TREA

11,12-Secoprostaglandins

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Information

  • Patent Grant
  • 4066692
  • Patent Number
    4,066,692
  • Date Filed
    Monday, March 22, 1976
    48 years ago
  • Date Issued
    Tuesday, January 3, 1978
    47 years ago
Information
Abstract
This invention relates to 11,12-secoprostaglandins and processes for their manufacture. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators, for the treatment of hypertension, for the prevention of thrombus formation, in preventing gastric secretion, and as regulators of the immune response.
Description
Claims
  • 1. The compound having the following formula: ##STR52## wherein R is carboxy, a carboxy salt, or carboxy having the formula --COOY wherein Y is alkyl having 1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloyloxy)ethyl, 2-acetamidoethyl, or diloweralkylaminoloweralkyl;
  • A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, or .beta.,.beta.-dimethylethylene;
  • R.sup.1 is formyl, acetyl, propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl, or 1-hydroxy-1-methylethyl;
  • Z is methylene, ethylene, trimethylene, tetramethylene, vinylene, or ethynylene;
  • R.sup.2 is independently hydrogen or methyl;
  • R.sup.3 is hydrogen;
  • R.sup.4 is selected independently from the group consisting of hydrogen and methyl;
  • R.sup.5 is selected from the group consisting of hydrogen, lower alkyl of 1-4 carbon atoms either straight or branched (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl, and 2,2,2-trifluoroethyl.
  • 2. The compound of claim 1 wherein R is carboxy; a carboxy salt having the formula:
  • --COO.sup.- Me.sup.+
  • wherein Me is a pharmaceutically acceptable cation derived from a metal or an amine; or carboxy having the formula:
  • -COOY
  • wherein Y is alkyl having 1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloyloxy)ethyl, 2-acetamidoethyl, or diloweralkylamino-loweralkyl.
  • 3. The compound of claim 2 wherein R is carboxy or a pharmaceutically acceptable carboxy salt.
  • 4. The compound of claim 3 which has the formula: ##STR53## wherein R.sup.1 is formyl, acetyl, propionyl, hydroxyacetyl, 1-hydroxyethyl, hydroxymethyl, or 1-hydroxy-1-methylethyl;
  • A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, or .beta.,.beta.-dimethylethylene;
  • Z is methylene, ethylene, trimethylene, or tetramethylene;
  • R.sup.4 is hydrogen or methyl; and
  • R.sup.5 is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl.
  • 5. The compound of claim 4 wherein A is ethylene and R.sup.4 is hydrogen.
  • 6. The compound of claim 5 wherein R.sup.1 is acetyl or propionyl.
  • 7. The compound of claim 6 wherein Z and A are ethylene, and R.sup.5 is ethyl.
  • 8. 8-Acetyl-12-hydroxyheptadecanoic acid, the compound of claim 7 wherein R.sup.1 is acetyl.
  • 9. 8-Acetyl-12-(R)-hydroxyheptadecanoic acid, the compound of claim 7 wherein R.sup.1 is acetyl and the carbon atom bearing the hydroxy group is in the R configuration.
  • 10. 8-Acetyl-12-(S)-hydroxyheptadecanoic acid, the compound of claim 7 wherein R.sup.1 is acetyl and the carbon atom bearing the hydroxy group is in the S configuration.
  • 11. 8-Propionyl-12-hydroxyheptadecanoic acid, the compound of claim 7 wherein R.sup.1 is propionyl.
  • 12. 8-Formyl-12-hydroxyheptadecanoic acid, the compound of claim 7 wherein R.sup.1 is formyl.
  • 13. 8-Acryloyl-12-hydroxyheptadecanoic acid, the compound of claim 6 wherein A and Z are ethylene, R.sup.1 is acryloyl, and R.sup.5 is ethyl.
  • 14. 8-Acetyl-12-hydroxy-17,17,17-trifluoroheptadecanoic acid, the compound of claim 6 wherein A and Z are ethylene, R.sup.1 is acetyl, and R.sup.5 is 2,2,2-trifluoroethyl.
  • 15. 8-Acetyl-12-hydroxy-16-heptadecenoic acid, the compound of claim 6 wherein A and Z are ethylene, R.sup.1 is acetyl, and R.sup.5 is vinyl.
  • 16. The compound of claim 6 wherein R.sup.5 is straight chain loweralkyl having 2-5 carbon atoms.
  • 17. 8-Acetyl-12-hydroxynonadecanoic acid, the compound of claim 16 wherein A and Z are ethylene, R.sup.1 is acetyl, and R.sup.5 is butyl.
  • 18. 8-Acetyl-12-hydroxy-16,16-dimethylheptadecanoic acid, the compound of claim 16 wherein A and Z are ethylene, R.sup.1 is acetyl, and R.sup.5 is tert-butyl.
  • 19. 8-Acetyl-12-hydroxy-13,13-dimethylheptadecanoic acid, the compound of claim 4 wherein R.sup.1 is acetyl, A and Z are ethylene, R.sup.4 is methyl, and R.sup.5 is ethyl.
  • 20. The compound of claim 3 which has the formula: ##STR54## wherein A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, .beta.,.beta.-dimethylethylene, or oxymethylene; R.sup.1 is acetyl or 1-hydroxyethyl; and R.sup.5 is hydrogen, loweralkyl of 1-4 carbon atoms, or 2,2,2-trifluoroethyl.
  • 21. 8-Acetyl-12-hydroxy-(E)-10-heptadecenoic acid, the compound of claim 20 wherein R.sup.1 is acetyl, A is ethylene, and R.sup.5 is ethyl.
  • 22. 8-(1-Hydroxyethyl)-12-hydroxy-(E)-10-heptadecenoic acid, the compound of claim 20 wherein R.sup.1 is 1-hydroxyethyl, A is ethylene, and R.sup.5 is ethyl.
  • 23. The compound of claim 3 which has the formula: ##STR55##
  • 24. 8-Acetyl-12-hydroxy-10-heptadecynoic acid, the compound of claim 23 wherein A is ethylene and R.sup.5 is ethyl.
  • 25. The compound of claim 3 which has the formula: ##STR56## wherein R.sup.1 is formyl, acetyl, propionyl, hydroxymethyl, 1-hydroxy-1-methylethyl, 1-hydroxyethyl, or hydroxyacetyl;
  • A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, or .beta.,.beta.-dimethylethylene;
  • Z is methylene, ethylene, trimethylene, tetramethylene, or vinylene; and
  • R.sup.5 is hydrogen, loweralkyl of 1-4 carbon atoms, or 2,2,2-trifluoroethyl.
  • 26. 8-Acetyl-12-hydroxy-12-methylheptadecanoic acid, the compound of claim 25 wherein A and Z are ethylene, R.sup.1 is acetyl, and R.sup.5 is ethyl.
  • 27. 8-(1-Hydroxyethyl)-12-hydroxy-12-methylheptadecanoic acid, the compound of claim 25 wherein A and Z are ethylene, R.sup.1 is 1-hydroxyethyl, and R.sup.5 is ethyl.
  • 28. 8-(1-Hydroxy-1-methylethyl)-12-hydroxy-12-methylheptadecanoic acid, the compound of claim 25 wherein A and Z are ethylene, R.sup.1 is 1-hydroxy-1-methylethyl, and R.sup.5 is ethyl.
  • 29. The compound of claim 3 which has the formula: ##STR57## wherein R.sup.1 is acetyl, propionyl, 3-hydroxypropionyl, acryloyl, formyl;
  • A is trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, or .beta.,.beta.-dimethylethylene; and
  • R.sup.5 is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl.
  • 30. 2-Methyl-8-acetyl-12-hydroxyheptadecanoic acid, the compound of claim 29 wherein A is .alpha.-methylethylene, R.sup.1 is acetyl, and R.sup.5 is ethyl.
  • 31. 3,3-Dimethyl-8-acetyl-12-hydroxyheptadecanoic acid, the compound of claim 29 wherein A is .beta.,.beta.-dimethylethylene, R.sup.1 is acetyl, and R.sup.5 is ethyl.
  • 32. The compound of claim 3 which has the formula: ##STR58## wherein R.sup.1 is hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, or 1,3-dihydroxypropyl;
  • A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, or .beta.,.beta.-dimethylethylene;
  • z is methylene, ethylene, trimethylene, tetramethylene, vinylene, or ethynylene;
  • R.sup.2 and R.sup.4 are selected independently from a group consisting of hydrogen and methyl; and
  • R.sup.5 is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl.
  • 33. The compound of claim 32 wherein A and Z are ethylene, R.sup.1 is hydroxymethyl or 1-hydroxyethyl, and R.sup.5 is loweralkyl.
  • 34. 8-Hydroxymethyl-12-hydroxyheptadecanoic acid, the compound of claim 33 wherein R.sup.1 is hydroxymethyl, R.sup.2 is hydrogen, and R.sup.5 is ethyl.
  • 35. 8-(1-Hydroxyethyl)-12-hydroxyheptadecanoic acid, the compound of claim 33 wherein R.sup.1 is 1-hydroxyethyl, R.sup.2 is hydrogen, and R.sup.5 is ethyl.
  • 36. The compound of claim 2 which has the formula: ##STR59## wherein A is ethylene;
  • R.sup.1 is acetyl, propionyl, hydroxymethyl, or 1-hydroxyethyl;
  • R.sup.2 is methyl or hydrogen;
  • R.sup.4 is selected independently from the group consisting of hydrogen and methyl;
  • R.sup.5 is selected from the group consisting of hydrogen, lower alkyl of 1-4 carbon atoms either straight or branched (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl, and 2,2,2-trifluroethyl;
  • and Y is alkyl having 1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloylethyl), 2-acetamidoethyl, or diloweralkylaminoloweralkyl.
  • 37. Methyl 8-acetyl-12-hydroxyheptadecanoate, the compound of claim 36 wherein R.sup.1 is acetyl, A and Z are ethylene, R.sup.2 and R.sup.4 are hydrogen, R.sup.5 is ethyl, and Y is methyl.
  • 38. A composition comprising the compound of claim 1 in a non-toxic, pharmaceutically-acceptable carrier.
  • 39. The composition of claim 38 which is suitable for oral administration in tablet form.
  • 40. The composition of claim 38 which is suitable for oral administration in capsule form.
  • 41. The composition of claim 38 which is suitable for parenteral administration.
  • 42. The composition of claim 38 which is suitable for use in suppository form.
  • 43. The compound having the following formula: ##STR60## wherein R is carboxy, a carboxy salt, or derivatized carboxy having the formula -COOY wherein Y is alkyl having 1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloyloxy)ethyl, 2-acetamidoethyl, or diloweralkylaminoloweralkyl;
  • A is ethylene, trimethylene, .alpha.-methylethylene, .beta.-methylethylene, .alpha.,.alpha.-dimethylethylene, or .beta.,.beta.-dimethylethylene;
  • R.sup.1 is formyl, acetyl, propionyl, or acryloyl:
  • Z is methylene, ethylene, trimethylene, tetramethylene, vinylene, or ethynylene;
  • R.sup.2 is independently hydrogen or methyl;
  • R.sup.3 is hydrogen;
  • R.sup.4 is selected independently from the group consisting of hydrogen and methyl; and
  • R.sup.5 is selected from the group consisting of hydrogen, lower alkyl of 1-4 carbon atoms either straigth or branched (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl, and 2,2,2-trifluoroethyl.
RELATIONSHIP TO OTHER APPLICATIONS

This application is a continuation-in-part application of copending U.S. Ser. No. 571,038 filed Apr. 23, 1975, abandoned; which in turn is a continuation-in-part of U.S. Ser. No. 389,901 filed Aug. 23, 1973 and now abandoned; which in turn is a continuation-in-part of U.S. Ser. No. 302,365 filed Oct. 30, 1972 and now abandoned. This invention relates to novel 11,12-secoprostaglandins which can be represented by the following formula: ##STR1## wherein R is selected from the group consisting of carboxy and a carboxy salt which incorporates a pharmaceutically acceptable cation, such as metal cations derived from alkali metals, alkaline earth metals, and amines such as ammonia, primary and secondary amines, and quaternary ammomium hydroxides. Especially preferred metal cations are those derived from alkali metals, e.g., sodium, potassium, lithium, and the like, and alkaline earth metals, e.g., calcium, magnesium, and the like and other metals, ie., aluminum, iron and zinc. Pharmaceutically acceptable cations can be formed from primary, secondary, or tertiary amines, or quaternary ammonium hydroxides such as mthylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, .alpha.-phenethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, 1,4-dimethylpiperazine, ethanolamine, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine, ephedrine, procaine, tetramethylammonium hydroxide, tetraethylammonium hydroxide, benzyltrimethylammonium and the like. R is also selected from alkoxycarbonyl (--COOY) wherein Y is alkyl having 1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloyloxy)ethyl, 2-acetamidoethyl or diloweralkylaminoloweralkyl; carbamoyl (--CONH.sub.2); substituted carbamoyl (--CONR.sup.6 R.sup.7) wherein R.sup.6 and R.sup.7 are selected from the group consisting of hydrogen, lower alkyl having 1-4 carbon atoms and diloweralkylaminoalkyl having 4-7 carbon atoms; and carbazoyl (--CONHNH.sub.2). A is selected from the group consisting of ethylene (--CH.sub.2 CH.sub.2), trimethylene (--CH.sub.2 CH.sub.2 CH.sub.2 --), .alpha.-methylethylene (--CH.sub.2 CH(CH.sub.3)--), .beta.-methylethylene (--CH.sub.2 CH(CH.sub.3)CH.sub.2), .alpha.,.alpha.-dimethylethylene (--CH.sub.2 C(CH.sub.3).sub.2 --), .beta.,.beta.-dimethylethylene (--C(CH.sub.2).sub.2 CH.sub.2 --) and oxymethylene (--O--CH.sub.2 --). (Note that when A consists of a two carbon bridge, the term ".alpha." refers to the carbon adjacent to R, while ".beta." refers to the other carbon atom.) R.sup.1 is selected from the group consisting of formyl, acetyl, propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl, and 1-hydroxy-1-methylethyl. Z is selected from the group consisting of methylene, ethylene, trimethylene tetramethylene, vinylene (--CH.dbd.CH--), and ethynylene (--C.tbd.C--). R.sup.2 is independently selected from the group consisting of hydrogen and methyl. R.sup.3 is selected from the group consisting of hydrogen, and lower alkanoyl of 1-5 carbon atoms, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, and the like. R.sup.4 is selected independently from the group consisting of hydrogen and methyl. R.sup.5 is selected from the group consisting of hydrogen, lower alkyl of 1-4 carbon atoms, either straight or branched (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl, and 2,2,2-trifluoroethyl. In addition, when R.sup.5 is lower alkyl and R.sup.2 is methyl, they can be joined together (with abstraction of hydrogen) to form a carbocyclic ring with from 6 to 9 members. Also, when R.sup.5 is lower alkyl and R.sup.2 is hydrogen, R.sup.5 can be joined to the carbon atom bearing R.sup.2 and OR.sup.3 to form a carbocyclic ring with from 5 to 8 members. It is to be recognized that the carbon atom marked by an asterisk (*) and, in some instances, the carbon atoms marked by a dagger ( ) are chiral. In addition, certain carbon atoms included in R.sup.5 are also chiral. The compounds of this invention are understood to include the individual stereoisomers and mixtures of stereoisomers, the biological activity of which will vary but which may readily be determined in the in vitro and in vivo assays described hereinbelow. A preferred embodiment of this invention relates to the 11,12-secoprostaglandins having the following general formula: ##STR2## wherein A' is ethylene or oxymethylene; R.sup.8 is acetyl, propionyl, 1-hydroxyethyl or 1-hydroxy-1-methylethyl; R.sup.2, R.sup.3, and R.sup.4 are as defined above and R.sup.9 is lower alkyl of 1-4 carbon atoms. In addition, when R.sup.2 is methyl, R.sup.9 and R.sup.2 can be joined together to form a carbocyclic ring with from 6 to 9 members. Also, when R.sup.2 is hydrogen, R.sup.9 can be joined to the carbon bearing R.sup.2 and OR.sup.3 to form a carbocyclic ring with from 5 to 8 members. The compounds of Formula I are described as 11,12-secoprostaglandins because of their structural relationship to the naturally-occurring prostaglandins. The prostaglandins constitute a biologically prominent class of naturally-occurring, highly-functionalized C.sub.20 fatty acids which are anabolized readily in a diverse array of mammalian tissues from three essential fatty acids; namely, 8,11,14-eicosatrienoic acid, 5,8,11,14-eicosatetraenoic acid, and 5,8,11,14,17-eicosapentaenoic acid. Each known prostaglandin is a formal derivative of the parent compound, termed "prostanoic acid"; the latter is a C.sub.20 fatty acid covalently bridged between carbons 8 and 12 such as to form a trans, vicinally-substituted cyclopentane in which the carboxy-bearing side chain is "alpha" or below the plane of the ring, and the other side chain is "beta" or above the plane of the ring as depicted in formula III: ##STR3## Prostaglandins have been shown to occur extensively in low concentrations in a myriad of mammalian tissues where they are both rapidly anabolized and catabolized and to exhibit a vast spectrum of pharmacological activities including prominent roles in (a) functional hyperemia, (b) the inflammatory response, (c) the central nervous system, (d) transport of water and electrolytes, and (e) regulation of cyclic AMP. Further details concerning the prostaglandins can be found in recent reviews of their chemistry [J. E. Pike, Fortschr. Chem. Org. Naturst., 28, 313 (1970) and G. F. Bundy, A. Rep. in Med. Chem., 7, 157 (1972)]; biochemistry [J. W. Hinman, A. Rev. Biochem., 41, 161 (1972)]; pharmacology [J. R. Weeks, A. Rev. Pharm., 12, 317 (1972)]; physiological significance [E. W. Horton, Physiol. Rev., 49, 122 (1969)]; and general clinical application [J. W. Hinman, Postgrad. Med. J., 46, 562 (1970)]. The potential application of natural prostaglandins as medicinally useful therapeutic agents in various mammalian disease states is obvious but suffers from three formidable major disadvantages, namely, (a) prostaglandins are known to be rapidly metabolized in vivo in various mammalian tissues to a variety of metabolites which are devoid of the desired original biological activities, (b) the natural prostaglandins are inherently devoid of biological specificity which is requisite for a successful drug, and (c) although limited quantities of prostaglandins are presently produced by both chemical and biochemical processes, their production cost is extremely high; and consequently, their availability is quite restricted. Our interest has, therefore, been to synthesize novel compounds structurally related to the natural prostaglandins, but with the following unique advantages: (a) simplicity of synthesis leading to low cost of production; (b) specificity of biological activity which may be either of a prostaglandin-mimicking or prostaglandin-antagonizing type; (c) enhanced metabolic stability. The combination of these advantages serves to provide effective, orally and parenterally active therapeutic agents for the treatment of a variety of human and animal diseases. Included are applications in renal, cardiovascular, gastrointestinal, respiratory, and reproductive systems, and in the control of lipid metabolism, inflammation, blood clotting, skin diseases, growth hormone release, selected cancers, and certain autoimmune diseases. The compounds of the present invention are useful as pharmaceutically active compounds. Thus, these compounds are orally active in the treatment of conditions which are responsive to the actions of the natural prostaglandins. It is, of course, necessary to determine by routine laboratory testing which of the compounds of the present invention are most suitable for a specific end use. Some of the compounds of the invention have prostaglandin-like activity in that they mimic the effect of prostaglandin E.sub.1 in stimulating the formulation of cyclic AMP in the mouse ovary in vitro. Examples of compounds which are useful in stimulating the formation of cyclic AMP in the mouse ovary are: Certain of the compounds of the invention which do not mimic the effect of prostaglandin E.sub.1 are active as antagonists of prostaglandin E.sub.1 in certain smooth muscle tissues, such as intestinal and uterine tissue. Such compounds would be useful in the prevention of abortion and in the treatment of diarrhea. An example of the compounds of our invention active in antagonizing the effect of prostaglandin E.sub.1 in uterus and intestinal tissue are compounds which have additional methyl substituents in the alpha position relative to the carboxy group, as for example, 2-methyl-8-acetyl-12-hydroxyheptadecanoic acid. In addition, certain of the compounds of the present invention mimic the effects of prostaglandin E.sub.1 in producing renal vasodilation in laboratory animals. Thus, they can be used to improve renal function in animals with poorly-functioning kidneys. Examples of such compounds are: Also, certain of the compounds of this invention have antihypertensive activity as shown by the fact that they lower blood pressure in a strain of laboratory rats which have blood pressure higher than that observed in normal rats, and thus are useful in the treatment of hypertension. An example of such a compound is 8-acetyl-12-hydroxyheptadecanoic acid. In addition, certain of the compounds of this invention are effective in inhibiting the aggregation of platelets in blood stimulated with collagen to cause platelet aggregation. Thus, in inhibiting platelet aggregation, they are useful in preventing thrombus formation. Examples of compounds of this type are: Also, certain of the compounds of our invention, for example 8-acetyl-12-hydroxyheptadecanoic acid, may have utility as antiulcer agents in that they are active in inhibiting gastric secretion in laboratory animals. In one test used to establish this activity, dogs with a chronic gastric fistula are treated with pentagastrin, a substance which ordinarily evokes secretion in such animals. Activity in the test compound is shown when the secretion caused by the test compound is inhibited to some degree. The compounds of this invention are also indicated to be useful in therapy as regulators of the immune response. The basis for their activity in this area is their ability to stimulate cyclic-AMP formation in cells. Agents, including the E prostaglandins, that increase cellular cyclic-AMP concentration, interfere with the cell-mediated immune response by inhibiting lymphocyte expression in response to antigen, by inhibiting release of pathological mediators from sensitized lymphocytes, and by inhibiting the killing of target cells by such lymphocytes. Various assays which depend upon the measurement of some function of the immunologically competent lymphocyte can be used to demonstrate that the prostaglandin analogs of this invention are similarly active. For example, the release of lymphokines (proteins that are agents of inflammation and tissue destruction) from sensitized lymphocytes in culture is strongly inhibited by these analogs in low concentrations. Thus, it is apparent that the compounds of this invention are applicable to the treatment of those autoimmune diseases in whose pathogenesis a cell-mediated immune reaction is involved. Such diseases range from contact dermatitis to such chronic destructive diseases as rheumatoid arthritis and possibly multiple sclerosis and systemic lupus erythematosus. The present prostaglandin analogs are also effective in preventing the rejection of transplanted organs. The biochemical basis for this action is the same as outlined in the preceding paragraph, for the rejection of organ grafts is considered to be predominantly a cell-mediated immune phenomenon and the hallmark of organ rejection is the infiltration of cytotoxic lymphocytes into the graft. Direct evidence that the compounds of this invention can retard or prevent transplant rejection has been obtained in the rat renal allograft model; in this system, administration of the compounds of the present invention prevents the rejection of the transplanted kidney and the subsequent death of the host rat, which events invariably occur in the cases of untreated rats or those treated with immunosuppressants. An example of a compound which is an effective regulator of immune responses of the types described above is 8-acetyl-12-hydroxyheptadecanoic acid. Because of their biological activity and ready accessibility, the compounds of the invention are also useful in that they permit large scale animal testing useful and necessary to understanding of these various disease conditions such as dwarfism caused by poorly-functioning pituitary glands, stroke (thrombus formation), and the like. It will be appreciated that not all of the compounds of this invention have these biological activities to the same degree but the choice of any particular ones for any given purpose will depend upon several factors including the disease state to be treated. The compounds of this invention can be administered either topically or systemically, i.e., intravenously, subcutaneously, intramuscularly, orally, rectally, or by aerosolization in the form of sterile implants for long action. They can be formulated in any of a number of pharmaceutical compositions and non-toxic carriers to this end. The pharmaceutical compositions can be sterile, injectable suspensions or solutions, or solid orally-administrable, pharmaceutically-acceptable tablets or capsules; the compositions can also be intended for sublingual administration, or for suppository use. It is especially advantageous to formulate compositions in dosage unit forms for ease and economy of administration and uniformity of dosage. "Dosage unit form" as a term used herein refers to physically discrete units suitable as unitary dosages for animal and human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired biological effect in association with the required pharmaceutical means. Illustratively, a sterile injectable composition can be in the form of aqueous or oleagenous suspensions or solutions. The sterile injectable composition can be aqueous or oleagenous suspension or solution. Suspensions can be formulated according to the known art using suitable dispersing and wetting agents and suspending agents. Solutions are similarly prepared from the salt form of the compound. For the laboratory animals, we prefer to use incomplete Freund's adjuvant or sterile saline (9%) as carrier. For human parenteral use, such as intramuscularly, intravenously, or by regional perfusion, the diluent can be a sterile aqueous vehicle containing a preservative; for example, methylparaben, propylparaben, phenol, and chlorobutanol. The aqueous vehicle can also contain sodium chloride, preferably in an amount to be isotonic; as well as a suspending agent, for example, gum arabic, polyvinyl pyrrolidone, methyl cellulose, acetylated monoglyceride (available commercially as Myvacet from Distillation Products Industry, a division of Eastman Kodak Company, monomethyl glyceride, dimethyl glyceride or a moderately high molecular weight polysorbitan (commercially available under the tradenames Tween or Span from Atlas Powder Company, Wilmington, Del.). Other materials employed in the preparation of chemotherapeutic compositions containing the compound may include glutathione, 1,2-propanediol, glycerol and glucose. Additionally, the pH of the composition is adjusted by use of an aqueous solution such as tris(hydroxymethyl)aminomethane (tris buffer). Oily pharmaceutical carriers can also be used, since they dissolve the compound and permit high doses. Many oily carriers are commonly employed in pharmaceutical use, such as, for example, mineral oil, lard, cottonseed oil, peanut oil, sesame oil, or the like. It is preferred to prepare the compositions, whether aqueous or oils, in a concentration in the range of from 2-50 mg./ml. Lower concentrations require needless qualities of liquid. Higher concentrations than 50 mg./mg. are difficult to maintain and are preferably avoided. Oral administration forms of the drug can also be prepared for laboratory animals or human patients provided that they are encapsulated for delivery in the gut. The drug is subject to enzymatic breakdown in the acid environment of the stomach. The same dosage levels can be used as for injectable forms; however, even higher levels can be used to compensate for biodegradation in the transport. Generally, a solid unit dosage form can be prepared containing from 0.5 mg. to 25 mg. active ingredient. Whatever the mode of administration, doses in the range of about 0.10 to 20 milligrams per kilogram of body weight administered one to four times per day are used. The exact dose depending on the age, weight, and condition of the patient, and the frequency and route of administration. The low cost and ready accessibility of the compounds of this invention make them particularly promising for applications in veterinary medicine in which field their utilities are comparable to those in human medicine. In preparing the new chemical compounds with which this invention is concerned, we have found it desirable to use as starting materials compounds which are readily available commercially in any desired amounts. There are a number of inter-related processes useful in preparing the compounds of formula I. These can all be described as the sub-synthesis of each of the three main moieties of the molecule (i.e., the (CH.sub.2).sub.4 A-R chain, ##STR4## and the R' group; all attached to the asymmetric carbon atom and then their reaction(s) to form the desired end product. Although not all compounds can be prepared by each process, there is much overlapping so that many compounds can be prepared by one, two, or three of these processes. Certain variant processes are involved and each variant of the main processes will be discussed in relation to the specific compound or compounds produced. One major process which can be used to prepare the compounds of this invention is the "acetoacetic ester process". This is used to yield compounds of formula I when R' is acetyl or (following optional variant procedures) 1-hydroxyethyl and 1-hydroxy-1-methylethyl, and R, A, Z, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined in formula I. The starting material is a lower alkyl ester of acetoacetic acid, ##STR5## wherein R.sup.10 is a lower alkyl group having 1-5 carbon atoms and is preferably tert-butyl. However, when reagents VII B or VII C are employed, as discussed infra, to prepare compounds of formula I wherein Z is vinylene or ethynylene, R.sup.10 must be methyl or ethyl. The starting compound IV is then treated with an equivalent of base such as sodium hydride, sodium ethoxide, sodium amide, or the like. The enolate anion thus produced is alkylated with a compound of the formula: Compound VI can then be treated with an equimolar amount of base such as NaH, NaOC.sub.2 H.sub.5, or NaNH.sub.2 and then alkylated with any one of the following reagents VII A, VII B, VII C or VII D: ##STR7## wherein X is halogen, preferably chlorine or bromine, Z' is methylene, ethylene, trimethylene, and tetramethylene, R.sup.4 and R.sup.5 are as defined for formula I, R.sup.12 is hydrogen, lower alkyl of 1-4 carbon atoms, straight or branched, and 2,2,2-trifluoroethyl. In intermediates VII C, when R.sup.12 is lower alkyl and R.sup.2 is methyl, they can be joined together to form a carbocyclic ring with from 6 to 9 members. Also in VII C, when R.sup.12 is lower alkyl and R.sup.2 is hydrogen, R.sup.12 can be joined to the carbon atom bearing R.sup.2 to form a carbocyclic ring with from 5 to 8 members. Whichever of the four reagents VII are employed, the reactant compounds are employed in approximately equimolar amounts. A solvent is employed such as dimethylformamide, dimethylformamide-benzene (1:1), or diglyme. The temperature of the reaction is between 60.degree. and 120.degree. C. The reaction is completed within 12-72 hours. The various intermediate products obtained, that is, ##STR8## are then further treated as follows to yield the final product I. For instance, compound VIII A in which R.sup.10 is tert-butyl, is heated in solution (preferably higher boiling inert solvents are used, i.e., toluene or xylenes) with a trace of acid to effect elimination and decarboxylation. This process yields the intermediate compound IX: ##STR9## which is submitted to mild basic hydrolysis (preferably a dilute solution of NaOH in aqueous methanol or ethanol) to yield compounds of formula I. Further, compound VIII A in which R.sup.10 is a primary or secondary lower alkyl group (e.g., methyl, ethyl, or butyl) can be subjected to basic hydrolysis to effect cleavage of the ester linkages and decarboxylation and to obtain compounds of formula I, i.e., X: ##STR10## The compound VIII B (in which R.sup.10 must be a primary or secondary lower alkyl group, i.e., methyl, ethyl, or butyl), is submitted to basic hydrolytic conditions to effect hydrolysis and decarboxylation and obtain compounds of formula I, i.e., XI: ##STR11## The compound VIII C (in which R.sup.10 must be a primary or secondary lower alkyl group, i.e., methyl, ethyl, or butyl) is submitted to basic hydrolytic conditions to effect hydrolysis and decarboxylation and obtain compounds of formula I, i.e., XII: ##STR12## Catalytic hydrogenation of compounds XII produces compounds of formula I, i.e., XIII: ##STR13## In the case of compound VIII D, if R.sup.10 is tert-butyl, the compound is first heated in an inert solvent with a trace of acid to effect elimination and decarboxylation and obtain compound XIV: ##STR14## The compound XIV is hydrated by the oxymercuration-demercuration process in which XIV is treated with mercuric acetate in aqueous tetrahydrofuran for a prolonged period to effect oxymercuration followed by treatment of the reaction mixture with sodium borohydride to effect demercuration. The product of this process is compound XV: ##STR15## Mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the ester function of compound XV yields compounds of formula I, i.e., XVI: ##STR16## In the case of compound VIII D, if R.sup.10 is a primary or secondary alkyl group, the compound is first subjected to basic hydrolysis to cleave ester linkages and effect decarboxylation and yield compound XVII: ##STR17## The compound XVII is hydrated by the oxymercuration-demercuration process described above to yield compounds of formula I, i.e., XVI. It should be pointed out that the exact order of reacting compound IV with compound V or any of compounds VII is not critical; either V or VII can be the first reactant. Subsequently, the other of the reactants is reacted with the recovered intermediate. The order described above is our preferred route, however. Another major route useful in preparing compounds of this invention is the Malonic Ester Process. This process is used to prepare a sub-group (formula XVIII) of compounds of formula I wherein ##STR18## R.sup.13 is propionyl, formyl, hydroxyacetyl, or hydroxymethyl, or following subsequent reactions, where R.sup.13 is 1-hydroxyethyl or 1,2-dihydroxyethyl; and R, A, Z', R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined previously. This process utilizes as starting material di-tert-butyl malonate. This ester is alkylated first with compound V and then with either of compounds VII A or VII D. The basic reagents used and the reaction conditions for these alkylations are essentially the same as in the alkylations described in the acetoacetic ester process. At this point, the compounds XIX and XX are obtained: ##STR19## Either of these compounds is heated in an inert solvent with a trace of acid to effect elimination of isobutylene and decarboxylation. Compounds XXI and XXII are obtained, respectively: ##STR20## In turn, either of these compounds is heated with thionyl chloride at 60.degree. to 120.degree. C. for 2 to 6 hours in an inert solvent (e.g., benzene, toluene) to yield the acid chloride intermediates XXIII and XXIV: ##STR21## The compounds XXIII and XXIV are key intermediates in that a variety of R.sup.13 groups can be introduced by the reaction of reagents with the chlorocarbonyl functional group. (1) To prepare compounds where R.sup.13 is propionyl, intermediates XXIII and XXIV are made to react with diethylcadmium. (2) To prepare compounds where R.sup.13 is hydroxymethyl, the chlorocarbonyl function is reduced with sodium borohydride in a suitable non-protic solvent such as diglyme. (3) To prepare compounds where R.sup.13 is formyl, the chlorocarbonyl function is reduced with lithium tri-tert-butoxyaluminum hydride. (4) To prepare compounds where R.sup.13 is hydroxyacetyl, the intermediate XXIII or XXIV is treated with diazomethane in ether to obtain the diazomethyl ketone which on acid hydrolysis (2N H.sub.2 SO.sub.4 in dioxane, preferably) gives the hydroxy-acetyl-substituted compound. When any of these derivatives are prepared from XXIV, a hydration step is needed in which the elements of water are added across the double bond. This is effected by the oxymercuration-demercuration process described previously. A final step in the preparation of the compounds of this invention is basic hydrolysis (sodium hydroxide, preferably, in methanol and ethanol) to hydrolyze the protecting ester functions and obtain compounds of formula I, i.e., XXV: ##STR22## It is frequently advantageous from a therapeutic standpoint to prepare compounds of this invention (formula I) in which the asymmetric carbon atom which bears R.sup.2 and OR.sup.3 is exclusively in the R or S configuration. The compounds of the instant invention, in which the C.sub.12 carbon is in the S-configuration, have greated biological activity than those in which the C.sub.12 -carbon is in the R-configuration. The relative biopotency of either isomer is readily determined in any particular instance by use of the in vitro or in vivo assays referred to hereinabove. In our series of 11,12-secoprostaglandins, compounds exclusively R or S at this center can be produced by employing in the acetoacetic or malonic processes, intermediates VII A or VII B which are optically active, i.e., resolved into their R and S isomeric forms. We have found it particularly advantageous to employ an optically active reagent VII E: ##STR23## in which R.sup.2 and R.sup.12 are as defined previously and the carbon atom marked with an asterisk is exclusively in either the R or S configuration. The use of VII E in the acetoacetic ester process gives intermediates VIII E: ##STR24## in which R.sup.10 must be a primary or secondary lower alkyl group, i.e., ethyl or methyl. Basic hydrolysis of intermediates VIII E accompanied by decarboxylation give products of formula I, i.e., XII A, in which the carbon bearing R.sup.2 and OH ##STR25## is exclusively in the R or S configuration. Catalytic hydrogenation of products XII a gives compounds of formula I, i.e., XIII a in which ##STR26## the carbon atom bearing R.sup.2 and OH is likewise exclusively in either the R or S configuration. A third, major process for preparing compounds of this invention is termed the "Wittig route" since a key step therein involves the condensation of a triphenyl phosphorane with a ketone. This process permits the preparation of compounds of formula I in which Z is ethylene, R.sup.2 and R.sup.3 are hydrogen and R, A, R.sup.1, R.sup.4, and R.sup.5 are defined as in formula I except when R.sup.1 is hydroxyacetyl or 1,2-dihydroxyethyl. The starting materials for this process are acid halides of the following formula: ##STR27## wherein R.sup.11 is a lower alkyl group having 1-5 carbon atoms, preferably methyl or ethyl, and X is a halogen, preferably chloro. Compounds of formula XXVI are allowed to react with the anions derived from a lower alkyl ester of acetoacetic acid, ##STR28## wherein R.sup.11 is a lower alkyl group having 1-5 carbon atoms, preferably methyl or ethyl; said anions are generated from reagents of type IV A via treatment with a strong base such as sodium hydride, sodium ethoxide, sodium amide or the like. This process is effected in an inert solvent, preferably benzene, toluene or the like, at a temperature of 0.degree. to 25.degree. for a period ranging from 2 to 24 hours and affords substitution products of formula XXVII: ##STR29## Treatment of compounds XXVII with an alkali metal alkoxide, preferably sodium methoxide, in an alcoholic medium, preferably methanol, at a temperature of about 0.degree. to 25.degree. for a period of 2 to 24 hours yields a .beta.-keto ester of formula XXVIII: ##STR30## Reagents of formula XXVIII are converted to their anions with an equivalent of a strong base such as sodium hydride, sodium amide, sodium methoxide or the like, and allowed to react in an inert solvent, preferably benzene, benzene-dimethylformamide (1:1) or the like, at a temperature ranging from 25.degree. to 120.degree. for a period of 48 to 120 hours and in the presence of a catalyst, preferably sodium iodide, with compounds of the following formula: ##STR31## where X=halogen, preferably chlorine or bromine and Z" is ethylene. The above process provides compounds of formula XXX: ##STR32## Treatment of compounds XXX with dilute aqueous alkali at a temperature ranging from 0.degree. to 40.degree. for a period of 12 to 74 hours followed by acidification and subsequent decarboxylation yields compounds of formula XXXI: ##STR33## The latter are converted to their sodium salts via treatment with a suitable base, preferably sodium hydride or sodium amide, in an inert solvent, preferably hexamethylphosphoric triamide or dimethyl sulfoxide, and allowed to react at 25.degree. to 140.degree. for 24 to 120 hours with the triphenyl phosphorane (Wittig reagent) derived by treatment of any one of the phosphonium salts represented by formula XXXII with a suitable strong base such as sodium hydride: ##STR34## In compounds XXXII, R.sup.14 is methyl, ethyl, benzyloxyethyl or methoxy and X is a halide, preferably bromide or iodide. The Wittig condensation yields alkenes of formula XXXIII: ##STR35## The latter, except where R.sup.14 is methoxy, are treated with m-chloroperbenzoic acid in methylene chloride at 0.degree.-5.degree. to yield oxiranes of the type represented by formula XXXIV: ##STR36## These compounds are then treated with boron trifluoride etherate in an inert solvent, preferably ether or the like, at 0.degree.-5.degree. C. to yield intermediate compounds XXXV: ##STR37## wherein R.sup.14 is methyl, ethyl, or benzyloxyethyl. Following removal of the benzyl blocking group by catalytic hydrogenolysis using hydrogen over palladium on charcoal, the following final products of structural formula I are obtained; namely, where R is carboxyl, R.sup.1 is acetyl, propionyl or 3-hydroxypropionyl, Z is ethylene, R.sup.2 and R.sup.3 are hydrogen and A, R.sup.4, and R.sup.5 as defined previously. Additional final products of structural formula I wherein R.sup.1 is 1,3-dihydroxypropyl and R, A, Z, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined above are obtained by selective ketone reduction of compounds of formula XXXV wherein R.sup.14 is 3-benzyloxypropionyl followed by subsequent debenzylation of the resulting carbinol diethers. Final products of structural formula I in which R.sup.1 is acryloyl and R, A, Z, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined above are obtained by exposure of their counterparts in which R.sup.1 is 3-hydroxypropionyl to mild acidic conditions, preferably silicic acid. Treatment of compounds of formula XXXIII wherein R.sup.14 is methoxy under acidic conditions followed by catalytic debenzylation provides final products of formula I in which R.sup.1 is formyl and R, A, Z, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined above. The directly obtained products of the acetoacetic, malonic and Wittig processes described supra can be derivatized in a variety of ways to yield other products of formula I. 1. The fundamental processes yield compounds where R is carboxy. To obtain carboxy salts the acid products are dissolved in a solvent such as ethanol, methanol, glyme and the like and the solution treated with an appropriate alkali or alkaline earth hydroxide or alkoxide to yield the metal salt, or with an equivalent quantity of ammonia, amine or quaternary ammonium hydroxide to yield the amine salt. In each instance, the salt either separates from the solution and may be separated by filtration, or, when the salt is soluble it may be recovered by evaporation of the solvent. Aqueous solutions of the carboxylic acid salts can be prepared by treating an aqueous suspension of the carboxylic acid with an equivalent amount of an alkaline earth hydroxide or oxide, alkali metal hydroxide, carbonate or bicarbonate, ammonia, an amine or a quaternary ammonium hydroxide. To obtain carboxy esters (i.e., compounds where R is alkoxycarbonyl) the acid products are treated in ether with an ethereal solution of the appropriate diazoalkane. For example, methyl esters are produced by reaction of the acid products with diazomethane. To obtain products where R is carbamoyl, substituted carbamoyl or carbazoyl the acid product is first converted to an active Woodward ester. For example, the acid product can be made to react with N-tert-butyl-5-methylisoxazolium perchlorate in acetonitrile in the presence of a base such as triethylamine to yield an active ester in which R is ##STR38## Active esters of this type can be reacted with ammonia to yield products of formula I where R is carbamoyl, with primary or secondary amines or di-lower-alkylaminoalkylamines to yield products where R is substituted carbamoyl, i.e, --CONR.sup.6 R.sup.7, and with hydrazine to yield products where R is carbazoyl. 2. The fundamental processes yield products where R.sup.3 is hydrogen. In compounds containing no additional hydroxy group and in which R.sup.2 is hydrogen, reaction with formic acid, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, pivalic anhydride and the like, without solvent and at temperatures from 25.degree. to 60.degree. C., gives compounds wherein R.sup.3 is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, and pivaloyl, respectively. 3. It is to be noted that in the carboxylic acid products of the fundamental processes, R' is acyl; that is, R' contains a ketone or aldehyde carbonyl group; this group can be reduced to an alcoholic functional group by the action of sodium or potassium borohydride. The following transformations are hereby effected in R': acetyl becomes 1-hydroxyethyl, hydroxyacetyl becomes 1,2-dihydroxyethyl, formyl becomes hydroxymethyl, and 3-hydroxypropionyl becomes 1,3-dihydroxypropyl. This reduction can be advantageously carried out by dissolving the acyl-containing compound in an aqueous or alcoholic solution of a base such as sodium hydroxide, sodium bicarbonate and the like and adding a 20 to 100% excess of sodium or potassium borohydride. The reaction is allowed to proceed at a temperature of from 20.degree. to 60.degree. for a period of 2 to 24 hours. 4. A related useful method of derivatization consists of treatment of the products of the fundamental processes with a large excess of a Grignard reagent, for example, methylmagnesium bromide. The carbonyl group of R' is thereby converted to an alcohol functional group. The following transformations in R' take place, for example, with methylmagnesium bromide: acetyl becomes 1-hydroxy-1-methylethyl; propionyl becomes 1-hydroxy-1-methylpropyl; formyl becomes 1-hydroxyethyl. In addition, products of the fundamental processes where R' is formyl, acetyl or propionyl and R.sup.2 is hydrogen can be treated with an oxidizing agent, for example, chromium trioxide, to oxidize the secondary alcoholic functional group (--C(R.sup.2)(OH)--) to a ketone carbonyl functional group. The resulting diketone is treated with a large excess of Grignard reagent, for example, methylmagnesium bromide. The Grignard reagent reacts at both ketone carbonyl groups. For example, when methylmagnesium bromide is employed, a methyl R.sup.2 group is introduced and R', if acetyl, is transformed to 1-hydroxy-1-methylethyl. 1. The reagents VII A which have the following general formula wherein X, Z', R.sup.4 and R.sup.5 are as described previously are prepared by two related processes: ##STR39## a. When Z' is methylene, a Grignard reagent R.sup.5 --(CH.sub.2).sub.2 --C(R.sup.4).sub.2 --MgBr(or I) is allowed to react in ether or tetrahydrofuran with 3-chloro- or 3-bromopropional-dehyde to give, after hydrolysis, the alcohols X--CH.sub.2 CH.sub.2 CH(OH)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.5. Treatment of the alcohols with acetyl chloride or preferably acetic anhydride with or without an inert solvent and at 25.degree.-100.degree. C. gives the reagents VII A where Z' is methylene. b. When Z' is ethylene, trimethylene or tetramethylene, a Grignard reagent R.sup.5 --(CH.sub.2).sub.2 --C(R.sup.4).sub.2 --MgBr(or I) is allowed to react in ether or tetrahydrofuran with a nitrile X--CH.sub.2 --Z'--CN. The immediately resulting imine is hydrolyzed in aqueous acidic solution to give ketones of the formula X--CH.sub.2 --Z'--C(.dbd.O)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.5. The ketones are reduced to the alcohols X--CH.sub.2 --Z'--CH(OH)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.5 with sodium or potassium borohydride in a suitable solvent such as methanol, ethanol or diglyme. Acetylation of these alcohols preferably with acetic anhydride as described previously gives the reagents VII A where Z' is ethylene, trimethylene, or tetramethylene. A variant of this process that is particularly useful when both R.sup.4 groups are methyl consists in reacting Grignard reagents R.sup.5 --(CH.sub.2).sub.2 --C(CH.sub.3).sub.2 --MgCl with acid chlorides X--CH.sub.2 Z'--C(.dbd.O)--Cl. The resulting ketones X--CH.sub.2 --Z'--C(.dbd.O)--C(CH.sub.3).sub.2 --(CH.sub.2).sub.2 --R.sup.5 are reduced to the alcohols X--CH.sub.2 --Z'--CH(OH)--C(CH.sub.3).sub.2 --(CH.sub.2).sub.2 --R.sup.5 with sodium or potassium borohydride and acetylated with acetic anhydride to give the reagents VII A where Z' is ethylene, trimethylene or tetramethylene. 2. The reagents VII B which have the following general formula wherein R.sup.4 and R.sup.12 are as described previously are prepared as follows: ##STR40## A Grignard reagent R.sup.12 --(CH.sub.2).sub.2 --C(R.sup.4).sub.2 MgBr(or I or Cl) is allowed to react with crotonaldehyde to give, after hydrolysis, the alcohols CH.sub.3 CH.dbd.CH--CH(OH)--C(R.sup.4).sub.2 (CH.sub.2).sub.2 --R.sup.12. These alcohols are acetylated, preferably with acetic anhydride without solvent at 30.degree.-100.degree. C. for 2-12 hours, to give the intermediates CH.sub.3 CH.dbd.CH--CH(OCOCH.sub.3)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.12. These intermediates are allowed to react with N-bromosuccinimide in chloroform at 50.degree.-70.degree. C. for 2.5 to 5 hours to effect allylic bromination and give the reagents of formula VII B. 3. The reagents VI C which have the following general formula wherein R.sup.2, R.sup.4 and R.sup.12 are as described previously are prepared as follows: ##STR41## The starting materials for the process are aldehydes (when R.sup.2 is hydrogen) or ketones with the structure R.sup.2 --C(.dbd.O)--C(R.sup.4).sub.2 --R.sup.12. Examples of such aldehydes and ketones are hexanal, 2-methylhexanal, 2-heptanone, and (when R.sup.12 is joined either with R.sup.2 when R.sup.2 is methyl or with the carbon bearing R.sup.2 when R.sup.2 is hydrogen as earlier specified) cyclohexanone or cyclooctanone. Such aldehydes or ketones are caused to react with lithium acetylide or ethynylmagnesium bromide to give alcohols of the structure HC.tbd.C--C(R.sup.2)(OH)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.12. These alcohols are acetylated preferably with acetic anhydride in pyridine solution. The resulting acetates are heated with formaldehyde (preferably introduced in the form of paraformaldehyde) and dimethylamine or diethylamine to give amines (Me).sub.2 N-- or (Et).sub.2 NCH.sub.2 C.tbd.C--C(R.sup.2)(OCOCH.sub.3)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.12. The amines are caused to react with cyanogen bromide preferably in ether solution at 25.degree.-35.degree. C. and for from 8 to 24 hours to give the reagents VI C. The optically active reagents VII E with the following general formula in which R.sup.2, R.sup.4 and R.sup.12 are as defined previously and the carbon atom marked with an asterisk is exclusively in either the R or S configuration are prepared by following exactly the procedures described immediately above. However, it is ##STR42## necessary in these cases to resolve into their R and S enantiomers the alcohols HC.tbd.C--C(R.sup.4) (OH)--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.12 and then carry the R and S enantiomers separately through the remaining steps of the procedure. In a particularly advantageous example the alcohol arising from the reaction of lithium acetylide and hexanal, 1-octyn-3-ol, HC.tbd.C--CHOH--C.sub.5 H.sub.11 is resolved into its enantiomers according to published procedures and these enantiomers according to published procedures and these enantiomers converted to the R and S enantiomers of compound of formula VII E, i.e., BrCH.sub.2 C.tbd.C--CH(OCOCH.sub.3)--C.sub.5 H.sub.11. The employment of these optically active reagents in the acetoacetic ester process gives rise to optically active products of formula I, i.e., ##STR43## where the resolved asymmetric carbon atom is marked with an asterisk. Hydrogenation of such products give rise to further optically active products of formula I, i.e., ##STR44## 4. The reagents VII D which have the following general formula wherein X, Z' and R.sup.12 are as ##STR45## described previously are prepared as follows: A grignard reagent R.sup.12 (CH.sub.2).sub.2 CH.sub.2 MgBr or R.sup.12 (CH.sub.2).sub.2 CH.sub.2 MgI is allowed to react with haloketones XCH.sub.2 --Z'--C(.dbd.O)CH.sub.3 to give, after hydrolysis, the tertitary alcohols X--CH.sub.2 Z'--C(OH)(CH.sub.3)--CH.sub.2 (CH.sub.2).sub.2 R.sup.12. These alcohols can be dehydrated by treatment with a variety of acidic reagents and with heat to give the reagents VII C. A preferred method of dehydration involves acetylation of the alcohols with acetic anhydride, and then heating the resulting esters in an inert solvent (benzene, toluene or the like) at from 80.degree. to 140.degree. in the presence of a trace of an acid such as sulfuric or p-toluenesulfonic acid to effect elimination of acetic acid. 5. The preparation of reagents of formula V has been described in the scientific and patent 6. The reagents of formula XXVI ##STR46## wherein R.sup.11, A and X are as previously defined, can be conveniently prepared from reagents V (see preceeding section, 5) via conversion of V to the 2-substituted dithianes: ##STR47## employing 2-lithiodithiane in an inert solvent, preferably ether or tetrahydrofuran, at a temperature of -78.degree. to -20.degree. for a period of 2 to 24 hours. Oxidative cleavage of the latter in an inert aqueous medium provides half acids HOOC--(CH.sub.2).sub.4 --A--COOR.sup.11 which are transformed to reagents of formula XXVI employing suitable acid halide forming reagents which can be used without a solvent, preferably oxalyl or thionyl chloride, at 20.degree. to 100.degree. for a period of 1 to 15 hours. 7. The reagents illustrated by formula XXIX ##STR48## in which R.sup.4, R.sup.5, Z" and Z are as previously defined in the section describing the Wittig route, are readily prepared by the following transformations. Condensation of the Grignard reagents BrMg--C(R.sup.4).sub.2 --(CH.sub.2).sub.2 --R.sup.5 with 3-chloropropionaldehyde provides alcohols ##STR49## which may be reacted, without solvent, with s-trioxane and dry hydrogen chloride (g) at temperatures of -10.degree. to 20.degree. for a period of 2 to 12 hours to yield chloromethyl ethers: ##STR50## The latter, upon metathesis with phenylmagnesium bromide in an inert solvent, preferably benzene, ether or tetrahydrofuran, at a temperature of 0.degree. to 40.degree. for 2 to 24 hours, provide reagents XXIX. 8. The phosphonium salts of formula XXXII Methods for obtaining optical antipodes of the compounds of this invention have been described supra [sections dealing with malonic acid process and preparation of intermediates (4)] whereby one of the components of the molecule is preresolved prior to its assembly into the whole molecule. Other methods also can be employed; for example, mixtures of racemates may be separated by taking advantage of the physiochemical differences between the components using chromatography and/or fractional crystallization. The racemic products and intermediates of this invention can be resolved into their optically active components by any one of a number of methods of resolution which are well described in the chemical literature. Those compounds which are carboxylic acids can be converted to the diastereoisomeric salts by treatment with an optically active base such as + or - .alpha.-methylbenzylamine, + or - .alpha.-(1-naphthyl)-ethylamine, bromine, cinchonine, cinchonidine, or quinine. These diastereoisomeric salts can be separated by fractional crystallization. The carboxylic acids of this invention also can be converted to esters using an optically active alcohol, such as, estradiol-3-acetate, or d- or 1-menthol and the diastereoisomeric esters resolved by crystallization or by chromatographic separation. Racemic carboxylic acids also may be resolved by reverse phase and absorption chromatography using an optically active support and absorbent. Compounds of this invention which contain free hydroxyl groups can be esterified with acid chlorides or anhydrides derived from optically active acids, such as, (+)-10-camphorsulfonic acid, (+)-.alpha.-bromocamphor-.pi.-sulfonic acid, or d- or l-6,6'-dinitrodiphenic acid to form esters which can be resolved by crystallization. Another method of obtaining pure optical isomers involves incubation of the racemic mixture with certain microorganisms such as fungi, by processes well established in the art, and recovering the product formed by the enzymatic transformation. The methods described supra are especially effective if one applies the process to a compund where one asymmetric center has been preresolved by the techniques already described.

Non-Patent Literature Citations (1)
Entry
derwent Abst. 44724 w/27, DT2458-911, Merck & Co., Inc.
Continuation in Parts (3)
Number Date Country
Parent 571038 Apr 1975
Parent 389901 Aug 1973
Parent 302365 Oct 1972