2.sub..alpha. ; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE.sub.2 and PGA.sub.2 as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen; and in the case of PGE.sub.2 and PGB.sub.2, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments.
Because of these biological responses, these known 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 compounds, and especially PGE.sub.2, are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 .mu.g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.
PGE.sub.2 and PGA.sub.2 are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range about 0.1 .mu.g. to about 500 .mu.g. per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact does depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
PGE.sub.2, PGA.sub.2, PGF.sub.2.sub..alpha. and PGF.sub.2.sub..beta. are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses in the range about 0.004 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
PGE.sub.2, PGA.sub.2, PGF.sub.2.sub..alpha., and PGF.sub.2.sub..beta. 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., limbs and organs, whether attached to the original 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 gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter 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 develop new methods and techniques for organ and limb transplants.
PGE.sub.2 is extremely potent in causing stimulation of smooth muscle, and is also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE.sub.2 is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For these purposes, PGE.sub.2 is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 .mu.g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.
PGE.sub.2, PGA.sub.2, and PGF.sub.2.sub..beta. are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 .mu.g. per kg. of body weight per minute or in single or multiple doses of about 25 to 500 .mu.g. per kg. of body weight total per day.
PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., and PGE.sub.2 are useful for controlling the reproductive cycle in ovulating female mammals, including humans and animals such as monkeys, rats, rabbits, dogs, cattle, and the like. For that purpose, PGF.sub.2.sub..alpha. is administered systemically at a dose level in the range 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 ending approximately at the time of menses or just prior to menses.
As mentioned above, PGE.sub.2 is a potent antagonist of epinephrine-induced mobilization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom alleviation, and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.
PGE.sub.2 and PGB.sub.2 promote and accelerate the growth of epidermal cells and keratin in animals, includng humans, useful domestic animals, pets, zoological specimens, and laboratory animals. For that reason, these compounds are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, and abrasions, and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homografts.
For these purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desired, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutically acceptable diluents. In some instances, for example, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous, for example, by intravenous injection or infusion, separate or in combination with the usual infusions of blood, plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. To illustrate, a wet dressing for topical application to second and/or third degree burns of skin area 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution containing 1 to 500 .mu.g./ml. of PGB.sub.2 or several times that concentration of PGE.sub.2. Especially for topical use, these prostaglandins are useful in combination with antibiotics, for example, gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, and oxytetracycline, with other antibacterials, for example, mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, and with corticoid steroids, for example, hydrocortisone, prednisolone, methylprednisolone, and fluprednisolone, each of those being used in the combintion at the usual concentration suitable for its use alone.
Racemic PGE.sub.2, racemic PGF.sub.2, racemic PGF.sub.2.sub..beta., racemic PGA.sub.2, and racemic PGB.sub.2 each are useful for the purposes described above for the optically active compounds, but these racemic compounds offer the enormous advantage of being available in unlimited quantities at much lower cost. Moreover, these racemic compounds are easier to purify since they are produced by chemical reactions rather than by extraction from biological materials or enzymatic reaction mixtures.
The other racemic compounds encompassed by formulas VIII, IX, X, and XI, and also the acetylenic compounds 5,6-dehydro-PGE.sub.2, 5,6-dehydro-PGF.sub.2.sub..alpha., 5,6-dehydro-PGF.sub.2.sub..beta., 5,6-dehydro-PGA.sub.2, and 5,6-dehydro-PGB.sub.2 and the other compounds encompassed by formulas XII, XIII, XIV, and XV each cause the biological responses described above for the corresponding known prostaglandins, ane each of these novel racemic compounds is accordingly useful for the above-described corresponding purposes, and is used for those purposes in the same manner as described above.
The known optically active prostaglandins PGE.sub.2, PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., PGA.sub.2, and PGB.sub.2 are all potent in causing multiple biological responses even at low doses. For example, PGE.sub.2 is extremely potent in causing vaso-depression and smooth muscle stimulation, and also is potent as an antilipolytic agent. In striking contrast, the analogs of formulas VIII, IX, X, and XI, and also the acetylenic formula XII, XIII, XIV, and XV are substantially more specific with regard to potency in causing prostaglandin-like biological responses. Therefore, each of these novel prostaglandin analogs is surprisingly and unexpectedly more useful than one of the corresponding above-mentioned prostaglandins for at least one of the pharmacological purposes indicated above for the latter. Use of the novel analog for that purpose results in smaller undesired side effects than when the known protaglandin is used for the same purpose.
To obtain the optimum combination of biological response specificity and potency, certain compounds within the scope of formulas VIII and IX are preferred. As discussed above, those formulas represent the PGE.sub.2 -type compounds and the PGF.sub.2.sub..alpha. -type compounds, respectively. Referring to formulas VIII and IX, when --CH.sub.2 --CH=CH--A--COOR.sub.1 is attached in alpha configuration and, in the case of formula IX, when the ring hydroxy is also attached in alpha configuration, stereochemistry typical of the known optically active PGE.sub.2 and PGF.sub.2.sub..alpha., it is preferred that terminal alkyl group R.sub.2 not be pentyl at the same time that alkylene group A is straight chain and unsubstituted. In other words, according to this invention, preferred formula VIII and IX compounds wherein --CH.sub.2 --CH=CH--A--COOR.sub.1 and ring hydroxy are alpha are those wherein R.sub.2 is branched chain or fluoro-substituted alkyl when A is straight chain unsubstituted alkylene, those wherein A is branched chain or fluoro-substituted when R.sub.2 is pentyl, and those wherein R.sub.2 is alkyl other than pentyl, i.e., alkyl of one to 4 carbon atoms, inclusive, or alkyl of 6 to 8 carbon atoms, inclusive. These preferred compounds exhibit superior biological response specificity and/or potency. For reasons not completely understood, fluoro-substitution or branching of at least one of A and R.sub.2 in these particular groups of formula VIII and formula IX compounds, increases biological response specificity and/or potency. This is especially true in the case of A and when R.sub.2 is pentyl.
Certain compounds within the scope of formulas VIII and XV are especially useful for one or more of the purposes stated above for PGE.sub.2, PGF.sub.2.sub..alpha., PGA.sub.2, and PGB.sub.2, because they have a substantially longer duration of activity than other compounds within the generic formulas, includng PGE.sub.2, PGF.sub.2.sub..alpha., PGF.sub.2.sub..beta., PGA.sub.2 , and PGB.sub.2, and because they can be administered orally, sublingually, intravaginally, buccally, or rectally, rather than by the usual intravenous, intramuscular, or subcutaneous injection or infusion as indicated above for the uses of these known protaglandins and the other compounds encompassed by formulas VIII to XV. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.
With reference to formulas VIII to XV, these special compounds include those wherein A is --(CH.sub.2).sub.b --Z--, wherein b is zero, one, 2, or 3, and Z is ethylene substituted by one or 2 fluro, methyl, or ethyl, or by one alkyl of 3 or 4 carbon atoms. These special compounds also include those wherein R.sub.2 is --(CH.sub.2 ).sub.d --X, wherein d is zero, one, 2, 3, or 4, and X is isobutyl, tert-butyl, 3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl. These special compounds also include those wherein A is --(CH.sub.2).sub.b --Z-- as above defined, and R.sub.2 is --(CH.sub.2).sub.d --X as above defined. Especially preferred among these special compounds are those wherein R.sub.3 and R.sub.4 are both hydrogen.
In the case of Z, the divalent ethylene group, --CH.sub.2 --CH.sub.2 --, is substituted on either or both carbon atoms, i.e., alpha and/or beta to the carboxylate function. For example, Z is --CH.sub.2 --CHF--, --CHF--CH.sub.2 --, --CH.sub.2 --CF.sub.2 --, --CF.sub.2 --CH.sub.2 --, --CHF--CHF--, --CH.sub.2 --CH(CH.sub.3)--, --CH(CH.sub.3)--CH.sub.2 --, --CH.sub.2 --C(CH.sub.3).sub.2 --, --C(CH.sub.3).sub.2 --CH.sub.2 --, --CH(CH.sub.3)--CH(CH.sub.3)--, and similarly for ethyl, and for one fluoro and one methyl, one fluoro and one ethyl, and one methyl and one ethyl. Z is alternatively ethylene substituted on either carbon atoms with propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.
Although all of the special compounds just described have the special advantages of long duration and oral, sublingual intravaginal, and rectal routes of administration, there is a still more limited group of compounds encompassed by these formulas which have these qualities in a particularly high degree. Those are the compounds wherein A is --CH.sub.2 --Z--, i.e., wherein b in --(CH.sub.2).sub.b --Z-- is one, especially when Z is ethylene with one fluoro or methyl, with 2 fluoro or 2 methyl on the same carbon atom, or with butyl, isobutyl, sec-butyl, or tert-butyl on the carbon atoms alpha (adjacent) to the carboxylate function, the compounds wherein R.sub.2 is --CH.sub.2 CH.sub.2 CH.sub.2 C(CH.sub.3).sub.3, --CH.sub.2 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CF.sub.3, --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CHF.sub.2, or --CH.sub.2 CH.sub.2 CH.sub.2 CF.sub.2 CH.sub.3, and the compounds wherein both A and R.sub.2 are both defined in these more limited ways.
Racemic PGE.sub.2, racemic PGF.sub.2.sub..alpha., racemic PGF.sub.2.sub..beta., racemic PGA.sub.2, racemic PGB.sub.2, the corresponding 5,6-dehydro, and the other compounds encompassed by formulas VIII to XV, including the special classes of compounds described above are used for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R.sub.1. However, it is preferred that the ester be alkyl of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.
Pharmacologically acceptable salts of these formula VIII to XV compounds useful for the purposes described above are those with pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth 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 are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, .alpha.-phenylethylamine, .beta.-phenylethylamine, ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydrophilic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(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 are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium, and the like.
As discussed above, the compounds of formulas VIII to XV are administered in various ways for various purposes; e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, buccally, sublingually, topically, and in the form of sterile implants for prolonged action.
For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubility that R.sub.1 in the formula VIII to XV compound be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixers, and simple solutions, with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.
Racemic PGE.sub.2, racemic PGF.sub.2.sub..alpha., racemic PGF.sub.2.sub..beta., racemic PGA.sub.2, racemic PGB.sub.2, the corresponding 5,6-dehydroprostaglandins, and the other compounds encompassed by formulas VIII to XV are produced by the reactions and procedures described hereinafter.
Racemic PGF.sub.2.sub..alpha., racemic PGF.sub.2.sub..beta., 5,6-dehydro-PGF.sub.2.sub..alpha., 5,6-dehydro-PGF.sub.2.sub..beta., and the other PGF.sub.2 -type compounds encompassed by formulas IX and XIII are prepared by carbonyl reduction of the corresponding PGE.sub.2 -type compounds encompassed by formulas VIII and XII. For example, carbonyl reduction of racemic PGE.sub.2 gives a mixture of racemic PGF.sub.2.sub..alpha. and racemic PGF.sub.2.sub..beta..
These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions of known prostanoic acid derivatives. See, for example, Bergstrom et al., Arkiv Kemi, 19, 563 (1963), and Acta Chem. Scand. 16, 969 (1962), and British Specification No. 1,097,533. Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are aluminum (tri-tert-butoxy) hydride and the metal borohydrides, especially sodium, potassium and zinc borohydrides. The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known 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). Especially preferred as separation methods are partition chromatographic procedures, both normal and reversed phase, preparative thin layer chromatography, and countercurrent distribution procedures.
Racemic PGA.sub.2, 5,6-dehydro-PGA.sub.2, and the other PGA.sub.2 -type compounds encompassed by formulas X and XIV are prepared by acidic dehydration of the corresponding PGE.sub.2 -type compounds encompassed by formulas VIII and XII. For example, acidic dehydration of racemic PGE.sub.2 gives racemic PGA.sub.2.
These acidic dehydrations are carried out by methods known in the art for acidic dehydrations of known prostanoic acid derivatives. See, for example, Pike et al., Proc. Nobel Symposium II, Stockholm (1966); Interscience Publishing Co., New York, pp. 162-163 (1967), and British Specification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especially acetic acid, are preferred acids for this acidic dehydration.
Racemic PGB.sub.2, 5,6-dehydro-PGB.sub.2, and the other compounds encompassed by formulas XI and XV are prepared by basic dehydration of the corresponding PGE.sub.2 -type compounds encompassed by formulas VIII and XII, or by contacting the corresponding PGA.sub.2 -type compounds encompassed by formulas X and XIV with base. For example, both racemic PGE.sub.2 and racemic PGA.sub.2 give racemic PGB.sub.2 on treatment with base. Presumably the base first causes dehydration of the PGE.sub.2 to PGA.sub.2, and then causes the ring double bond of PGA.sub.2 to migrate to a new position.
These basic dehydrations and double bond migrations are carried out by methods known in the art for similar reactions of known prostanoic acid derivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238, 3555 (1963). The base is any whose aqueous solution has pH greater than 10. Preferred bases are the alkali metal hydroxides. A mixture of water and sufficient of a water-miscible alkanol to give a homogeneous reaction mixture is suitable as a reaction medium. The PGE.sub.2 -type or PGA.sub.2 -type compound is maintained in such a reaction medium until no further PGB.sub.2 -type compound is formed, as shown by the characteristic ultraviolet light absorption near 278 m.mu. for the PGB.sub.2 -type compound.
These various transformations of the PGE.sub.2 -type compounds of formulas VIII and XII to the PGF.sub.2 -type, PGA.sub.2 -type, and PGB.sub.2 -type compounds are shown in Chart A, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, A, and .about. are as defined above, and V is cis--CH=CH-- or --C=C--.
Racemic PGE.sub.2, 5,6-dehydro-PGE.sub.2, and the other PGE.sub.2 -type compounds encompassed by formulas VIII and XII are prepared by the multi-step processes outlined in Charts B, C, D, E, and F. ##SPC8## ##SPC9## ##SPC10## ##SPC11## ##SPC12## ##SPC13##
The bicyclo-ketone of formula XVI in Chart B is the initial reactant in these multi-step processes. That ketone exists in four isomeric forms, exo and endo with respect to the attachment of the --CR.sub.4 =CR.sub.2 R.sub.3 moiety, and cis and trans with respect to the double bond in that same moiety. Each of those isomers separately or various mixtures thereof are used as reactants according to this invention to produce substantially the same final PGE.sub.2 type or 5,6-dehydro-PGE.sub.2 -type product mixture.
In exo configuration, the formula XVI keto is known to the art. See Belgian Pat. No. 702,477; reprinted in Farmdoc Complete Specifications, Book 714, No. 30,905, page 313, March 12, 1968.
In that Belgian patent, the reaction sequence leading to exo ketone XVI is as follows: The hydroxy of 3-cyclopentenol is protected, for example, with a tetrahydropyranyl group. Then a diazoacetic acid ester is added to the double bond to give an exo-endo mixture of a bicyclo[ 3.1.0]hexane substituted at 3 with the protected hydroxy and at 6 with an esterified carboxyl. The exo-endo mixture is treated with a base to isomerize the endo isomer in the mixture to more of the exo isomer. Next, the carboxylate ester group at 6 is transformed to an aldehyde group or ketone group, --CHO or ##EQU12## wherein R.sub.4 is as defined above. Then, said aldehyde group or said keto group is transformed by the Wittig reaction to a moiety of the formula --CR.sub.4 =CR.sub.2 R.sub.3 which is in exo configuration relative to the bicyclo ring structure, and is the same as shown in formula XVI. Next, the protective group is removed to regenerate the 3-hydroxy which is then oxidized, for example, by the Jones reagent, to give said exo ketone XVI.
Separation of the cis-exo and trans-exo isomers of XVI is described in said Belgian patent. However, as mentioned above, that separation is usually not necessary since the cis-trans mixture is useful as a reactant in the next process step.
The process described in said Belgian Pat. No. 702,477 for producing the exo form of bicyclo-ketone XVI uses as an intermediate, the exo form of a bicyclo[ 3.1.0]hexane substituted at 3 with a protected hydroxy, e.g., tetrahydropyranyloxy and at 6 with an esterified carboxyl. When the corresponding endo compound is substituted for that exo intermediate, the Belgian patent process leads to the endo form of bicyclo-ketone XVI. That endo intermediate used in the Belgian patent process has the formula: ##SPC14##
As for exo XVI, this process produces a mixture of endo-cis and endo-trans. These are separated as described for the separation of exo-cis and exo-trans XVI, but this separation is usually not necessary since, as mentioned above, the cis-trans mixture is useful as a reactant in the next process step.
In the process of said Belgian Pat. No. 702,477, certain organic halides, e.g., chlorides and bromides, are necessary to prepare the Wittig reagents used to generate the generic moiety --CR.sub.4 =CR.sub.2 R.sub.3 of bicyclo-ketone XVI. These organic chlorides and bromides ##EQU13## are known in the art or can be prepared by methods known in the art.
To illustrate the availability of these organic chlorides and bromides, consider the above-described special compounds of formula VIII, for example, wherein R.sub.2 is --(CH.sub.2).sub.d --X; wherein d is zero, one, 2, 3, or 4, and X is isobutyl, tert-butyl, 3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl. The halides are advantageously prepared by reacting the corresponding primary alcohol, R.sub.2 CH.sub.2 OH, or secondary alcohol ##EQU14## wherein R.sub.3 is as defined above, with PCl.sub.3, PBr.sub.3, or any of the other halogenating agents known to the art to be useful for this purpose.
In the case of X being isobutyl or tert-butyl, some of the necessary lower molecular weight primary alcohols, e.g., (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.2 OH and (CH.sub.3).sub.3 CCH.sub.2 OH, are known. The remainder of the alcohols are prepared by reacting the bromides corresponding to those known alcohols with sodium cyanide, hydrolyzing the resulting nitriles to the corresponding carboxylic acids, and then reducing those acids to the corresponding primary alcohols with lithium aluminum hydride, thus extending the carbon chain one carbon atoms at a time until all primary alcohols are prepared. The corresponding secondary alcohols, ##EQU15## are prepared by transforming the --COOH of the correspond carboxylic acid, all of which are known or prepared as just described, to ##EQU16## by known procedures, for example, R.sub.2 COCl + (R.sub.3).sub.2 Cd, the resulting ketone then being reduced to the secondary alcohol with sodium borohydride.
In the case of X being 3,3-difluorobutyl, the necessary alcohols are prepared from ketocarboxylic acids of the formula, CH.sub.3 --CO--(CH.sub.2).sub.n --COOH, wherein n is 2, 3, 4, 5, or 6. All of those acids are known. The methyl esters are prepared and reacted with sulfur tetrafluoride to produce the corresponding CH.sub.3 --CF.sub.2 --(CH.sub.2).sub.n --COOCH.sub.3 compounds, which are then reduced with lithium aluminum hydride to CH.sub.3 --CF.sub.2 --(CH.sub.2).sub.n --CH.sub.2 OH, or transformed as described above to ##EQU17## These alcohols are then transformed to the bromide or chloride by reaction with PBr.sub.3 or PCl.sub.3 .
In the case of X being 4,4-difluorobutyl, the initial reactants are the known dicarboxylic acids, HOOC--(CH.sub.2).sub.f --COOH, wherein f is 3, 4, 5, 6, or 7. These dicarboxylic acids are esterified to CH.sub.3 OOC--(CH.sub.2).sub.f --COOCH.sub.3 and then half saponified, for example with barium hydroxide, to give HOOC--(CH.sub.2).sub.f --COOCH.sub.3. The free carboxyl group is transformed first to the acid chloride with thionyl chloride and then to an aldehyde by the Rosenmund reduction. Reaction of the aldehyde with sulfur tetrafluoride then gives CHF.sub.2 --(CH.sub.2).sub.f --COOCH.sub.3 which by successive treatment with lithium aluminum hydride and PBr.sub.3 or PCl.sub.3 gives the necessary bromides or chlorides, CHF.sub.2 --(CH.sub.2).sub.f --CH.sub.2 Br or CHF.sub.2 --(CH.sub.2).sub.f --CH.sub.2 Cl. Those formulas can be rewritten as CHF.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2).sub.d --CH.sub.2 Br or CHF.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 (CH.sub.2 ).sub.d --CH.sub.2 Cl. Corresponding secondary alcohols are prepared as described above.
In the case of X being 4,4,4-trifluorobutyl, aldehydes of the formula CH.sub.3 OOC--(CH.sub.2).sub.f --CHO are prepared as described above. Reduction of the aldehyde with sodium borohydride gives the alcohol CH.sub.3 OOC--(CH.sub.2).sub.f --CH.sub.2 OH. Reaction with PBr.sub.3 or PCl.sub.3 then gives CH.sub.3 OOC--(CH.sub.2).sub.f --CH.sub.2 --X, wherein X is Br or Cl. Saponification of that ester gives the carboxylic acid which by reaction with sulfur tetrafluoride gives the necessary CF.sub.3 --(CH.sub.2).sub.f --CH.sub.2 --Br or CF.sub.3 --(CH.sub.2).sub.f --CH.sub.2 --Cl. Corresponding secondary alcohols are prepared by transforming CH.sub.3 OOC--(CH.sub.2).sub.f --CHO to CH.sub.3 OOC--(CH.sub.2).sub.f --COCH.sub.3 by known methods, and then proceeding with that ketone as described above for the aldehyde.
For the above reactions of SF.sub.4, see U.S. Pat. No. 3,211,723 and J. Org. Chem. 27, 3164 (1962).
The transformation of bicyclo-ketone-olefin XVI to glycol XVII (chart B) is carried out by reacting olefin XVI with a hydroxylation reagent. Hydroxylation reagents and procedures for this purpose are known in the art. See, for example, Gunstone, Advances in Organic Chemistry, Vol. I, pp. 103-147, Interscience Publishers, New York, N.Y. (1960). Various isomeric glycols are obtained depending on whether olefin XVII is cis or trans and endo or exo, and on whether a cis or a trans hydroxylation reagent is used. Thus endo-cis olefin XVI gives a mixture of two isomeric erythro glycols of formula XVII with a cis hydroxylation agent, e.g., osmium tetroxide. Similarly, the endo-trans olefin XVI gives a similar mixture of the same two erythro glycols with a trans hydroxylation agent, e.g., hydrogen peroxide. The endo-cis olefins and the endo-trans olefins XVI give similar mixtures of two threo isomers with cis and trans hydroxylation reagents, respectively. These various glycol mixtures are separated into individual isomers by silica gel chromatography. However, this separation is usually not necessary, since each isomeric erythro glycol and each isomeric threo glycol is useful as an intermediate according to this invention and the processes outlined in Charts B, C, E, and F to produce final products of formulas VIII and XII, and then, according to Chart A, to produce the other final products of this invention. Thus the various isomeric glycol mixtures encompassed by formula XVII produced from the various isomeric olefins encompassed by formula XVI are all useful for these same purposes.
The transformation of glycol XVII to the cyclic ketal of formula XVIII (Chart B) is carried out by reacting said glycol with a dialkyl ketone of the formula ##EQU18## wherein R.sub.12 and R.sub.13 are alkyl of one to 4 carbon atoms, inclusive, in the presence of an acid catalyst, for example potassium bisulfate or 70% aqueous perchloric acid. A large excess of the ketone and the absence of water is desirable for this reaction. Examples of suitable dialkyl ketones are acetone, methyl ethyl ketone, diethyl ketone, methyl propyl ketone, and the like. Acetone is preferred as a reactant in this process.
The transformation of cyclic ketal XVIII to cyclic ketal XIX is carried out by alkylating ketal XVIII with an acetylenic alkylating agent of formula XX (Chart C), wherein A is as defined above, and Hal is clorine, bromine, or iodine.
Any of the alkylation procedures known in the art to be useful for alkylating cyclic ketones with alkyl halides, especially haloalkanoic esters, are used for the transformation of XVIII to XIX. See, for example, the above mentioned Belgian Pat. No. 702,477 for procedures useful here and used there to carry out similar alkylations.
For this alkylation, it is preferred that Hal be bromo. Any of the usual alkylation bases, e.g., alkali metal alkoxides, alkali metal amides, and alkali metal hydrides, are useful for this alkylation. Alkali metal alkoxides are preferred, especially tert-alkoxides. Sodium and potassium are preferred alkali metals. Especially preferred is potassium tert-butoxide. Preferred diluents for this alkylation are tetrahydrofuran and 1,2-dimethoxyethane. Otherwise, procedures for producing and isolating the desired formula XIX compound are within the skill of the art.
This alkylation procedure produces a mixture of alpha and beta alkylation products, i.e., a mixture of formula XIX products wherein part has the --CH.sub.2 --C.tbd.C--A--CH.sub.2 O ##SPC15##
The alkylating agent of formula XX is prepared by the series of reactions shown in Chart C. The initial reactants, Br--A--CH.sub.2 OH, are omega bromoalcohols which are known in the art or can be prepared by methods known in the art. For example, when A in the final product is to be trimethylene as it is in racemic PGE.sub.2 and 5,6--dehydro--PGE.sub.2, the necessary 4-bromobutanol is prepared by reacting tetrahydrofuran with hydrogen bromide.
To illustrate the availability of the other bromoglycols of formula XXIV (Chart C), consider the above-described special compounds of formula VIII, wherein A is --(CH.sub.2).sub.b --Z--, wherein b is zero, one, 2, or 3, and Z is ethylene substituted by one or 2 fluoro, methyl, or ethyl, or by one alkyl of 3 or 4 carbon atoms. These omega-bromoalcohols, Br--(CH.sub.2).sub.b --Z--CH.sub.2 OH, are prepared by starting with the appropriate succinic acid, HOOC--Z--COOH, all of which are known or easily accessible by known methods. These succinic acids are transformed to the corresponding anhydrides by known procedures. Each anhydride is then reacted with an alkanol, for example, methanol, to give the corresponding succinic acid half ester, e.g., HOOC--Z--COOCH.sub.3. When Z is unsymmetrical, e.g., substituted with one fluoro, a mixture of isomeric half esters is obtained, HOOC--Z--COOCH.sub.3 and CH.sub.3 --OOC--Z--COOH, which is separated to give the desired isomer.
When it is desired that b is Br--(CH.sub.2).sub.b --Z--CH.sub.2 OH be zero, the succinic acid half ester is subjected to the Hunsdiecker reaction, thereby producing Br--Z--COOCH.sub.3, which is reduced by lithium aluminum hydride to Br--Z--CH.sub.2 OH. When b is to be one, the carboxyl group of the succinic acid half ester is changed to acid chloride with thionyl chloride, to aldehyde by the Rosenmund reduction, to alcohol with sodium borohydride, and to --CH.sub.2 Br with PBr.sub.3, giving Br--CH.sub.2 --Z--COOCH.sub.3, which is then reduced to Br--CH.sub.2 --Z--CH.sub.2 OH with lithium aluminum hydride. When b is to be 2 or 3, the succinic acid half ester is subjected once or twice to the Arndt-Eistert reaction to produce HOOC--CH.sub.2 --Z--COOCH.sub.3 or HOOC--CH.sub.2 CH.sub.2 --Z--COOCH.sub.3, which is then subjected to the same series of reactions given above to give Br--CH.sub.2 CH.sub.2 --Z--CH.sub.2 OH or Br-- CH.sub.2 CH.sub.2 CH.sub.2 --Z--CH.sub.2 OH.
Referring again to Chart C, the several process steps, XXIV to XXIII, XXIII to XXII, XXII to XXI, and XXI to XX are exemplified hereinafter in the case wherein A is trimethylene. Those procedures are used when A is other than trimethylene and within the scope of A as defined above.
The transformation of alkylation product XIX to primary alcohol XXV (Chart B) is carried out by treating the tetrahydropyranyl ether XIX with any strong acid under such conditions that the cyclic acetal group remains intact. Hydrolysis of tetrahydropyranyl ethers under such conditions is well known to those skilled in the art. Oxalic acid is especially preferred for this acid hydrolysis of XIX to XXV.
The oxidation of primary alcohol XXV to carboxylic acid XXVI (Chart B) is carried out by oxidizing XXV with any oxidizing agent which will not also attack the acetylenic linkage in XXV. An especially useful reagent for this purpose is the Jones reagent, i.e., acidic chromic acid. See J. Chem. Soc. 39 (1946). Acetone is a suitable diluent for this purpose, and a slight excess of oxidant and temperatures at least as low as about 0.degree. C., preferably about -10.degree. to about -20.degree. C. should be used. The oxidation proceeds rapidly and is usually complete in about 5 to about 30 minutes. Excess oxidant is destroyed, for example, by addition of a lower alkanol, advantageously isopropyl alcohol, and the aldehyde is isolated by conventional methods, for example, by extraction with a suitable solvent, e.g., diethyl ether. Other oxidizing agents can also be used. Examples are mixtures of chromium trioxide and pyridine or mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide. See, for example, J. Am. Chem. Soc. 87, 5661 (1965).
As shown on Charts B, D, and E, carboxylic acid XXVI leads to PG.sub.2 -type compounds (Chart E) or 5,6-dehydro-PG.sub.2 -type compounds (Chart F) depending on whether the --C.tbd.C-- bond of XXVI is reduced to cis--CH=CH--. When a PG.sub.2 -type compound is desired, XXVI is reduced to cis-olefin XXVIII (Chart B) with hydrogen and a catalyst which catalyzes hydrogenation of --C.tbd.C-- only to cis--CH=CH--. Such catalysts and procedures are well known to the art. See, for example, Fieser et al., "Reagents for Organic Synthesis", pp. 566-567; John Wiley & Sons, Inc., New York, N.Y. (1967). Palladium (5%) on barium sulfate, especially in the presence of pyridine as a diluent, is a suitable catalyst for this purpose.
The transformations of cyclic ketals XXVI and XVIII to glycols XXVII and XXIX, respectively, (Charts B and D) are carried out by reacting the cyclic ketal with an acid with pK less than 5. Suitable acids and procedures for hydrolyzing cyclic ketals to glycols are known in the art. Suitable acids are formic acid and hydrochloric acid. Especially preferred as a diluent for this reaction is tetrahydrofuran.
The transformations of glycol-acids XXIX and XXVII to glycol-esters XXX and XXXII, respectively, (Chart D) are esterifications carried out by procedures known in the art to be useful for transforming carboxylic acids to esters --COOR.sub.14 wherein R.sub.14 is as defined above. For example, a diazohydrocarbon, e.g., diazomethane, advantageously in diethyl ether solution, is reacted with the acid to produce the ester, e.g., the methyl ester, by known procedures. When R.sub.14 is ethyl substituted with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo, the glycol acid is reacted with the appropriate haloethanol, e.g., .beta.,.beta.,.beta.-trichloroethanol when R.sub.4 is to be --CH.sub.2 CCl.sub.3, in the presence of a carbodiimide, e.g., dicyclohexylcarbodiimide, and a base, e.g., pyridine. This mixture, advantageously with an inert diluent, e.g., dichloromethane, usually produces the desired haloethyl ester within several hours at about 25.degree. C. The other esters within the scope of R.sub.14 in formulas XXX and XXXII are prepared by procedures known to the art.
The bis-alkanesulfonic acid esters XXXI and XXXIII (Chart D) are prepared by reacting glycol-esters XXX and XXXII, respectively, with an alkylsulfonyl chloride or bromide, or with an alkanesulfonic acid anhydride, the alkyl in each containing one to 5 carbon atoms, inclusive. Alkylsulfonyl chlorides are preferred for this reaction. The reaction is carried out in the presence of a base to neutralize the byproduct acid. Especially suitable bases are tertiary amines, e.g., dimethylaniline or pyridine. It is usually sufficient merely to mix the two reactants and the base, and maintain the mixture in the range 0.degree. to 25.degree. C. for several hours. The formula XXXI and XXXIII bis-sulfonic acid esters are then isolated by procedures known to the art.
Referring now to Chart E, bis-sulfonic acid esters XXXI are transformed either by PGE.sub.2 -type compounds VIII or to PGA.sub.2 -type compounds X. Referring to Chart F, bis-sulfonic acid esters XXXIII are transformed either to 5,6-dehydro-PGE.sub.2 -type compounds XII or to 5,6-dehydro-PGA.sub.2 -type compounds XIV.
The transformations of XXXI and XXXIII to VIII and XII, respectively, are carried out by reacting XXXI and XXXIII with water in the range about 0.degree. to about 60.degree. C. In making racemic PGE.sub.2 or 5,6-dehydro-PGE.sub.2, usually 25.degree. C. is a suitable reaction temperature, the reaction then proceeding to completion in about 5 to 10 hours. It is advantageous to have a homogenous reaction mixture. This is accomplished by adding sufficient of a water-soluble organic diluent which does not enter into the reaction. Acetone is a suitable diluent. The desired product is isolated by evaporation of excess water and diluent if one is used. The residue contains a mixture of formula VIII or formula XII isomers which differ in the configuration of the side chain hydroxy, that being either R or S. These are separated from byproducts and from each other by silica gel chromatography. A usual byproduct is the mono-sulfonic acid ester of formula XXXIV (Chart E) or formula XXXVII (Chart F). This mono-sulfonic acid ester is esterified to the formula XXXI or XXXIII bis-sulfonic acid ester in the same manner described above for the transformation of glycol XXX or XXXII to bis-ester XXXI or XXXIII, and thus is recycled back to additional formula VIII or XII final product.
For the transformation of bis-esters XXXI and XXXIII to final products VIII and XIII, respectively, it is preferred to use the bis-mesyl esters, i.e., compounds XXXI and XXXIII wherein R.sub.15 is methyl.
The configuration of the --CH.sub.2 --CH=CH--A--COOR.sub.14 moiety in the formula XXXI bis-ester and the configuration of the --CH.sub.2 --C.tbd.C--A--COOR.sub.14 moiety in the formula XXXIII bis ester do not change during these transformations of XXXI to VIII or XXXIII to XII. Therefore, when in formula XXXI, R.sub.2 is pentyl, R.sub.3 and R.sub.4 are hydrogen, and A is trimethylene, racemic PGE.sub.2 esters are obtained when the --CH.sub.2 CH=CH--A--COOR.sub.14 is attached initially in alpha configuration, and racemic 8-iso-PGE.sub.2 esters are obtained when that moiety is attached in beta configuration. Similarly, when in formula XXXIII, R.sub.2 is pentyl, R.sub.3 and R.sub.4 are hydrogen, and A is trimethylene, 5,6-dehydro-PGE.sub.2 esters are obtained when the --CH.sub.2 --C.tbd.C--A--COOR.sub.14 moiety is attached initially in alpha configuration, and 8-iso-5,6-dehydro-PGE.sub.2 esters are obtained when that moiety is attached in beta configuration.
Referring again to Charts E and F, the transformations of bis-sulfonic acid esters XXXI and XXXIII to formula X PGA.sub.2 -type compounds and formula XIV 5,6-dehydro-PGA.sub.2 -type compounds, respectively, is carried out by heating the formula XXXI or formula XXXIII bis-ester in the range 40.degree. to 100.degree. C. with a combination of water, a base characterized by its water solution having a pH 8 to 12, and sufficient inert water-soluble organic diluent to form a basic and substantially homogeneous reaction mixture. A reaction time of one to 10 hours is usually used. Preferred bases are the water-soluble salts of carbonic acid, especially alkali metal bicarbonates, e.g., sodium bicarbonate. A suitable diluent is acetone. The products are isolated and separated as described above for the transformation of bis-esters XXXI and XXXIII to final products VIII and XII. The same mono-sulfonic acid esters XXXIV and XXXVII observed as byproducts in those transformations are also observed during preparation of final products X and XIV. Also, as for the production of VIII and XII the bis-mesyl esters of XXXI and XXXIII are preferred when making X and XIV. Also as for the production of VIII and XII, during production of X and XIV, alpha XXXI and alpha XXXIII give alpha X and alpha XIV, respectively, beta XXXI and beta XXXIII give beta X and beta XIV, respectively, and in each case, alpha and beta X and XIV, a mixture of R and S isomers is obtained. These R and S isomer mixtures are separated by silica gel chromatograph.
The formula VIII, X, XII, and XIV produced according to the processes outlined in Charts B, C, D, E, and F and discussed above are all R.sub.14 carboxylic acid esters, wherein R.sub.14 is as described above. Moreover, when these compounds are used to produce compounds of formulas IX, XI, XIII, and XV according to the process outlined in Chart A and discussed above, corresponding R.sub.14 esters are likely to be produced, especially in the case of the PGF.sub.2 and 5,6-dehydro-PGF.sub.2 compounds of formulas IX and XIII, respectively. For some of the uses described above, it is preferred that these formula VIII to XV compounds be in free acid form, or in salt form which requires the free acid as a starting material. The formula IX, XI, XIII, and XV R.sub.14 esters are easily hydrolyzed or saponified by the usual known procedures, especially when R.sub.14 is alkyl of one to 4 carbon atoms, inclusive. Therefore it is preferred when the free acid form of compounds IX, XI, XIII, and XV is desired, that R.sub.14 be such alkyl, especially methyl or ethyl.
On the other hand, the formula VIII, X, XII, and XIV final products are difficult to hydrolyze or saponify without unwanted structural changes in the desired acids. There are two other procedures useful to make the free acid form of formula VIII, X, XII, and XIV products.
One of those procedures is applicable mainly in preparing the free acids from the corresponding alkyl esters wherein the alkyl group contains one to 8 carbon atoms, inclusive. That procedure comprises subjecting the alkyl ester corresponding to formula VIII, X, XII, or XIV to the acylase enzyme system of a microorganism species of Subphylum 2 of Phylum III, and thereafter isolating the acid. Especially preferred for this purpose are species of the orders Mucorales, Hypocreales, Moniliales, and Actinomycetales. Also especially preferred for this purpose are species of the families Mucoraceae, Cunninghamellaceae, Nectreaceae, Moniliaceae, Dematiaceae, Tuberculariaceae, Actinomycetaceae, and Streptomycetaceae. Also especially preferred for this purpose are species of the genera Absidia, Circinella, Gongronella, Rhizopus, Cunninghamella, Calonectria, Aspergillus, Penicillium, Sporotrichum, Cladosporium, Fusarium, Nocardia, and Streptomyces.
Examples of microorganisms falling within the scope of those preferred orders, families, and genera are listed in U.S. Pat. No. 3,290,226.
This enzymatic ester hydrolysis is carried out by shaking the formula VIII, X, XII, or XIV alkyl ester in aqueous suspension with the enzyme contained in a culture of one of the above-mentioned microorganism species until the ester is hydrolyzed. A reaction temperature in the range 20.degree. to 30.degree. C. is usually satisfactory. A reaction time of one to 20 hours is usually sufficient to obtain the desired hydrolysis. Exclusion of air from the reacton mixture, for example, with argon or nitrogen is usually desirable.
The enzyme is obtained by harvest of cells from the culture, followed by washing and resuspension of the cells in water, and cell disintegration, for example, by stirring with glass beads or by sonic or ultrasonic vibrations. The entire aqueous disintegration mixture is used as a source of the enzyme. Alternatively and preferably, however, the cellular debris is removed by centrifugation or filtration, and the aqueous supernatant or filtrate is used.
In some cases, it is advantageous to grow the microorganism culture in the presence of an alkyl ester of an aliphatic acid, said acid containing 10 to 20 carbon atoms, inclusive, and said alkyl contaning one to 8 carbon atoms, inclusive, or to add such an ester to the culture and maintain the culture without additional growth for one to 24 hours before cell harvest. Thereby, the enzyme produced is sometimes made more effective in transforming the formula VIII, X, XII, or XIV ester to the free acid. An example of a useful alkyl ester for this purpose is methyl oleate.
Although, as mentioned above, most of the R.sub.14 esters encompassed by formulas VIII, X, XII, and XIV are not easily hydrolyzed or saponified to the corresponding free acids, certain of those esters are transformed to free acids by another method. Those esters are the haloethyl esters wherein R.sub.14 is --CH.sub.2 CCl.sub.3, are transformed to free acids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbon atoms, preferably acetic acid. Zinc dust is preferred as the physical form of the zinc. Mixing the haloethyl ester with the zinc dust at about 25.degree. C. for several hours usually causes substantially complete replacement of the haloethyl moiety of the formula VIII, X, XII, or XIV ester with hydrogen. The free acid is then isolated from the reaction mixture by procedures known to the art. This procedure is also applicable to the production of the free acid form of the formula IX, XI, XIII and XV compounds from the corresponding haloethyl esters thereof.
The preparation of these haloethyl esters is described above during the discussion of the esterification of acids XXIV and XXVII to esters XXX and XXXII, respectively.
As described above, the alkylation of cyclic ketal-ketone XVIII to ketone XIX (Chart B) usually produces a mixture of alpha and beta alkylation products with respect to the --CH.sub.2 --C.tbd.C--A--CH.sub.2 O ##SPC16##
One of those methods involves isomerization of the final product of formula VIII or formula XII wherein R.sub.14 is as defined above or hydrogen. Either the alpha isomer of formula VIII or XII, or the beta isomer of formula VIII or XII is maintained in an inert liquid diluent in the range 0.degree. to 80.degree. C. and in the presence of a base characterized by its water solution having a pH below about 10 until a substantial amount of the isomer has been isomerized to the other isomer, i.e., alpha to beta or beta to alpha. Preferred bases for this purpose are the alkali metal salts of carboxylic acids, especially alkanoic acids of 2 to 4 carbon atoms, e.g., sodium acetate. Examples of useful inert liquid diluents are alkanols of one to 4 carbon atoms, e.g., ethanol. This reaction at about 25.degree. takes about one to about 20 days. Apparently an equilibrium is established. The mixtures of the two isomers, alpha and beta, are separated from the reaction mixture by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography, recrystallization, or a combination of those. The less preferred isomer is then subjected to the same isomerization to produce more of the preferred isomer. In this manner, by repeated isomerizations and separations, substantially all of the less preferred isomer of the formula VIII or formula XII compound is transformed to more preferred isomer.
The second method for favoring production of a preferred final formula VIII or formula XII isomer involves any one of the intermediates of formulas XIX, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, or XXXII (Charts B and D). Either the alpha form or the beta form of one of those intermediates is transformed to a mixture of both isomers by maintaining one or the other isomer, alpha or beta, in an inert liquid diluent in the presence of a base and in range 0.degree. to 100.degree. C. until a substantial amount of the starting isomer has been isomerized to the other isomer. Preferred bases for this isomerization are alkali metal amides, alkali metal alkoxides, alkali metal hydrides, and triarylmethyl alkali metals. Especially preferred are alkali metal tert-alkoxides of 4 to 8 carbon atoms, e.g., potassium tert-butoxide. This reaction at about 25.degree. C. proceeds rapidly (one minute to several hours). Apparently an equilibrium mixture of both isomers is formed, starting with either isomer. The isomer mixtures in the equilibrium mixture thus obtained are isolated by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography. The less preferred isomer is then subjected to the same isomerization to produce more of the preferred isomer. In this manner, by repeated isomerization and separations, substantially all of the less preferred isomer of any of these intermediates is transformed to the more preferred isomer. Cyclic acetalketone intermediates XIX and XXV are preferred over the other intermediates for this isomerization procedure.
The final formula VIII to XV compounds prepared by the processes of this invention, in free acid form, are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quaternary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the formula VIII to XV acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. 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 solid inorganic salt if that form is desired.
To produce an amine salt, the formula VIII to XV acid 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 corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by mixing the formula VIII to XV acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
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3505387 |
Beal et al. |
Apr 1970 |
|
Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
807405 |
Mar 1969 |
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Patent Grant
3959346
