PROSTAGLANDIN COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING PERIPHERAL VASCULAR DISEASE AND PULMONARY HYPERTENSION

Abstract: Prostaglandin and analogs thereof which include protective groups attached to at least one site which are pharmaceutically acceptable and which are capable of slowing the metabolic rate of the active groups for administration to a warm blooded animal for the treatment of peripheral vascular disease and pulmonary hypertension. In fact, Figure 1 graphically shows the effects on pulmonary arterial pressure of a dose of mPEG20kDa-aminde-Compound X, given as an intravenous infusion to a sheep intravenously-induced with a pulmonary hypertensive agent.

Description: PROSTAGLANDIN COMPOUNDS, COMPOSITIONS AND METHODS OF TREAΗNG PERIPHERAL VASCULAR DISEASE AND PULMONARY HYPERTENSION Field of the Invention The present invention relates to modified prostaglandins, specifically long- acting prostaglandin-containing compositions for use in the treatment of peripheral vascular disease and pulmonary hypertension. Background of the Invention Nearly every tissue in the body produces prostaglandins. No other autocoids or hormones show more numerous or diverse effects than prostaglandins. Due to rapid degradation which is most commonly caused by enzymes in the blood and lungs, the effective life of most prostaglandins is only about 3 to 10 minutes. Prostaglandins including prostacyclin, a prostaglandin analog produced by the body and is implicated in maintaining proper function of blood vessels. Natural prostacyclin is inherently unstable, with an effective life of less than about six minutes. Prostaglandins including prostacyclins appear to act in three ways to keep blood vessels functioning properly, 1 ) they dilate blood vessels, where necessary, enabling proper blood flow ; 2) they prevent platelet aggregation; and 3.) it contributes to regulation of proliferation of smooth muscle cells surrounding the vessels, which otherwise would constrict the vessels and obstruct blood flow. Some vascular diseases are characterized by the degradation of lining of the blood-vessel walls, the aggregation of platelets and the disruption of smooth muscle cell function These conditions contribute to the blockages of blood vessels, and affect their ability to provide an unimpeded flow of blood through the circulatory system. Diseases which include one or more of these conditions are peripheral vascular disease and pulmonary hypertension Though each disease affects a specific area of blood vasculature, both diseases are characterized by vasoconstriction wherein the blood vessels undesirably constrict and thereby reduce blood flow, raise blood pressure and vascular resistance In addition, such diseases exhibit a reduction in the production of natural prostaglandins, such as prostacyclin Pulmonary hypertension is a progressive, life-threatening vascular disease that is difficult to diagnose and treat, and is currently incurable It is characterized by elevated pressure in the blood vessels between the heart and lungs, known as the pulmonary blood vessels, but normal blood pressure in the rest of the body The high blood pressure is caused by the narrowing of pulmonary blood vessels A condition which is coincident with reduced production of prostacyclin in the affected blood vessels. Elevated pulmonary blood pressure typically causes a strain on the right side of the heart as the heart works to pump blood to the lungs Patients with early-stage pulmonary hypertension are typically unaware that they have the disease As the disease progresses, however, patients suffer difficulty in breathing, fainting spells and the like making it difficult to carry out normal daily activities Patients with untreated advanced pulmonary hypertension often become disabled and may die from heart failure Traditionally, pulmonary hypertension is thought to consist of two distinct conditions primary pulmonary hypertension and secondary pulmonary hypertension Primary pulmonary hypertension is defined as pulmonary hypertension with no identified specific cause Secondary pulmonary hypertension is defined as pulmonary hypertension with a known cause such as heart lung or liver dysfunction or schleroderma, a disease of the connective tissue The term "pulmonary hypertension" is used herein to include both primary and secondary pulmonary hypertension Thousands of people in the United States have been diagnosed with primary pulmonary hypertension, while even more people have been diagnosed with advanced secondary pulmonary hypertension According to a 1989 report published in "Chest", the official publication of the American College of Chest Physicians, the prevalence of pulmonary hypertension in the U S male population is between 8% and 13% for men between the ages of 35 and 44 It is also reported that the prevalence of pulmonary hypertension in men age 65 and older exceeds 20% Primary pulmonary hypertension and advanced secondary pulmonary hypertension have been shown to be responsive to the presence of prostacyclin When the blood and lymph vessels are affected outside the pulmonary system, the condition is generally referred to as peripheral vascular disease The disease includes, but is not limited to ischemic cerebrovascular disease, arteriovenous fistulas, ischemic leg ulcers, phlebitis, venous insufficiency, gangrene, hepatorenal syndrome, non-patent ductus arteπosus, non-obstructive mesenteric ischemia, arteritis lymphangitis and the like While the precise cause of peripheral vascular disease is unknown, diabetes, obesity, atherosclerosis, smoking, lack of exercise, and cardiovascular disorder are often associated with the disease. In the early stages of the disease, the patient is at first free of symptoms and then experiences mild to severe pain while walking As the disease progresses, the patient experiences leg pain while at rest and suffers from delayed wound healing which sometimes leads to ulcers, gangrene and amputation The mean survival period of late-stage peripheral vascular disease patient is about six years Peripheral vascular disease affects approximately six million people in the United States. Additionally, there are approximately 350,000 new cases of peripheral vascular disease confirmed annually in the United States Peripheral vascular disease is also responsive to the presence of prostaglandins including prostacyclin. Prostaglandins are useful for treating peripheral vascular diseases and pulmonary hypertension in humans because they have a positive effect on blood flow by preventing undesirable constriction of blood vessels However, many prostaglandin and analogs thereof including prostacyclin, have very short effective lives and thus require continuous and sustained treatment to provide effective therapy for the patient. To date, the use of prostaglandins and analogs thereof has been severely limited in the treatment of peripheral vascular disease and pulmonary hypertension because of chemical instability, short effective life and limited modes of administration The short effective life of prostaglandins is due to a) rapid deactivation of the active groups of the molecules by enzymes, and b) their low molecular weight which makes them easily cleared or excreted from the body Prostaglandins have active sites typically in the form of hydroxyl and carboxyl groups. Enzymes can rapidly deactivate the active groups thereby rendering the compound ineffective To overcome the problem, continuous infusion or frequent administration of high doses of prostaglandins have been employed to maintain therapeutically effective levels of the compound in the patient Such dosage regimens, however, are disadvantageous because the treatment is expensive and there is a relatively high possibility of unwanted side effects Some of the side effects include nausea, swelling, gastrointestinal upset, jaw pain, rash, and headaches In some patients severe adverse reactions have required discontinuing of treatment Numerous prostaglandins and analogs thereof such as prostacyclin have been prepared with the goal of discovering pharmaceutically acceptable agents that offer increased stability, a greater range of modes of administration, more effective activity and/or longer effective life Investigators have sought prostaglandins and analogs thereof which can be effectively delivered orally to provide a less invasive and more convenient medical treatment Current oral forms of prostaglandins and analogs thereof typically have an effective life of only up to about 1 5 hours and in some cases only a few minutes The short effective life requires the patient to undertake frequent dosing, and therefore makes administration problematical for the patient, especially those suffering from chronic disease Conjugating biologically-active substances such as proteins, enzymes and the like to polymers has been suggested to increase the effective life, water solubility or antigenicity of the active substance in vivo For example, coupling peptides or polypeptides to polyethylene glycol (PEG) and similar water-soluble polyalkylene oxides (PAO) is disclosed in U S Pat No 4 179,337 the disclosure of which is incorporated herein by reference See also, Nucci M , Shorr RGL and Abuchowski A ," Advanced Drug Delivery Reviews", 6 133-151 1991 , Harris JM (ed.); and "Polyethylene Glycol Chemistry Biotechnical and Biomedical Application", Plenum Press, NY, 1992 Conjugates are generally formed by reacting a therapeutic agent with, for example, a several fold molar excess of a polymer which has been modified to contain a terminal linking group The linking group enables the active substance to bind to the polymer Polypeptides modified in this manner exhibit reduced immunogenicity/ antigenicity and tend to have a higher effective life in the bloodstream than unmodified versions thereof To conjugate polyalkylene oxides with an active substance, at least one of the terminal hydroxyl groups is converted into a reactive functional group This process is frequently referred to as "activation" and the product is called an "activated polyalkylene oxide " Other substantially non-antigenic polymers are similarly "activated" or "functionalized " The activated polymers are reacted with a therapeutic agent having nucleophihc functional groups that serve as attachment sites One nucleophilic functional group commonly used as an attachment site is the e-amino groups of lysines Free carboxyiic groups, suitably activated carbonyl groups oxidized carbohydrate moieties and mercapto groups have also been used as attachment sites Biologically active polymer conjugates can be formed having hydrolyzable bonds (linkages) between the polymer and the parent biologically-active moiety to produce prodrugs (where the parent molecule is eventually liberated in vivo) Several methods of preparing prodrugs have also been suggested Prodrugs include chemical derivatives of a biologically-active parent compound which upon administration, will eventually liberate the active parent compound in vivo Prodrugs are advantageous because they enable modification of the onset and/or duration of action of a biologically-active compound in vivo Prodrugs are often biologically inert or substantially inactive forms of the active compound The rate of release of the active drug is influenced by several factors including the rate of hydrolysis of the linker which joins the biologically active compound to the prodrug carrier (e g polymer) Although prostaglandins and analogs thereof such as prostacyclin hold much promise as therapeutic agents, there is a need to a) improve the stability of such compounds, b) extend the effective life of the compounds and c) enable the compounds to be administered in a more patient friendly dosage regimen than is currently available It would therefore be a significant advance in the art of drug therapy especially for the treatment of peripheral vascular disease and pulmonary hypertension, if prostaglandins and analogs thereof and compositions employing the same can be developed which have improved stability an effective life of sufficient duration to enable administration at a reasonable frequency and in a more patient-friendly manner than current therapies employing prostaglandins and analogs thereof Summary Of The Invention The present invention is generally directed to novel prostaglandin compounds and analogs thereof which possess activity suitable for the treatment of peripheral vascular disease and pulmonary hypertension The present invention provides compounds, compositions and methods of administering the compounds and compositions for the treatment of peripheral vascular disease and pulmonary hypertension The compounds of the present invention have increased chemical stability and effective life, in a warm-blooded animal which improves delivery of the compound for treatment of peripheral vascular disease and pulmonary hypertension in the form of a pharmaceutically acceptable composition Improved stability, effective life and more acceptable modes of administration and dosage regimens are achieved by modifying one or more of the active sites of the known prostaglandin compounds Thus, in one aspect of the present invention one or more active sites of the prostaglandin compounds or analogs thereof of the present invention are provided with a pharmaceutically acceptable group which slows the metabolic rate of the compound. A reduction in the metabolic rate provides an increase in the effective life of the active compound which a) provides a more efficient administration of the active compound, and b) enables a more patient-friendly dosage regimen In another aspect of the present invention there is provided a method of treating a warm-blooded animal exhibiting pulmonary hypertension and/or peripheral vascular disease comprising administering to the animal a therapeutically effective amount of the modified prostaglandin compounds and analogs thereof of the present invention In another aspect of the present invention there is provided a compound having the Formula la or lb as shown below [P— T]— z la P— [T— Z] n lb wherein P is a prostaglandin compound or analog thereof T represents a modified active group of P, Z is a pharmaceutically acceptable group which is bound to T and which slows the metabolic rate of said compound, and n is an integer of at least 1 , and pharmaceutically acceptable salts thereof Brief Description of the Drawings Figure 1 is a graph showing the effects on pulmonary arterial pressure of a dose of mPEG20kDa-amιde-Compound X given as an intravenous infusion to a sheep intravenously-induced with a pulmonary hypertensive agent Figure 2 is a graph depicting the effects of a dose of mPEG20kDa-ester- Compound X, given as an intravenous bolus, on the pulmonary arterial pressure of a sheep intravenously-induced with a pulmonary hypertensive agent, Figure 3 is a graph depicting the effects of a dose of mPEG20kDa-ester- Compound X, given as an aerosol, on the pulmonary arterial pressure of a sheep intravenously-induced with a pulmonary hypertensive agent, Figure 4 is a graph depicting the effects of a dose of mPEG20kDa-ester- Compound X, given as an intravenous bolus, on the pulmonary arterial pressure of a sheep intravenously-induced with a pulmonary hypertensive agent, and Figure 5 is a graph showing the effects of mPEG5kDa-ester-Compound X and native Compound X, each administered in the form of an aerosol on the pulmonary arterial pressure of respective sheep intravenously-induced with a pulmonary hypertensive agent Detailed Description of the Invention The present invention is directed to novel prostaglandins and analogs thereof in which at least one active site has attached thereto an inert, non-antigenic, non- immunogenic group having a structure which protects the active site when administered to a warm-blooded animal including humans and therefore provides a longer effective life for the compound As a result more of the compound is available for treating vascular disease by being present to treat the target area (e g afflicted tissue and vasculature regions, such as the pulmonary artery) for a longer period of time Because more of the active compound is available, dosage regimens may be less burdensome to the patient As used herein the term "effective life" shall mean the time period during which the present compounds are in their active form in a warm-blooded animal The protection of at least one active group generally increases the effective life of the prostaglandin compounds and therefore makes them more suitable for various modes of administration as compared to native or unprotected forms of the prostaglandin compounds As used herein the term "prostaglandin compounds and analogs thereof", hereinafter collectively referred to as "prostaglandin compounds", shall mean all prostaglandin compounds, and variations thereof which have at least one active group, (e.g., a COOH group and/or an OH group) and which are at least minimally effective for the treatment of peripheral vascular disease and pulmonary hypertension in warm-blooded animals As used herein, the term "present prostaglandin compounds" shall refer to prostaglandin compounds as defined, which have been modified in accordance with the present invention As used herein, the term "active group" shall mean a site on the prostaglandin compound, which is capable of binding to or otherwise engaging a targeted tissue such as vascular tissue. The present invention includes present prostaglandin (PG) compounds of all types. For example, the present prostaglandin compounds employed in the present invention include modified PGA, PGB, PGC, PGD, PGE, PGF, and PGI type compounds as well as all subtypes of the foregoing The prostaglandin compounds can be isolated or extracted from a warm-blooded animal source or prepared synthetically by techniques known to those of ordinary skill in the art Preferred present prostaglandin compounds are represented by Formula II wherein Z, and Z 2 are independently selected from hydrogen and the groups previously defined for Z in Formula I, with the proviso that at least one of Z, and Z 2 is not hydrogen; and X is selected from O or NH More highly preferred compounds of Formula II are compounds of Groups 1 , 2 and 3 as defined below, wherein for the Group 1 compounds Z 1 is a pharmaceutically acceptable polymer which binds to X and slows the metabolic rate of the compound, and X is selected from O and NH, and Z 2 is selected from H and an acetyl group, for the Group 2 compounds Z., is hydrogen, X is O, and Z 2 is a pharmaceutically acceptable polymer which slows the metabolic rate of the compound and is attached to the oxygen through an ester group; and for the Group 3 compounds. Z 1 is a pharmaceutically acceptable polymer as defined in Group 1 , X is 0 or NH, and Z 2 is a pharmaceutically acceptable polymer as defined in Group 2, attached to the oxygen through an ester group Preferred compounds are also represented by Formula wherein Z and Z 2 include the same groups as previously defined in Formula II; f is an integer of from 1 to 3; X is selected from O and NH; and R is selected from hydrogen and an alkyl group preferably having 1 -6 carbon atoms More highly preferred compounds of Formula III are compounds of Groups 4. 5 and 6, wherein: for the Group 4 compounds: Z., is a pharmaceutically acceptable polymer which binds to X and slows the metabolic rate of the compound; X is selected from O and NH, and Z 2 is selected from hydrogen and an acetyl group; for the Group 5 compounds. Z-, is hydrogen, X is O, and Z 2 is an acetyl group, or a pharmaceutically acceptable polymer which slows the metabolic rate of the compound and is attached to the oxygen through an ester or ether group, for the Group 6 compounds: Z, is a pharmaceutically acceptable polymer as defined in Group 4, X is selected from 0 and NH, and Z 2 is a pharmaceutically acceptable polymer as defined in Group 5 Highly preferred compounds are those where the Z 1 and/or Z 2 groups are polyethylene glycols having the formula CH 3 OCH 2 CH 2 (OCH 2 CH 2 ) a , wherein a is from 1 to about 1000 A particularly preferred group of present prostaglandin compounds are those having the Formula IV wherein a and X are as defined above. Preferably a is from about 6 to 600 most preferably from about 6 to 460. The present invention also provides a method of treating a warm-blooded animal afflicted with vascular disease including peripheral vascular disease and/or pulmonary hypertension comprising administering to the warm-blooded animal an effective amount of a compound of Formula I Compositions containing said compounds which are suitable for administration to warm-blooded animals for said purposes are part of the present invention Peripheral vascular disease is characterized by decrease in blood flow to the legs and feet with accompanying ischemia Deposition of plaque on the inner lining of the blood vessels and the progressive thickening and hardening of major arteries is characteristic of this disorder. Organic peripheral vascular disease is also accompanied by inflammation and tissue damage Chronic mild to severe pain, loss of mobility, gangrene, ischemic ulcers, delayed wound healing and loss of limbs is typically associated with peripheral vascular disease Pulmonary hypertension is characterized by narrowing of the blood vessels in the lungs and dangerously high blood pressure of the pulmonary arteries Abnormal interaction between the endothelial cells and the smooth muscle cells cause the smooth muscle to contract is characteristic of this disorder Organic pulmonary hypertension is also accompanied by inflammation and tissue damage producing scar tissue which further narrows the blood vessels and thickens the walls. Chronic mild to severe pain, loss of mobility, eventual failure of the heart and death is associated with pulmonary hypertension Both vascular diseases are characterized by abnormal constriction of blood vessels causing decrease in blood flow and increase in vascular resistance Administration of present prostaglandin compounds to a patient afflicted with peripheral vascular disease, promotes increased blood flow through the afflicted blood vessels and thereby increases oxygenation of ischemic tissue Furthermore anti-platelet aggregatory and cytoprotective activities of the present prostaglandin compounds is believed to promote healing by inhibiting inflammatory response in damaged tissue With regard to pulmonary hypertension, it is believed that vasodilation is triggered by the present prostaglandin compounds and results in the relaxation of smooth muscle in the small arteries in the lungs the lowering of the diasto c blood pressure, the prevention of clot formation, and the reversing of scarring in the lungs In combination, these effects induce a substantial drop in pulmonary arterial pressure and pulmonary vascular resistance Furthermore as in the case with peripheral vascular disease, the inherent anti-platelet aggregation and cytoprotective activities of the present prostaglandin compounds are also believed to promote healing by inhibiting the inflammatory response in the damaged tissue In one aspect of the present invention, one or more of the active groups of the present prostaglandin compounds (e g , COOH and OH) are attached to linear, branched and/or circular polymers and copolymers which are inert, non-antigenic and non-immunogenic In addition, the polymers must be capable of separating from the present prostaglandin compounds at a rate which is suitable for delivering the present prostaglandin compounds to the target area of the warm-blooded animal To the extent that any of the polymer remains attached to the prostaglandin compound, it should not adversely affect the treatment of peripheral vascular disease and pulmonary hypertension To conjugate the prostaglandin to polymers such as polyalkylene oxides one or more of the hydroxyl groups of the polymer is converted into a reactive functional group which allows conjugation The activated polymers are reacted with the prostaglandin compound so that attachment preferably occurs at the free carboxyhc acid groups and/or hydroxyl groups Suitably activated carbonyl groups, oxidized carbohydrate moieties and mercapto groups if available or made available on the prostaglandin compound can also be used as conjugation sites In a preferred aspect of the invention, amide or ester linkages are formed between the carboxyhc or hydroxyl groups and the activated polyalkylene oxides Polymers activated with urethane-forming linkers or the like, and other functional groups which facilitate attachment of the polymer to the prostaglandin compound via carboxyhc or other groups are encompassed by the present invention Among the substantially non-antigenic polymers, polyalkylene oxides (PAO's) especially mono-activated, alkyl-terminated polyalkylene oxides such as polyethylene glycols (PEG) and especially monomethyl-terminated polyethylene glycols (mPEG's) Bis-activated polyethylene oxides are also contemplated for purposes of cross-linking the prostaglandin compound or providing a means for attaching other moieties such as targeting agents for localizing the polymer- prostaglandin conjugate in the target area such as, for example, the lungs or blood vessels in the extremities Suitable polymers especially PEG or mPEG, will vary substantially by weight Polymers having molecular weights ranging from about 200 to about 80,000 daltons are typically employed in the present invention Molecular weights from about 2,000 to 42,000 daltons are preferred, and molecular weights of from about 5,000 to 28,000 daltons are particularly preferred The polymers preferably employed in the present invention as protective groups are water-soluble at room temperature A non-limiting list of such polymers include polyalkylene oxide homopolymers such as PEG and mPEG or polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof. In addition to mPEG, C |.4 alkyl-terminated polymers are also useful As an alternative to PAO-based polymers, effectively non-antigenic materials such as dextran, polyvinyl pyrrohdones, polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and the like can be used Modifications of the prostaglandin compounds may further include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, pidation, and acylation Those of ordinary skill in the art will realize that the foregoing list is merely illustrative and that all polymer materials having the qualities herein are contemplated The prostaglandin compounds are coupled to the protective groups as described to provide present prostaglandin compounds which effectively deliver the active compound to the target area and maintain the present prostaglandin compound within the target area for a longer period of time than achieved with known prostaglandin compounds The present prostaglandin compounds are therefore particularly suited for the treatment of peripheral vascular disease and pulmonary hypertension. As previously indicated, many of the known prostaglandin compounds which are used in peripheral vascular disease and pulmonary hypertension therapy have a very short effective life in a warm blooded animal, typically less than one hour In accordance with the present invention, present prostaglandin compounds are provided which have an improved effective life which may last up to several hours A longer effective life may reduce the number of times that the present prostaglandin compound may be administered and may therefore enable the present prostaglandin compounds to be delivered in lower dosage unit amounts and with less frequency. The active groups of the present prostaglandin compounds include COOH and OH groups One or more of these active groups are protected by a protective group as more specifically set forth hereinafter The protective groups may generally have a molecular weight of up to 500,000 or more In a preferred form of the invention, a group having a molecular weight of at least 5,000 daltons should be 11 conjugated to the COOH when the OH groups are not protected, more preferably at least 20,000 daltons It has also been observed that protective groups of molecular weight of at least 5,000 daltons can slow excretion of the compounds, thereby contributing to increased effective life in a warm blooded animal The protective groups are any groups which serve to protect the active groups (COOH and OH) from premature metabolism but can readily separate from the active groups in a controlled manner and/or may be attached to the active group without adversely affecting the function of the compound Such protective groups include, for example, polymers, straight and branched chain alkyl groups, aralkyl groups, aryl groups, acyl groups, heterocychc groups, alkylene groups all of which may be substituted with substituents selected from, for example, alkyl, aryl, and aralkyl groups and the like Among the polymers that may be conjugated to the active group include polyglycols, polyvinyl polymers, polyesters, polyamides, polysacchaπdes, and polymeric acids, lipids, ammo acids, nucleic acids, carbohydrates, and combinations thereof. The preferred polyglycols include polyethylene glycol and polypropylene glycol. The preferred polysacchaπdes are those selected from polysacchaπde B Among the polyacids which may preferably be used in accordance with the present invention, are polyamiπo acids and polyactic acid The preferred polymers among the classes of polymers mentioned above are polyethylene glycols (PEG) In addition to the polymers mentioned above such polymers as dextran, cellulosic polymers and starches may be also used in accordance with the present invention The polymers may be attached to the active COOH or OH group through a group such as for example, an amide group, an ester group or the like The compounds of Formula I are typically employed as part of a pharmaceutical composition including a pharmaceutically acceptable carrier for the treatment of vascular disease including peripheral vascular disease and pulmonary hypertension The compounds employed for this purpose are typically administered in an amount of from 0 5 to 100 mg/kg/day, preferably from about 25 to 35 mg/kg/day The pharmaceutical composition comprising at least one compound of Formula I may be formulated, for example by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those known in the art of pharmaceutical formulation. The compounds of Formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders, sublingually; bucally; parenterally, such as subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e g , as sterile injectable aqueous or non-aqueous solution or suspensions), nasally such as by inhalation spray; topically, such as in the form of a cream or ointment, or rectally such as in the form of suppositories; in dosage unit formulations containing non- toxic, pharmaceutically acceptable vehicles or diluents The present prostaglandin compounds may be based for immediate release or extended release by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps The present invention may also be administered liposomaliy. Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystallme cellulose for imparting bulk algmic acid or sodium algmate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art, and immediate release tablets which may contain, for example, microcrystallme cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, dismtegrants, diluents and lubricants such as those known in the art. The present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration Molded tablets, compressed tablets or freeze-dπed tablets are exemplary forms which may be used Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextπns Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e g Gantrez), and agents to control release such as polyacry c copolymer (e g Carbopol 934) Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art Exemplary compositions for parenteral administration include mjectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1 ,3-butanedιol, water, Ringer's solution, an isotonic sodium chloride solution or other suitable dispersing or wetting and suspending agents including synthetic mono- or diglyceπdes, and fatty acids, including oleic acid Exemplary compositions for rectal administration include suppositories which may contain, for example, a suitable non-irπtating excipient, such as cocoa butter or synthetic glyceπde esters, which are solid at ordinary temperatures but liquify and/or dissolve in the rectal cavity to release the drug Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene) The effective amount of the present prostaglandin compound may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human from about 0 5 to 100 mg/kg of body weight of present prostaglandin compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound the species age body weight general health sex and diet of the subject, the mode and time of administration rate of excretion drug combination, and severity of the particular condition Preferred subjects for treatment include animals most preferably mammalian species such as humans and domestic animals such as dogs, cats and the like subject to vascular diseases Generally, a significantly lower dosage of the present prostaglandin compounds in comparison with known native or unconjugated prostaglandin compounds, is required to obtain the desired effect i e vasodilating the associated diseased vasculature Because of the rapid metabolism of known native or unconjugated forms of known prostaglandin compounds in vivo long continuous infusions of relatively large doses of these drugs have been required to maintain an effective blood level in the patient being treated However hypotension tachycardia and diarrhea, among other side effects caused by high blood levels of known prostaglandin compounds limit the amount of the known prostaglandin compounds which can be administered Furthermore the high cost of prostaglandin compound makes it prohibitively expensive to administer such large doses intravenously The methods of the present invention provide for effective administration of the present prostaglandin compounds at reduced cost and with reduced side effects The present prostaglandin compounds of the present invention may be administered subcutaneously in the form of a liquid reconstituted form a lyophilized powder which may additionally contain preservatives buffers dispersants etc Preferably, the prostaglandin compounds are reconstituted with a medium normally utilized for intravenous injection, e g , preservative-free sterile water Administration may be accomplished by continuous intravenous or subcutaneous infusion or by intravenous injection For continuous infusion the daily dose can be added to normal saline or other solution and the solution infused by mechanical pump or by gravity The following examples illustrate embodiments of the present invention One skilled in the art will readily recognize that changes modifications and variations can be made therein without departing from the spirit and scope of the invention as defined in the claims forming part of the application EXAMPLE 1 Synthesis of mPEG-5kDa-amιde-Compound X hereinafter referred to as "Compound 1 " A compound of Group 4 wherein Z, is a mPEG with a molecular weight of about 5,000 daltons, X is NH and Z 2 is hydrogen was prepared in the following manner 200 mg of Compound X having the formula shown below was placed in a round bottom flask along with mPEG5k amine (2 5 g), 2- hydoxybenzyltnazole (HOBT, 67mg), 4-(dιmethylamιno)pyrιdιne (DMAP, 61 mg) and dicyclohexylcarbodiimide (DCC, 140 mg) The materials were mixed with 60 ml of anhydrous methylene chloride The mixture was stirred at room temperature overnight and thereafter the solvent was removed by vaporization The residue was dissolved in 25 ml of 1 ,4 dioxane and the insoluble solid was removed by filtration The solvent was condensed and then precipitated into 100 ml of 50 50/ether isopropanol The precipitate was collected by filtration and dried under vacuum The resulting yield was 2 5 g (93%) 1 H NMR(DMSO-d 6 ) δ 3 5 (br m PEG), 7 897 (t, -PEGNH-CO-(Compound X)), 4 49 (d, (Compound X)-OjH 1 ) 4 24 (d (Compound X)-OH 2 ), 0 864 (t, (Compound X)-CH 3 ) 4 436 (s, (Compound X)- CH 2 CONHPEG), 7 045 (t, Compound X aromatic proton) 6 7 (d+d Compound X aromatic proton) EXAMPLE 2 Synthesis of mPEG5kDa-ester-Compound X diacetate hereinafter referred to as "Compound 2" A compound of Group 4 wherein Z, is a mPEG with a molecular weight of about 5,000 daltons, X is O and each Z 2 is an acetyl group was prepared in the following manner In a round-bottom flask, Compound X (400 mg) and pyπdine (200 μl) were mixed in 35 ml of anhydrous methylene chloride 500 μl of acetic anhydride was added to the suspension The mixture became homogenous in a few hours and the solution was stirred at room temperature overnight The solvent was condensed and phosphate buffer (0 1 M, pH 7 4) was added to the residue The mixture was rapidly stirred for 30 minutes, and the mixture was extracted with methylene chloride three times The combined organic phase was dried over sodium sulfate and the solvent was removed by vaporization An oily product, Compound X diacetate was obtained The yield was 340 mg (80%) 1 H NMR(DMSO-d 6 ) 1 91 (s, (Compound X)-0 1 COCH 3 ), 2 00 (s, (Compound X)-0 2 COCH 3 ), 0 84 (t, (Compound X)-CH 3 ) In a round-bottom flask, mPEG5k (3 8 g), Compound X diacetate from the previous step (320 mg), 2-hydroxybenzyltrιazole (HOBT, 103 mg), 4- (dιmethylamιno)pyrιdιne (DMAP, 93 mg) and dicyclohexylcarbodiimide (DCC, 238 mg) were dissolved with 50 ml of anhydrous methylene chloride The solution was stirred at room temperature overnight and the solvent removed by vaporization The residue was dissolved in 35 ml of 1 ,4 dioxane and the insoluble solid was removed by filtration The solvent was condensed and then precipitated into 100 ml of 50 50/ether isopropanol The precipitate was collected by filtration and dried under vacuum The resulting yield was 3 2 g (78%) 1 H NMR(DMSO-d 6 ) δ 3 5 (br m PEG), 4.23 (t, -PEGOCH 2 CH 2 0-CO- (Compound X)), 1 91 (s, (Compound X)- O 1 COCH 3 ), 2 00 (s, (Compound X)-0 2 COCH 3 ), 0 84 (t, (Compound X)-CH 3 ), 4 77 (s, (Compound X)-CH 2 COOPEG), 7 03 (t, Compound X aromatic proton), 6 7 (d+d, Compound X aromatic proton) Example 3 Synthesis of mPEG20KDa-ester-Compound X hereinafter referred to as "Compound 3" A compound of Group 5 wherein each Z 2 is a mPEG having a molecular weight of about 20,000 daltons attached through a group -CO-(CH 2 ) 2 -O-, was prepared in the following manner In a round-bottom flask, Compound X (200 mg) and sodium hydroxide (21 mg) were mixed in 40 ml of anhydrous acetonitπle 90 mg of benzyl bromide was added to the suspension and the mixture was refluxed for two days The solid was removed by filtration, the solvent condensed, and the residue dried under vacuum An oily product, Compound X-benzyl ester, was obtained The yield was 210 mg (100%) 1 H NMR(DMSO-d 6 ) δ 7 37 (s, C 6 H 5 -CH 2 -OCO- (Compound X)) 5 19 (s, C 6 H 5 -CH 2 -OCO- (Compound X)), 4 83 (s, (Compound X)-CH 2 COOBz), 4 49 (d, (Compound X)-OH 1 ), 4.24 (d, (Compound X)-Oj ), 0 864 (t, (Compound X)-CH 3 ), 7.025 (t, Compound X aromatic proton), 6 7 (d+d, Compound X aromatic proton) In a round-bottom flask, mPEG 20k (3 g) Compound X-benzyl ester (prepared in the previous step, 100 mg), HOBT (3 mg), DMAP (25 mg) and DCC (42 mg) were dissolved in 40 ml of anhydrous methylene chloride The solution was stirred at room temperature overnight, and the solvent was removed by vaporization The residue was dissolved in 30 ml of 1 ,4 dioxane and the insoluble solid was removed by filtration. The solvent was condensed and then precipitated into 100 ml of 50: 50/ether: isopropanol The precipitate was collected by filtration and dried under vacuum The yield was 2 7 g (90%) 1 H NMR(DMSO-d 6 ) δ 3 5 (br m, PEG), 2.48 (t, mPEG-OCH 2 CH 2 COO- (Compound X)), 7 35 (s, C 6 H 5 -CH 2 -OCO- (Compound X)), 5.17 (s, C 6 H 5 -CH 2 -OCO- (Compound X)) 4 83 (s (Compound X)- CH 2 COOBz), 0.857 (t, (Compound X)-CH 3 ), 7.025 (t, Compound X aromatic proton), 6.7 (d+d, Compound X aromatic proton) A solution of mPEG- Compound X benzyl ester (obtained in the previous step, 2.7 g) in 1 , 4-dιoXane (30 ml) was hydrogenated with H 2 (2 atm pressure) and 1 gram of Pd/C (10%) overnight. The catalyst was removed by filtration and the catalyst was washed with fresh methylene chloride The combined solution was condensed by rotary evaporation and the residual syrup was added into 300 ml of ethyl ether The product was collected by filtration and dried under vacuum The yield was 2 gram (74%). 1 H NMR(DMSO-d 6 ) δ 3 5 (br m PEG), 2 48 (t, mPEG- OCH 2 CH 2 COO- (Compound X)), 4.61 (s, mPEG- (Compound X)-CH 2 COOH), 0 857 (t, (Compound X)-CH 3 ), 7.025 (t, Compound X aromatic proton). 6 7 (d+d. Compound X aromatic proton) Example 4 Anti-Platelet Effects of Compound X and Compounds 1 -3 on Human Plasma in Vitro INTRODUCTION The anti-platelet activity of Compound X and Compounds 1 -3 of the present invention on human plasma taken from healthy human volunteers was determined in the following manner In addition, the anti-platelet responses of each compound following incubation with platelet-poor plasma (PPP) and with aqueous vehicle (acetate buffer) for various times were measured METHODS Preparation of Platelet-Rich Plasma (PRP) Blood from healthy human volunteers who had not taken any medicine for at least 14 days was collected by venopuncture into 3 15% (w/v) tπ-sodium citrate (9 1 v/v) The blood was centrifuged at 800 g for 15 minutes to produce PRP The PRP was further centrifuged at 12,000 g for 1 minute to produce PPP Photometric Measurement of Platelet Aggregation Platelet aggregation was measured using a dual channel Payton aggregometer calibrated with PRP (0%) and PPP (100%) with respect to the degree of light transmission Aliquots of PRP (500 μl) were added to si conized cuvettes stirred (1000 revs/mm) and warmed to 37° C The platelets were incubated for 1 minute to establish a stable baseline prior to testing A submaximal concentration of the aggregating agent collagen (1 μg/ml) was added to the PRP and the platelet aggregation was monitored as the increase in light transmission observed over a 4 minute period Anti-Aggregatory Response Compound X (1-100ng/ml) and Compounds 1 -3 (0 1 -10 mg/ml) were each incubated with PRP for 1 minute prior to the addition of collagen (1 μg/ml) a clotting agent The percent inhibition of the platelet aggregation was calculated using the peak increase in light transmission observed over the 4 minute period following the addition of collagen, as compared to that of the control This experiment was repeated using PRP from at least three human volunteers The test results are presented in Table 1 The results in Table 1 exemplify the concentration-dependent effects of Compound X and Compounds 1 through 3 on human platelet aggregation under the test conditions described above Anti-Aggregatory Response After Incubation with Aqueous Vehicle and PPP In separate experiments, samples of Compound X (30 and 300 ng/ml) and samples of Compound 1 (0 3 and 3 mg/ml) Compound 2 (0 03 0 3 and 3 mg/ml) and Compound 3 (3 mg/ml) were incubated with 500 μl of an aqueous vehicle (Acetate Buffer) for various times including 15 minutes 1 hour, and 4 hours at 37°C After the incubation period, a 50 μl aliquot of the aqueous vehicle with the corresponding sample compound was added to fresh PRP (450 μl) for determination of anti-aggregatory activity following challenge with collagen This experiment was repeated using PPP from at least three human volunteers The effects of Compound X and Compounds 1 -3 on human platelet aggregation after incubation with an aqueous vehicle (acetate buffer) for 15 minutes, 1 hour and 4 hours are, respectively, detailed in Table 2 The effects of Compound X and Compounds 1 -3 on human platelet aggregation after incubation with PPP for 15 minutes, 1 hour and 4 hours, respectively, are detailed in Table 3 The data in both Tables 2 and 3 are shown as the mean and the standard error of n number of donors RESULTS Effects of Compound X on Platelet Aggregation As shown in Table 1 , Compound X (1 -100 ng/ml) incubated with PRP for 1 minute prior to the addition of collagen, caused a concentration-dependent inhibition of collagen-induced platelet aggregation At the higher concentrations (30 and 100 ng/ml), Compound X completely inhibited the aggregation response (see Table 1 ) The concentration of Compound X inhibiting aggregation by 50% (ID 50 ) was determined to be 20 ng/ml Referring to Table 3, the incubation of Compound X (3 and 300 ng/ml) with PPP for 15 minutes, 1 hour and 4 hours had no significant effect on the anti-platelet activity Likewise, the incubation of Compound X (30 and 300 ng/ml) with the aqueous vehicle alone for 15 minutes, 1 hour and 4 hours had no significant effect on the degree of anti-platelet activity as shown in Table 2 Effects of Compound 1 on platelet aggregation Compound 1 (0 1 -3 mg/ml) incubated with PRP for 1 minute prior to the addition of collagen caused a concentration-dependent inhibition of platelet aggregation, as shown in Table 1 At the highest concentration (3 mg/ml) Compound 1 completely inhibited the aggregation response to collagen (see Table 1 ) By comparison to the anti-aggregatory activity of Compound X Compound 1 was about 10 times less active in inhibiting platelet aggregation after 1 minute of incubation As shown in Table 3 the anti-aggregatory activity of Compound 1 was increased in a time-dependent manner following incubation with PPP for 1 hour and 4 hours, respectively Thus, after 1 hour the activity had increased by 7-fold while after 4 hours, this activity was some 22-fold greater than the activity observed after 1 minute incubation (see Table 3) By comparison, incubation of Compound 1 with aqueous vehicle alone had no effect on anti-platelet activity at any time point tested (see Table 2) Effects of Compound 2 on platelet aggregation As shown in Table 1 , compound 2, at the highest concentration evaluated (10 mg/ml), cause approximately 20% inhibition of platelet aggregation when incubated with PRP for 1 minute Lower concentrations of Compound 2 had no significant anti- platelet activity after this 1 minute incubation (see Table 1 ) As shown in Table 3, the activity of Compound 2 was observed to substantially increase in a time-dependent manner following incubation with PPP for 1 hour and 4 hours This activity had increased by 50-fold when incubated for 1 hour in PPP as compared to 1 minute of incubation Furthermore this activity was increased by at least 3, 500-fold greater after 4 hour incubation than activity observed after 1 minute incubation (see Table 3) However, incubation of Compound 2 with aqueous vehicle alone had no such effect on anti-platelet activity at any time point tested (see Table 2) Effects of Compound 3 on Platelet Aggregation As shown in Table 1 , Compound 3 (0 3-10 mg/ml) incubated with PRP for 1 minute, caused a concentration-dependent inhibition of platelet aggregation At the highest concentration (10mg/ml), Compound 3 completely inhibited the aggregation response (see Table 1 ) Incubation of Compound 3 (300 μg/ml) with PPP for 4 hours at a concentration that was ineffective after 1 minute, caused an increase in activity, reaching 40% inhibition of platelet aggregation (see Table 3) Because of the weak activity even after this period of incubation, no further concentrations were evaluated Incubation of Compound 3 with aqueous vehicle had no effect on anti-platelet activity at any time point tested (see Table 2) CONCLUSION These present findings with the samples of Compound X and Compounds 1 -3 indicate that inclusion of a PEG moiety of 5 000 to 20,000 Dalton molecular weight along with acetate groupings, reduces anti-aggregatory activity of Compound X However, the activity of these compounds increases during incubation over a four (4) hour period with human plasma, but not with buffer alone indicating the presence of enzymatic hydrolysis of these derivatives which indicates prolonged release of the active compound TABLE 1 Concentration-dependent Effects of Compound X and Compounds 1 -3 on Human Platelet Aggregation TABLE 2 Effects of Compound X and Compounds 1 -3 on Human Platelet Aggregation after Incubation with Aqueous Vehicle (Acetate Buffer) TABLE 3 Effects of Compound X and Compounds 1 -3 on Human Platelet Aggregation after Incubation with Human PPP EXAMPLE 5 Systemic Hemodynamic Effects of Intravenously Administered Compound X and Compounds 1 -3 in Anesthetized Rats in Vivo INTRODUCTION This study reports on the potency, activation and duration of biological activity of Compounds 1 -3 in comparison to Compound X in thiopentone- anesthetized rats The effects of these compounds on blood pressure (BP) and heart rate following bolus intravenous injection were observed for each of the compounds The time for onset and maximal response were evaluated as well as the time taken for the response to return to 50% of the baseline value for comparing effective lives MATERIALS AND METHODS Male Wistar rats were anesthetized with thiopentone sodium (INTRAVAL ® 120 mg kg "1 i p ) The trachea was cannulated to facilitate breathing The right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL), for the measurement of mean arterial pressure (MAP) and heart rate (HR) which were continuously recorded on a 4-channel Grass 7D polygraph recorder (Grass, Mass , USA) The left femoral vein or the right jugular vein was cannulated for the administration of drugs The body temperature of the test animal was maintained at 37±1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard Apparatus Ltd) After a 15 minute stabilization period, the animals were injected once intravenously with selected doses of each compound, and hemodynamic parameters were continuously monitored for three hours in order to ascertain the duration of action of the compounds under study RESULTS The administration of Compound X in intravenous dosages of 0 1 mg/kg and 1 mg/kg, respectively, caused an immediate, dose related decline in the MAP, in association with a dose-related increase in heart rate A maximum decline of about 70 mm Hg in the MAP, occurred within the first minute after administration of the Compound X The effective life of the Compound X which directly correlates with the MAP response returning to 50% of the baseline value was found to be about fifteen minutes for the 0 1 mg/kg dose and about thirty minutes for the 1 0 mg/kg dose of the Compound X With Compound 1 , the administration in intravenous dosages of 0 1 mg/kg and 1 mg/kg, caused an immediate, dose-related decline in the MAP which was associated with a dose-related increase in heart rate The maximum fall in MAP of about 60 mm Hg occurred within the first minute after the administration of Compound 1 The effective life being a function of the duration of the MAP decline before returning to 50% of the baseline value for10 mg/kg and 30 mg/kg of Compound 1 , was about 15 minutes and about 30 minutes, respectively With Compound 2, an immediate decline in MAP occurred upon administration of both 10 and 30 mg/kg dosages in association with a dose-related increase in heart rate Following injection of 10 mg/kg of Compound 2 a maximum decline in the MAP of 30 mm Hg occurred within ten minutes after administration of the compound The effective life being a function of the duration of the MAP decline caused by 10 mg/kg of Compound 2, was about 125 minutes Following injection of 30 mg/kg of Compound 2, a maximum decline in the MAP of about 30 mm Hg occurred within five minutes after the administration of the compound Thereafter the MAP appeared to return towards baseline However there was a second decline in the MAP at about thirty minutes (which was as pronounced as the first one) The effective lives of the two observed falls in the MAP caused by the 30 mg/kg of Compound 2 were 105-160 minutes respectively With the administration of Compound 3 at a dosage of 30 mg/kg a small but immediate decline in the MAP was observed However, 45 and 120 minutes after injection of Compound 3, there was a gradual decline in the MAP This delayed decline in the MAP returned towards baseline between 135-165 minutes after injection of Compound 3 The maximum decline in the MAP of about 30 mm Hg occurred within 75 minutes after administration of the compound The effective life of the decline in the MAP caused by 30 mg/kg was greater than 105 minutes CONCLUSION It was confirmed that Compound X caused a substantial dose-related fall in MAP Similarly to Compound X, Compound 1 causes a dose-related fall of similar magnitude and duration in MAP Compounds 2 and 3 produced smaller falls in MAP, but their respective duration of action was relatively long Compound 2 induces a significant, longer-lasting fall in blood pressure, which at dose of 10 mg/kg was not associated with a marked increase in heart rate The finding that the immediate fall in MAP produced by Compound 2 was not as substantial as that produced by Compound X and Compound 1 offers an advantage in terms of better safety profile EXAMPLE 6 Synthesis of Compound X Diacetate hereinafter referred to as Compound 4" A compound of Group 5 wherein Z, is hydrogen X is O and each Z 2 is an acetyl group, was prepared in the following manner In a round-bottom flask, Compound X (400 mg) and pyπdine (200 μl) were mixed in 35 ml of anhydrous methylene chloride 500 μl of acetic anhydride was added to the suspension The mixture became homogenous in a few hours and the solution was stirred at room temperature overnight The solvent was condensed and phosphate buffer (0.1 M, pH 7 4) was added to the residue The mixture was rapidly stirred for 30 minutes, and the mixture was extracted with methylene chloride three times The combined organic phase was dried over sodium sulfate and the solvent was removed by vaporization An oily product, Compound X Diacetate was obtained The yield was 340 mg (80%) 1 H NMR(DMSO-d 6 ) 1 91 (s, (Compound X)-O 1 COCjH 3 ), 2 00 (s, (Compound X)-O 2 COCH 3 ), 0 84 (t, (Compound X)-CH 3 ) EXAMPLE 7 Synthesis of mPEG20K-ester-Compound X Diacetate hereinafter referred to as "Compound 5" A compound of Group 4 wherein Z, is a mPEG with a molecular weight of about 20,000 daltons, X is O and each Z 2 is an acetyl group, was prepared in the following manner In a round bottom-flask, mPEG 20k daltons (5 2 g), Compound X diacetate (140 mg), 1 -hydroxybenzyltπazole (HOBT, 35 mg), 4-(dιmethylamιno)pyrιdιne (DMAP, 30 mg) and dicyclo-hexylcarbodnmide (DCC 75 mg) were dissolved in 60 ml of anhydrous methylene chloride The solution was stirred at room temperature overnight and the solvent removed by vaporization The residue was mixed with 35 ml of 1 ,4 dioxane and the insoluble solid was removed by filtration The solution was concentrated under vacuum and then added to 200 ml of 50.50/ether isopropanol The resulting precipitate was collected by filtration and dried under vacuum Yield 4 8 g (92%) 1 H NMR (DMSO-d 6 ) δ 3 5 (br m PEG) 4.23 (t, -PEGOCH 2 CH 2 O-CO-(Compound X)), 1 91 (s, (Compound X)-OCOCH 3 ), 2 00 (s, (Compound X)-OCOCH3), 0 84 (t, (Compound X)-CH3) 4 77 (s (Compound X)-CH 2 COOPEG), 7 03 (t, Compound X aromatic proton), 6 7 (d+d Compound X aromatic proton) EXAMPLE 8 Anti-Platelet Effects of Compound X and Compounds 4-7 on Human Plasma in Vitro INTRODUCTION The anti-platelet activity of acetylated Compound X referred hereinafter as Compound 4, and Compounds 5-7 of the present invention on human plasma taken from healthy human volunteers was determined in the following manner and compared to the anti-platelet activity of the native Compound X The anti-platelet responses of each compound following incubation with platelet-poor plasma (PPP) and aqueous vehicle (acetate buffer) for various times over a four (4) hour period were also investigated Compounds 6 and 7 are respectively, mPEG 20kDa-amιde-Compound X and mPEG20kDa-amιde-Compound X Diacetate and were prepared similarly to Compound 1 of Example 1. Each of Compounds 6 and 7 are compounds of Group 4 wherein Z., is a mPEG having a molecular weight of about 20,000 daltons and X is NH. For Compound 6, Z 2 is hydrogen, while for Compound 7, Z 2 is an acetyl group METHODS Preparation of Platelet-Rich Plasma (PRP) Blood from healthy human volunteers who had not taken any medicine for at least 14 days was collected by venopuncture into 3 15% (w/v) tπ-sodium citrate (9 1 v/v). The blood was centrifuged at 800 g for 15 minutes to produce PRP The PRP was further centrifuged at 12,000 g for 1 minute to produce PPP. A total of 12 volunteers donated blood for the study Photometric Measurement of Platelet Aggregation Platelet aggregation was studied using a dual channel Payton aggregometer calibrated with PRP (0%) and PPP (100%) with respect to the degree of light transmission. Aliquots of PRP (500 μl) were added to si conized cuvettes, stirred (1000 revs/min) and warmed to 37° C The platelets were incubated for 1 minute to establish a stable baseline prior to investigation A submaximal concentration of the aggregating agent collagen (1 μg/ml) was added to the PRP and the platelet aggregation was monitored as the increase in light transmission observed over a 4 minute period Anti-Aggregatory Activity Compound X (1 -100 ng/ml), Compound 4 (1 -300 ng/ml) and the PEG conjugated derivatives, Compound 5-7 (0 1 -10 mg/ml) were each incubated with PRP for 1 minute prior to the addition of collagen (1 μg/ml) a clotting agent The percentage inhibition of the platelet aggregation was calculated using the peak increase in light transmission observed over the 4 minute period following addition of collagen, as compared to that of control This experiment was repeated using PRP from at least three human volunteers for each compound under study Anti-Aggregatory Response After Incubation with Aqueous Vehicle and PPP In separate experiments, concentrations of Compound X (30 and 300 ng/ml) Compound 4, and Compounds 5-7, were incubated with 500 μl PPP or aqueous vehicle (acetate buffer) for various times including 15 minutes 1 hour, and 4 hours at 37°C After the incubation period, an aliquot of the PPP or aqueous vehicle (50 μl) was added to fresh PRP (450 μl) for determination of anti-platelet activity This experiment was repeated using PPP from at least three human volunteers for each compound RESULTS Effects of Compound X on platelet aggregation Compound X (1 -100 ng/ml), incubated with PRP for one (1 ) minute, caused a concentration dependent inhibition of collagen-induced platelet aggregation At the higher concentrations (30 and 100 ng/ml), Compound X completely inhibited the aggregation response. The concentration of Compound X inhibiting aggregation by 50% (IC 50 ) was 19±1 ng/ml. Effects of Compound 4 on platelet aggregation Compound 4, the Compound X diacetate (1 -300 μg/ml), incubated with PRP for one (1 ) minute, cause a concentration-dependent inhibition of platelet aggregation. At the highest concentration (300 μg/ml), Compound 4 completely inhibited the aggregation response to collagen, with an inhibiting aggregation by 50%) concentration of 68± 2 μg/ml. By comparison to the anti-aggregatory activity of Compound X, Compound 4 was some 3 x 10 3 times less active in inhibiting platelet aggregation after one (1 ) minute of incubation The anti-platelet activity of Compound 4 increased over the first 15 minutes following incubation with PPP. After 15 minutes, the activity had increased by some 10-fold, with an IC 50 of 5±0.2 μg/ml This effect was also observed during incubation of the compound in saline. However, no further increase in activity was observed when incubated in PPP for up to 4 hours Effects of Compound 5 on platelet aggregation Compound 5, at the highest concentration evaluated (10 mg/ml), caused approximately ten percent (10%) inhibition of platelet aggregation when incubated with PRP for one (1 ) minute Lower concentrations of Compound 5 had no significant anti-platelet activity after this one (1 ) minute incubation The activity of high concentrations of Compound 5 increased in a time- dependent manner following incubation with PPP for one (1 ) hour and four (4) hours This activity increased by greater than ten (10)-fold when incubated for four (4) hours in PPP, with an IC 50 of 513±18 μg/ml However incubation of Compound 5 with aqueous vehicle had no such effect on anti-platelet activity at any time point tested Effects of Compound 6 on platelet aggregation Compound 6 (0 1 - 3 mg/ml), incubated with PRP for one (1 ) minute caused a concentration-dependent inhibition of platelet aggregation At the highest concentration (3 mg/ml), Compound 6 near-maximally inhibited the aggregation response The IC 50 of Compound 6 was 600± 34 μg/ml Incubation of Compound 6 (100 μg/ml) with PPP for four (4) hours at a concentration that was ineffective after one (1 ) minute caused an increase in activity, reaching 85% inhibition of platelet aggregation The IC 50 of Compound 6 after four (4) hour incubation was 60±5 μg/ml Because of the weak activity even after this period of incubation, no further concentrations were evaluated Incubation of Compound 6 with aqueous vehicle had no effect on anti-platelet activity at any time point tested Effects of Compound 7 on platelet aggregation Compound 7 (10 mg/ml), incubated with PRP for one (1 ) minute , at the highest concentration, did not significantly inhibit the aggregation response Incubation of Compound 7 (10 mg/ml) with PPP or aqueous vehicle for four (4) hour, showed no increase in activity Because of the weak activity even after this period of incubation, no further concentrations were evaluated CONCLUSION The present study confirms the potent platelet anti-aggregatory activity in vitro of the benzmdene derivative of prostacyclin, Compound X in human platelet- rich plasma, as determined in an optical aggregometer The potency of this compound after a one (1 ) minute incubation with the platelet suspension in the present study is similar to that previously reported in Example 4 As in the previous study, the anti-platelet activity was not affected by incubation with platelet-free plasma or aqueous vehicle for periods up to four (4) hours at 37°C, confirming its chemical stability under physiological conditions The findings of the present study indicate that Compound X has significantly greater anti-platelet activity than the diacetate derivative, Compound 4, the diacetate being about 3,000 times less active This acetylated derivative did increase its activity some 10-fold on incubation with plasma or aqueous vehicle over an initial ten (10) minute period, but this increase in activity was no greater after four (4) hours of incubation The mechanism of this early increase in activity may reflect a transient instability of the diacetate when incubated in the PPP media The present study also indicates that Compound X had significantly greater anti-platelet activity than Compounds 4-7 Compound 6 was the most active of the three PEG conjugated derivatives (Compounds 5-7), after incubation with the platelet-rich plasma for one (1 ) minute, but was considerably less potent than Compound X, being some 3 x 10 4 fold less active The anti-platelet activity of Compounds 5-7 were variably affected by incubation with platelet-poor plasma (PPP) for periods up to four (4) hours Time points greater than four (4) hours could not be tested using human plasma in vitro because the platelet aggregation response declines rapidly after 6 hours post- collection. The activity of Compounds 5 and 6 increased over the four (4) hours of incubation by 10-fold or greater, an effect not seen when incubated in saline These findings suggest that the active moiety of these PEG conjugated derivatives (Compounds 5-7) is released in a time-dependent manner by enzymes present in human plasma, after incubation at 37°C over four (4) hours, i e hydrolysis of the ester and acetate groupings respectively on these molecules in human plasma However, it should be noted that the increased in activity observed with the compounds was substantially lower than that observed with some of the compounds from the study in Example 4 These findings with Compounds 5-7 indicate that inclusion of the PEG moiety of 20,000 daltons molecular weight, along with acetate groupings reduces the anti- aggregatory activity of Compound X However the activity of Compounds 5 and 6 increases on incubation over a four (4) hour period with human plasma indicating hydrolysis of these substituent groupings A ten-fold increase in activity of these compounds was observed following incubation over a 4 hour period with human plasma, but not when incubated in buffer alone indicating enzymatic hydrolysis of the ester and amide linkages in these derivatives with release of the active moiety The present findings confirm the creation of slow-release derivatives of Compound X based on PEG substitution, that can be activateα in human plasma 35 EXAMPLE 9 Systemic Hemodynamic Effects of Compound X and Compounds 4-7 in Anesthetized Rats in Vivo INTRODUCTION In this study, cardiovascular activity of Compounds 4-7 were observed in thiopentone-anesthetized rat The effects of these compounds on blood pressure (BP) and heart rate following bolus intravenous injection were determined The time for onset and maximal response were noted as well as the time taken for the response to return towards the baseline Each compound was administered as a single dose to individual animals, to establish the dose-response curve Among its other effects, Compounds 4-7 in vitro induce a concentration- dependent relaxation of mesenteric arteries which causes a measurable decrease in mean arterial pressure (MAP) when administered intravenously in anesthetized rats To confirm the improvement of the effective life of Compounds 4-7 over the Compound X, Applicants sought to measure the changes in MAP over time to extrapolate the effective life of the compounds which is defined as the time taken for the response to return to 50% of the baseline value MATERIALS AND METHODS This study involved the use of male Wistar rats anaesthetized with thiopentone sodium (Intraval ® , 120 mg kg '1 i p ) The trachea was cannulated to facilitate breathing. The right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL), for the measurement of mean arterial pressure (MAP) and heart rate (HR) which were continuously recorded on a 4- channel Grass 7D polygraph recorder (Grass, Mass , USA) The left femoral vein or the right jugular vein was cannulated for the administration of drugs Body temperature was maintained at 37±1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard Apparatus Ltd) After a 15 minute stabilization period, the animals were injected with single intravenous injections of selected doses of native Compound X, and Compounds 4- 7, respectively, and hemodynamic parameters were continuously monitored for three hours in order to ascertain the duration of action of the compounds under study. RESULTS The administration of Compound 4 in the intravenous dosages of 1. 3, and 10 mg/kg, respectively, caused a rapid, dose-related fall in MAP, which was associated with a dose-dependent increase in heart rate Following injection of 1 mg/kg, a maximum fall in MAP of about 30 mm Hg occurred 30 minutes after administration of the compound The effective life of the fall in MAP caused by 1 mg/kg of compound 4 was about 110 minutes Administration of a dose of Compound X (1 mg/kg i v ) caused a similar, maximal fall in MAP to the highest dose of Compound 4 (10 mg/kg i v ) When compared to Compound X, the fall in MAP caused by Compound 4 was of a substantially longer duration, with a effective life of over 90 minutes compared to 30 minutes for Compound X The duration of effects of Compound 4 was longer than that elicited by a 10-fold maximal dose of Compound X The findings indicate that the increased duration of action as observed with this derivative cannot be achieved by supramaximal doses of Compound X Furthermore the tachycardia caused by Compound 4 was slower in onset than the tachycardia caused by Compound X It should be noted that the tachycardia caused by Compound 4 was still significant at 3 hours after injection of the compound Administration of Compound 5 (3, 10, and 30 mg/kg i v ) caused a dose- related fall in MAP which was less pronounced than that produced by Compound 4 or Compound X, and which was not associated with a significant increase in heart rate. The response reached its maximum after 15 minutes with a very long duration of action, with a effective life of about 120 minutes Administration of Compound 6 (3, 10, and 30 mg/kg i v ) caused an immediate dose-related fall in MAP, which was slow in onset and at higher dosages appeared to be maximal at 3 hours after injection of the compound The maximum fall was about 60 mm Hg within 10 minutes However, the duration of the initial phase of this response was short, and was followed by a slower phase of recovery of blood pressure towards the resting values Interestingly, Compound 6 did not cause a significant change in heart rate Compound 4 and Compound 6 both resulted in rapid and substantial falls in MAP However, in the case of Compound 4 the drop in MAP was also accompanied by a pronounced increase in heart rate Although the fall in MAP produced by Compound 4 was of longer duration, the rapid fall in MAP and the resultant tachycardia would be disadvantageous as to its safety profile In contrast, Compound 7 ( 3, 10 and 30 mg/kg i v ) caused a gradual fall in MAP which reached its plateau levels only after 135-165 minutes The gradual fall was progressive and appeared to reach a maximum of about 30 mm Hg at the end of the 3 hour experimental period This fall in MAP was not associated with tachycardia CONCLUSION The cardiovascular profile of the present compounds permits some definition of the structure-activity relationship, and hence design of Compound X derivatives that exhibit a long duration of action. In addition, it appears such compounds may be formulated with a slow onset of action that would minimize the possibility of any initial hypotensive crisis. Comparison of the profile of compounds conjugated to either 5,000 or 20,000 daltons PEG suggests that although there appears to be no difference in MAP profile or the duration of hypotensive effects with either PEG size, there is a trend towards less of an effect on heart rate with the compounds containing 20,000 daltons PEG The potential clinical advantage or problems associated with the absence of reflex tachycardia requires further consideration Comparison of the profiles for compounds linked to the PEG substituent via either the amide or ester linkage suggests that the fall in MAP for the amide is slower in onset than that observed with the ester and was not observed to trigger reflex tachycardia. EXAMPLE 10 Systemic Hemodynamic Effects of Subcutaneous Administration of Compound 2 in Anesthetized Rat Compound 2 was evaluated following subcutaneous administration Male Wistar rats (250-330 g) were anesthetized with thiopentone sodium (INTRAVAL®, 120 mg/kg i.p.). The trachea was cannulated to facilitate respiration The right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL), for the measurement of mean arterial pressure (MAP) and heart rate (HR) which were continuously recorded on a 4-channel Grass 7D polygraph recorder (Grass, Mass , U.S. A ). Body temperature was maintained at 37±1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard Apparatus Ltd ) After a 15 minute stabilization period, compound 2 was injected as a bolus subcutaneously in the neck Subcutaneous administration of Compound 2 (30mg/kg s c ) caused a substantial fall in MAP, which was slow in onset and reached a maximum at 45 minutes after injection of the compound In addition, Compound 2 caused an increase in heart rate When compared to intravenous administration of Compound 2 (30 mg/kg i v.) of Example 5, the long-lasting fall in MAP caused by the subcutaneous administration was more pronounced, but slower in onset At 3 hours, a larger magnitude was produced that was of larger magnitude than that produced by intravenous administration of the same compound A further analysis of the subcutaneous administration of this and other compounds is warranted EXAMPLE 1 1 Systemic Hemodynamic Effects of Subcutaneously Administered Compound X Compound 4, Compound 7 and mPEG5kDa-amιde-Compound X Diacetate in Anesthetized Rats in Vivo Compound X Compound 4 Compound 7 and mPEG5kDa-amιde-Compound X Diacetate hereinafter referred to as Compound 8 were evaluated following subcutaneous administration Male Wistar rats (250-330 g) were anesthetized with thiopentone sodium (INTRAVAL®, 120 mg/kg i p ) The trachea was cannulated to facilitate respiration The right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL) for the measurement of mean arterial pressure (MAP) and heart rate (HR) which were continuously recorded on a 4- channel Grass 7D polygraph recorder (Grass Mass U S A ) Body temperature was maintained at 37±1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard Apparatus Ltd ) After a 15 minute stabilization period native Compound X Compound 4 Compound 7 or Compound 8 were injected as a bolus subcutaneously in the neck Compound 8 referred was prepared similarly to Compound 1 of Example 1 Compound is a compound of Group 4 wherein Z, is a mPEG having a molecular weight of about 20,000 daltons, X is NH and Z 2 ιs an acetyl group RESULTS Administration of Compound 4 in the subcutaneous dosages of 1 3 and 10 mg/kg, respectively caused a dose-related fall in MAP which was also associated with a dose-dependent increase in heart rate Following injection of 1 mg/kg a maximum fall in MAP of about 26 mm Hg occurred 60 minutes after administration of the compound with another fall occurring 210 minutes to 28 mm Hg The effective lives of the fall in MAP caused by each of the three respective dosages of Compound 4 were >300, >330 and >300 minutes respectively (See Table 5) Administration of Compound X (0 1 0 3 and 1 mg/kg s c ) caused a rapid dose-related fall in MAP, which was associated with a dose-dependent increase in heart rate (See Table 4) Following subcutaneous injection of 1 mg/kg a maximum fall in MAP of about 70 mm Hg occurred 15 minutes after administration of the compound When compared to Compound X the fall in MAP caused by Compound 4 was of a substantially longer duration The tachycardia caused by Compound 4 was substantially slower in onset than the tachycardia caused by Compound 4 It should be noted that the tachycardia caused by Compound 4 was still significant for the 10 mg/kg dosage at 6 hours after injection of the compound At lower dosages the heart rate stabilized at about 5 minutes and 45 minutes after injection for 1 mg/kg and 3 mg/kg, respectively Administration of Compound 7 (3, 10 and 30 mg/kg) caused a gradual progressive dose-related fall in MAP, which continued to fall 6 hours after the injection The magnitude of activity was less than the native Compound X and Compound 4 The maximum falls in MAP were 35 29 and 25 mm Hg for 3 10 and 30 mg/kg dosages, respectively All the maximum falls occurred at about 330 to 360 minutes after injection (See Table 6) Administration of Compound 8 (3, 10 and 30 mg/kg s c ) caused a slow dose related fall in MAP and appeared to reach a maximum of about 24 mm Hg for the maximal dose at about 240 minutes after the injection The effective life was greater than 120 minutes (See Table 7) TABLE 4 Mean Arterial Pressure (mm Hg) Measured over a 6 hour time course for Compound X (Subcutaneous Administration) TABLE 5 Mean Arterial Pressure (mm Hg) Measured over a 6 hour time course for Compound 4 (Subcutaneous administration) TABLE 6 Mean Arterial Pressure (mm Hg) Measured over a 6 hour time course for Compound 7 (Subcutaneous administration) TABLE 7 Mean Arterial Pressure (mm Hg) Measured over a 6 hour time course for Compound 8 (Subcutaneous Administration) EXAMPLE 12 Synthesis of mPEG350Da-amιde-Compound X Diacetate hereinafter referred to as "Compound 9" A compound of Group 4 wherein Z λ is a mPEG with a molecular weight of about 350 daltons, X is NH and each Z 2 is an acetyl group, was prepared in the following manner In a round-bottom flask, Compound X (400 mg) mPEG(350 Da) amme (360 mg), HOBT (15 mg), and DCC (267 mg) were mixed with 20 ml of anhydrous methylene chloride and the mixture was stirred at room temperature overnight The insoluble solid was removed by filtration and the organic solution was washed with 5 wt % sodium bicarbonate solution The organic phase was dried over sodium sulfate and the solvent removed under vacuum The resulting product was dissolved in 10 ml of acetonitnle and the insoluble solid was removed by filtration To the solution was added acetic anhydride (3 ml) and pyridme (0 3 ml) The resulting solution was heated at 40° C overnight To the solution was added 300 ml of 5 wt % sodium bicarbonate solution and the mixture was stirred 30 minutes at room temperature The mixture was extracted with methylene chloride and the organic phase was washed with phosphate buffer (0 1 M, pH 2) and dried over sodium sulfate The solvent was removed and the product dried under vacuum The yield was 600 mg (70%) 1 H NMR (DMSO-d 6 ) δ 3 5 (br m, PEG) 7 897 (t, -PEGNH-CO-(Compound X)), 1 91 (s, (Compound X)-0 1 COCH 3 ), 2 00 (s (Compound X)-0 2 COCH 3 ) 0 864 (t, (Compound X)-CH 3 ), 4 436 (s, (Compound X)-CH 2 CONHPEG), 7 045 (t, Compound X aromatic proton), 6 7 (d+d, Compound X aromatic compound) EXAMPLE 13 Synthesis of mPEG350Da-ester-Compound X Diacetate hereinafter referred to as "Compound 10" A compound of Group 4 wherein Z is a mPEG with a molecular weight of about 350 daltons, X is O and each Z 2 is an acetyl group was prepared in the following manner In a round-bottom flask, Compound X (3 g) and tπethylamine (TEA, 1 5 μl) were mixed in 100 ml of anhydrous acetonitrile To the solution was added 3 ml of acetyl chloride The mixture was stirred at room temperature overnight The solution was then mixed with 5 wt % sodium bicarbonate solution and stirred 30 minutes at room temperature The aqueous phase was extracted with methylene chloride The organic phase was washed with phosphate buffer (0 1 M, pH 2) and then dried over sodium sulfate The yield was 3 3 g (80%) 1 H NMR(DMSO-d 6 ) 1 91 (s, (Compound X)-O 1 COCH 3 ), 2 00 (s, (Compound X)-0 2 COCH 3 ) 0 84 (t (Compound X)-CH 3 ) In a round-bottom flask, mPEG (350 Da) (550 mg), Compound X diacetate from the previous step (750 mg), HOBT (60 mg), DMAP (150 mg) and DCC (375 mg) were dissolved in 30 ml of anhydrous methylene chloride The solution was stirred at room temperature overnight The insoluble solid was removed by filtration and the solution was washed with 5 wt % sodium bicarbonate solution and phosphate buffer (0 1 M, pH 2) The organic phase was dried over sodium sulfate and concentrated under vacuum The resulting product was dissolved in 10 ml of acetonitrile and the insoluble solid was removed by filtration The solvent was removed by vaporization and the product was obtained as a clear oil The yield was 1 g (76 %) 1 H NMR(DMSO-d 6 ) δ 3 5 (br m, PEG), 4 23 (t -PEGOCH 2 CH 2 0-CO- (Compound X)), 1 91 (s, (Compound X)-0 1 COCH 3 ) 2 00 (s, (Compound X)- O 2 COCH 3 ), 0 84 (t, (Compound X)-CH 3 ), 4 77 (s, (Compound X)-CH 2 COOPEG), 7.03 (t, Compound X aromatic proton), 6 7 (d+d, Compound X aromatic proton) EXAMPLE 14 Evaluation of the Effects of mPEG 350Da-amιde-Compound X Diacetate on Systemic Hemodynamics in Anesthetized Rats In Vivo In this study, the cardiovascular activity of novel, lower polyethylene glycol (PEG) derivatives of the chemically stable benzmdene analog of prostacyclin, Compound X following both intravenous and oral administration in rats was evaluated The mPEG350Da-amιde-Compound X Diacetate or Compound 9 hereinafter, was synthesized in an attempt to produce a derivative that would be effective by the oral route An orally effective analog would develop further the clinical potential of stable prostacyclin analogs in a number of therapeutic utilities Previous studies have evaluated a number of derivatives of Compound X linked to moieties of varying weights In those studies high molecular weight polymers of PEG of 5,000 and 20,000 daltons were attached to different regions of the native compound by ester or amide linkages, while the effects of acetylating the free hydroxyl groups were also studied Their systemic hemodynamic profile were studied in the anesthetized rat following intravenous bolus administration and in the later study, following subcutaneous bolus injection The current study has evaluated the actions of the 350 molecular weight PEG derivative on rat systemic arterial blood pressure following either intravenous or oral administration Compound under Evaluation The compound used in the present study was the acetylated mPEG 350 Da Compound X-amide (mPEG 350-NHCO-Compound X-Ac) hereinafter referred to as "Compound 9", in which the PEG of 350 daltons molecular weight is linked to the carboxyhc group of Compound X through an amide linkage and the hydroxyl groups of Compound X are acetylated General Methodology The series of studies described herein are on the cardiovascular activity of these compounds in the thiopentone-anesthetized rat In these studies, the effects of the Compound 9 on blood pressure (BP) and heart rate following bolus intravenous and oral administration were observed The time for onset and maximal response was determined, as well as the time taken for the response to return towards 50% of the baseline value Each compound was administered as a single dose to individual animals in the group, to establish the dose-response relationship and the cardiovascular parameters determined for 3 hours after the intravenous administration and 6 hours after the oral administration Male Wistar rats (250-330 g) were anesthetized with thiopentone sodium (INTRAVAL®, 120 mg kg 1 i p ) The trachea was cannulated to facilitate respiration The right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL), for the measurement of mean arterial pressure (MAP) and heart rate (HR) which were continuously recorded on a 4-channel Grass 7D polygraph recorder (Grass, Mass , U S A ) The left femoral vein or the right jugular vein was cannulated for the administration of drugs Body temperature was maintained at 37±1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard Apparatus Ltd ) Methodology for Intravenous Administration The Compound 9 was dissolved in absolute ethanol to give a stock solution of 200 mg/ml, which was stored in the freezer at -20°C Aliquots of the stock solution were removed immediately prior to use, and dissolved in saline Rats receiving 3, 10, and 30 mg/kg of the Compound 9 thus received 1 5% 5% and 15% of ethanol in 0 3 ml In the control group, the rats received the highest concentration of ethanol, 0 3 ml i v of an ethanohc solution of 15% After a 15-mιnute stabilization period, the Compound 9 (3 10 and 30 mg/kg) was administered as an intravenous bolus Methodology for Oral Administration A rubber catheter was positioned in the stomach (via the esophagus) to facilitate oral dosing After a 20 minute stabilization period Compound 9 was administered as a total of 1 ml bolus down this tube The Compound 9 was dissolved in absolute ethanol to give a stock solution of 200 mg/ml, which was stored in the freezer at -20°C Aliquots of the stock solution were removed immediately prior to use and dissolved in saline Rats received 30 mg/kg of the Compound 9, thus 15% of ethanol in 1 0 ml In the control group, the rats received 1 ml of an ethanohc solution of 15% The study was conducted in either non-fasted animals, that had food in the stomach at post mortem, or rats that had had food removed some 15 hours prior to investigation. Results of the Intravenous Administration In the anesthetized rat, intravenous injection of Compound 9 (3. 10 and 30 mg/kg i.v.) caused a rapid dose-dependent fall in MAP (See Table 8A), but had no significant effect on heart rate With the maximal dose, this hypotensive response reached its peak value well within 15 minutes, but had a long duration of action, with a effective life of at least 120 minutes It should be noted that the higher doses of the Compound 9 appeared to cause a transient fall in heart rate (See Table 8B) TABLE 8 A Dose Response from Intravenous Administration of Compound 9 (Mean Arterial Pressure, mm Hg) TABLE 8B Dose Response from Intravenous Administration of Compound 9 (Heart Rate) Results of the Oral Administration In the anesthetized rats, oral administration of Compound 9 (30 mg/kg) to either fed or starved rats caused a fall in MAP, which was slow in onset, progressive and of long duration (See Table 9A). The fall in MAP reached its peak after 120 minutes, with the MAP remaining depressed at the end of the 6 hour observation period. A maximum fall in MAP of about 33 mm Hg was observed at the end of the observation period at 6 hours. It should be noted, however, that the vehicle containing ethanol (0.3 ml of 15% ethanol) also caused a small, gradual fall in MAP, which was slow in onset and reached a maximum of 20 mm Hg after 6 hours (See Table 9A). There appeared to be no difference between the vasodepressor response to the Compound 9 in either the fed or starved rats The ethanohc vehicle also caused a progressive fall in heart rate (see Table 9B), which was more pronounced than any fall in heart rate caused by the test drug itself (see Table 9B) TABLE 9A Response from Oral Administration of Compound 9 (Mean Arterial Pressure, mm Hg) TABLE 9B Response from Oral Administration of Compound 9 (Heart Rate) Conclusion These findings in the rat following intravenous administration of Compound 9 indicated that this molecule has a rapid onset of action with a long duration of action However, despite having a ten-fold lower molecular weight, the potency of the Compound 9 as a vasodepressor was only comparable to that of the mPEG 5kDa-amιde Compound X (Compound 1 ) reported in a previous study The reason for this is not readily apparent, but may reflect slower transformation to the active species Such a possibility would be difficult to explain with the current knowledge of PEG derivatives, but may represent an important feature of the enzymatic hydrolysis of the amide linkage, as well as the removal of the protective acetyl moieties as the hydroxyl group The lower molecular weight PEG may be less constrained than the more rigid higher molecular size PEG group, and may not allow adequate exposure of the amide linkage on the Compound X, making the molecule less amenable to attack and release of active species How the different size substituents would affect the electrostatic charge distribution on Compound X benzmdene chemical backbone is not known but this could also modulate the rate of hydrolysis of the PEG analogue or the subsequently released free native Compound X, if this is the active species that elicits the hypotensive responses Previous studies with intravenous administration of the di-acetylated compounds linked to with 5,000 daltons or 20 000 daltons PEG through an amide bond showed that acetylation caused the molecules to produce a smaller gradual fail in MAP with a slow rate of recovery This gradual decline in MAP was not associated with reflex tachycardia In contrast, in the present study, the Compound 9 had a rapid onset of action and was associated with an initial fall in heart rate Thus, it would appear that the protection of the hydroxyl groups by acetylation as in 5,000 or 20,000 daltons molecular weight PEG linked by ester or amide groups, does not modulate the release of the active species in the lower molecular weight compound Whether this will also apply to the low molecular weight acetylated ester derivative will await further studies However it is of relevance that the acetylated form of the Compound X, not linked to PEG, likewise gave a rapid onset of action This suggests that this chemical approach for attenuating the rapid onset of action following parenteral administration only operates in PEG derivatives of above 350 daltons Following oral administration, the highest doses of Compound 9 did produce a gradual fall in MAP, although the magnitude of this effect was obscured by the small gradual fall in MAP with the vehicle, that contained ethanol the solvent required for solubilismg the oil supplied Because of the magnitude of this action lower doses were not investigated However, this vasodepressor action was compared in both fasted and fed rats, the data suggests that there was comparable bioavailabihty under both these conditions Because of the dissimilar nature of the blood pressure profile of Compound 9 following intravenous and oral administration it is difficult to determine the absolute bioavailabihty by the oral route in these studies Previous findings that the hemodynamic profile of the acetylated mPEG 5,000 or 20,000 daltons Compound X amide derivatives was similar following intravenous or subcutaneous administration suggests slow activation followed by slow metabolism or elimination of these analogs By contrast, the current study with Compound 9 suggests that this compound does not offer an increased potency despite its lower molecular weight, nor the potential benefits of the slow onset of action of the cardiovascular events following parenteral administration However, the use of the low molecular weight PEG derivatives may offer a rational chemical approach for the development of novel long acting orally absorbed prostacyclin derivatives EXAMPLE 15 Evaluation of the Effects of mPEG 350 Da-ester-Compound X Diacetate on Systemic Hemodynamics in Anesthetized Rats In Vivo In this study, the cardiovascular activity of novel, lower polyethylene glycol (PEG) derivatives of the chemically stable benzmdene analog of prostacyclin Compound X, following intravenous administration in rats is evaluated The mPEG 350 Da -ester-Compound X Diacetate, hereinafter referred to as ' Compound 10" was synthesized in an attempt to investigate the compound's effects on systemic hemodynamics Compound under Evaluation The compound tested was the acetylated mPEG 350 Da-ester-Compound X, hereinafter referred to as "Compound 10", in which the mPEG of 350 daltons molecular weight is linked to the carboxyhc group of Compound X through an ester linkage and the hydroxyl groups of Compound X are acetylated Methods Male Wistar rats (250-330 g) were anesthetized with thiopentone sodium (INTRAVAL®, 120 mg kg "1 i.p.) The trachea was cannulated to facilitate respiration The right carotid artery was cannulated and connected to a pressure transducer (Spectramed P23XL), for the measurement of mean arterial pressure (MAP) and heart rate (HR) which were continuously recorded on a 4-channel Grass 7D polygraph recorder (Grass, Mass., U.S A ) The left femoral vein or the right jugular vein was cannulated for the administration of drugs Body temperature was maintained at 37±1 °C by means of a rectal probe thermometer attached to a homeothermic blanket control unit (Harvard Apparatus Ltd ) After a 15 minute stabilization period, Compound 10 (0 3, 3, 10 and 30 mg/kg) was administered as an intravenous bolus. Compound 10 was dissolved in ethanol for storage at -20°C Aliquots of the stock solution were removed for dilution in the aqueous vehicle prior to use Results Intravenous administration of Compound 10 (0 3, 3, 10 and 30 mg/kg i v ) caused a dose-related fall in MAP (See Table 10A) Higher doses of Compound 10 (10 and 30 mg/kg) caused a small increase in heart rate or reflex tachycardia which was maximal at 45 minutes after administration of Compound 10 (See Table 10B) TABLE 10A Dose Response from Intravenous Administration of Compound 10 (Mean Arterial Pressure mm Hg) TABLE 10B Dose Response from Intravenous Administration of Compound 10 (Heart Rate) The systemic hemodynamic effects of Compound 10 were compared to the effects elicited by Compound 9 in Example 12 At doses of 3 mg/kg, the fall in MAP caused by the Compound 10 was more pronounced (about 30 mm Hg) than that caused by the Compound 9 (maximum about 15 mm Hg) The effects of both compounds on heart rate were similar At doses of 10 mg/kg, the fall in MAP caused by the Compound 10 was more pronounced (about 33 mm Hg) than that caused by the Compound 9 (maximum about 25 mm Hg) The Compound 10 caused a small increase in heart rate while the Compound 9 appeared to cause a small reduction in heart rate The reduction in heart rate effect observed with Compound 9 may be due to the final concentration of ethanol in the vehicle of the Compound 9 (4 5% v/v) being greater than the final concentration of ethanol used as vehicle for the Compound 10 (2 5% v/v) At 30 mg/kg, the maximum fall in MAP caused by the Compound 10 and Compound 9 were similar (about 45 mm Hg) The Compound 10 caused a small increase in heart rate, while the Compound 10 appeared to cause a small reduction in heart rate The latter effect again may be due to the difference in concentration of ethanol in the vehicle of the Compound 9 (15% v/v) and the vehicle of Compound 10 (8.5% v/v) The systemic hemodynamic effects of Compound 10 were also compared to those elicited by either mPEG 5kDa-ester-Compound X diacetate (Compound 2) or mPEG 20kDa-ester-Compound X diacetate (Compound 5) Clearly, according to the results, the fall in MAP was dependent on the size of the PEG-moiety, with compound possessing the lowest PEG molecular weight eliciting the largest fall in MAP. For instance, at 10 mg/kg, the maximum fall in MAP elicited by Compound 10 was 35 mm Hg, while the fall in MAP caused by Compound 5 was 20 mm Hg Similarly the compound containing the lowest molecular weight PEG also caused the largest reflex tachycardia At 30 mg/kg, the maximum fall in MAP elicited by Compound 10 was about 40mm Hg, while the fall in MAP caused by Compound 5 was about 30 mm Hg The effects of all the compounds on heart rate were similar The systemic hemodynamic effects of Compound 9 were also compared to those elicited by either mPEG 5kDa-amιde-Compound X diacetate (Compound 8) or mPEG 20kDa-amιde-Compound X diacetate (Compound 7) The fall in MAP was dependent on the size of the PEG-moiety, as the compound containing the lowest molecular weight PEG elicited the most rapid fall in MAP. For example, at 10 mg/kg, the fall in MAP elicited by Compound 9 within 1 minute was about 20 mm Hg (maximum, about 25 mm Hg at 60 minutes), while the fall in MAP caused by Compound 7 within 1 minute was negligible (maximum about 30 mm Hg at 180 minutes). The Compound 9 which was dissolved in ethanol (4.5%o) caused a small fall in heart rate, while the others (dissolved in acetate buffer) had not effect on heart rate At 30 mg/kg, the fall in MAP elicited by Compound 9 within 1 minute was about 45 mm Hg (maximum: about 45 mm Hg at 1 minute), while the fall in MAP caused by Compound 7 within one minute was negligible (maximum about 30 mm Hg at 180 minutes) The Compound 9, which was dissolved in ethanol (15%) caused a significant fall in heart rate, while the others (dissolved in acetate buffer) had no effect on heart rate EXAMPLE 16 Effects of Compound X and PEG coniuqated Compound X on Pulmonary Vascular Hypertension in Sheep In Vivo Each sheep was monitored for measurement of pulmonary arterial pressure (PPA), left atrial pressure (PLA), systemic arterial pressure (PSA), cardiac output (CO), and heart rate (HR) Plasma samples were taken from the sheep subjects to measure drug levels within the blood throughout the experiment The experiment began upon intravenously infusing a known pulmonary arterial hypertension inducer in a customary manner The rate of inducement was adjusted to cause the pulmonary vascular resistance (PVR) to increase 3 to 4 times that of the initial baseline PVR PVR is calculated as the difference between PPA and PLA divided by the CO After a stabilization period, a sample of a present prostaglandin compound was administered via a surgically prepared tracheotomy using a MEDICATOR® aerosol drug delivery system (Healthline Medical Inc , Baldwin Park CA), or via intravenous infusion Experiments were conducted to determine the effects of intravenously infused mPEG20kDa-amιde-compound X which was prepared similarly to Compound 1 of Example 1 , and mPEG20kDa-ester-compound X previously referred to as Compound 3 of Example 3, and aerosolized mPEG 20kDa-ester-compound X (Compound 3) during pulmonary hypertension inducement Referring to Figure 1 after about a 15 minute baseline was established, pulmonary hypertension was induced by the intravenous administration of a known drug (a PGH 2 analog, U44069 or 9,11 -dιdeoxy,9α, 1 l α-epoxymethanoprostaglandιn F 2α ) into the sheep After allowing the sheep to achieve a steady state for about 85 minutes mPEG20kDa- amide-Compound X (1 25 g I V ) was intravenously infused into the sheep After about 75 minutes of infusion of mPEG20kDa-amιde-Compound X, a complete reversal of the pulmonary arterial hypertension was observed for the rest of the duration of the experiment Referring to Figure 2, a intravenous bolus administration of mPEG20kDa- ester-Compound X (1.25g IN.) was made upon allowing the sheep to achieve a steady state for 30 minutes. The PPA-PLA reading dropped from about 28 cmH 2 0 to about 17 cmH 2 0 within 30 minutes after administration The pressure remained depressed at about the same level for about 5 hours thereafter, and gradually rose to about 25 cmH 2 O over the next hour thereafter Referring to Figure 3, after the sheep was permitted to achieve steady state for about 30 minutes after infusion of U44069, mPEG20kDa-ester-Compound X (0.625 g) was administered as an aerosol for about 1 hour The PPA-PLA rapidly dropped from about 32.5 cmH 2 O to about 21 cmH 2 0 The pressure rose slightly to about 22.5 cmH 2 O before the aerosol infusion was discontinued The pressure remained stable at about 22 5 cmH 2 0 for about another 135 minutes and very gradually rose to about 32 5 cmH 2 0 over 105 minutes thereafter Referring to Figure 4, the sheep was permitted to reach steady state for about 30 minutes after infusion of U44069, before a smaller intravenous bolus of mPEG 20kDa-ester-Compound X (0 625 g I V ) was administered The PPA-PLA dropped to about 31 cmH 2 0 from a maximum reading of about 37 5 over a 1 hour period. The pressure remained stable for about 90 minutes before the pressure began to slowly rise to about 35 cmH 2 O for about another hour thereafter Referring to Figure 5, in another experiment using the same methods described above, a comparison is shown between the effects of native Compound X and a mPEG5k-ester-Compound X prepared similarly to Compound 3 of Example 3 during U44069-ιnduced pulmonary hypertension After allowing the U44069- infused sheep to reach steady state for about 90 minutes native Compound X at 1 μg/kg was administered in an aerosol formulation over a 15 minute period The PPA-PLA levels were normalized in this figure A drop from about 1 1 25 cmH 2 0 to about 5 cmH 2 0 was observed 10 minutes after termination of the aerosolized infusion of native Compound X Thereafter the pressure increased sharply to about 10 cmH 2 0 after only 30 minutes after termination of the Compound X infusion After allowing the U44069-ιnfused sheep to reach steady state for about 90 minutes, mPEG5k-ester-Compound X at 1 mg/kg was administered as an aerosol formulation over a 15 minute period A substantial dramatic drop in pressure from about 18 25 cmH 2 0 to about 1 cmH 2 0 below baseline reading occurred 30 minutes after the infusion was terminated The pressure remained depressed at about 1 5 cmH 2 O for another hour thereafter The pressure increased very gradually over the next 2 5 hours thereafter to about 7 5 cmH 2 0 The pressure stayed below the 50% maximal reading over the entire 240 minute period after termination of the aerosolized infusion of mPEG5k-ester-Compound X EXAMPLE 17 Systemic Hemodynamic Effects from Aerosolized Administration of Present Prostaglandin Compounds in Sheep in Vivo General Protocol The aerosolized administration of the present prostaglandin compounds to sheep subjects is performed to determine the effects of such compounds on systemic hemodynamics Each sheep is monitored for measurement of pulmonary arterial pressure (PPA), left atrial pressure (PLA), systemic arterial pressure (PSA), cardiac output (CO), and heart rate (HR) Plasma samples are taken from the sheep subjects to measure drug levels within the blood throughout the experiment The experiment begins upon intravenously infusing U44069 (9 1 1 -dideoxy 9α 1 1 α- epoxymethanoprostaglandin F 2α a PGH 2 analog) to artificially induce pulmonary arterial hypertension The rate of U44069 infusion is adjusted to create pulmonary vascular resistance (PVR) to increase 3 to 4 times that of the initial baseline PVR PVR is calculated as the difference between PPA and PLA divided by the CO After a stabilization period, one of the present prostaglandin compounds is administered via a surgically prepared tracheotomy using a MEDICATOR® aerosol drug delivery system (Healthline Medical Inc , Baldwin Park CA) Specific Protocols A A first series of experiments is performed to determine a reasonable effective dose of the present prostaglandin compounds which would reverse U44069-ιnduced pulmonary arterial hypertension, and ascertain the effective period of the particular dose of present prostaglandin compounds administered After obtaining a baseline measurement of all listed variables for 20 minutes, U44069 is infused intravenously at a rate sufficient to cause PVR to increase 3 to 4 times its baseline value After allowing 10 minutes to reach a relatively stable response, one of the present prostaglandin compounds is administered via aerosol at a rate of 3000 ng per kg per minute for 60 minutes (i e , for a 30 kg sheep 3000 ng*30*60= 5 4 mg of drug or 270 mg of drug/PEG) If the present prostaglandin compound provides a measurable effect on the elevated PVR, the U44069 is continuously infused until a stable response is observed Upon reaching a stable response, the U44069 is discontinued for 20 minutes and resumed for another ten minutes This process is repeated until the U44069 induced increase in PVR is no longer attenuated by the sample present prostaglandin compound If the sample compound dose is not effective from 30 to 60 minutes of its administration, the dosage is increased by a three-fold amount If the sample compound dose is effective, then a new sheep subject is used and the experiment is repeated with the new dosage being one-third the previous dosage This procedure is repeated until the minimal effective dosage and its corresponding effective dosage is determined B A second series of experiments is performed to determine the effects of the present prostaglandin compounds on control sheep Three doses of the present prostaglandin compounds is prepared for additional experiments The first dose is the dose determined to be the minimal effective dose from the first series of experiments The second dose of the present prostaglandin compounds is twice the minimal effective dose, and the third dose is five times that of the minimal effective dose The sheep administered with the corresponding dose is monitored for a minimum of 2 hours per dose administered 91

Claims: What Is Claimed: 1. A compound of Formula la or lb [P — τι—z la P— [T— Zln lb wherein P is a prostaglandin compound or analog thereof, T is an active group of P, and Z is a pharmaceutically acceptable group which is bound to T and which slows the metabolic rate of said compound; n is an integer of at least 1 , and pharmaceutically acceptable salts thereof 2. The compounds of claim 1 wherein T is selected from the group consisting a carboxyl group, a hydroxyl group, a carbonyl group, an oxidized carbohydrate, and a mercapto group. 3. The compounds of claim 1 wherein T is a carboxyl group or a hydroxyl group. 4. The compounds of claim 1 wherein Z is a pharmaceutically acceptable polymer or an acetyl group. 5. The compounds of Claim 4 wherein the pharmaceutically acceptable polymers are selected from the group consisting of polyalkylene oxides, dextran, polyvinyl pyrrohdones, polyacrylamides, polyvinyl alcohols, and carbohydrate based polymers. 6. The compounds of claim 5 wherein the pharmaceutically acceptable polymers are selected from polyalkylene oxides 7. The compounds of claim 6 wherein the polyalkylene oxides are selected from polyethylene glycols 8. The compounds of claim 7 wherein the molecular weight of the polyethylene glycols is from about 200 to 80,000 9. The compounds of claim 7 wherein the molecular weight of polyethylene glycols is from about 2,000 to 42,000 10. The compounds of claim 9 wherein the molecular weight of the polyethylene glycols is from about 5,000 to 25,000 11 The compounds of claim 1 having the Formula wherein Z and Z 2 are each independently selected from the group consisting of hydrogen, a pharmaceutically acceptable polymer and an acetyl group with the proviso that at least one of Z, and Z 2 are not hydrogen, and X is selected from 0 and NH 12 The compounds of claim 11 selected from Group 1 compounds wherein Z λ is a pharmaceutically acceptable polymer, X is selected from 0 and NH and each Z 2 is independently selected from hydrogen and an acetyl group 13 The compounds of claim 11 selected from Group 2 compounds wherein Z is hydrogen, X is selected from 0 and at least one Z 2 is a pharmaceutically acceptable polymer attached to the oxygen atom through an ester group 14 The compounds of claim 11 selected from Group 3 compounds wherein Z is a pharmaceutically acceptable polymer, X is selected from 0 and NH and at least one Z 2 is a pharmaceutically acceptable polymer attached to the oxygen atom through an ester group 15. The compounds of claim 1 having the Formula III wherein Z., and Z 2 are each independently selected from the group consisting of hydrogen, a pharmaceutically acceptable polymer and an acetyl group f is an integer of from 1 to 3, X is selected from O and NH; and R is selected from hydrogen and an alkyl group 16 The compounds of claim 15 wherein R is an alkyl group having 1 -6 carbon atoms 17 The compounds of claim 15 selected from Group 4 compounds wherein Z, is a pharmaceutically acceptable polymer, X is selected from 0 and NH and each Z 2 is independently selected from hydrogen and an acetyl group 18 The compounds of claim 15 selected from group 5 compounds wherein Z 1 is hydrogen, X is 0 and each Z 2 is an acetyl group or a pharmaceutically acceptable polymer attached to the oxygen atom through an ester or an ether group 19 The compounds of claim 15 selected from Group 6 compounds wherein Z Λ is a pharmaceutically acceptable polymer X is selected from 0 and NH and each Z 2 is a pharmaceutically acceptable polymer attached to the oxygen atom through an ester or an ether group 20 The compounds of claim 1 1 where the pharmaceutically acceptable polymer is a polyethylene glycol having a molecular weight of from about 200 to 80,000 21 The compounds of claim 20 wherein the molecular weight of the polyethylene glycol is from about 2,000 to 42,000 22 The compounds of claim 15 where the pharmaceutically acceptable polymer is a polyethylene glycol having a molecular weight of from about 200 to 80,000 23 The compounds of claim 22 wherein the molecular weight of the polyethylene glycol is from about 2 000 to 42 000 24 The compounds of claim 15 having the Formula IV wherein a is from about 6 to 600 25 The compounds of claim 15 wherein Z λ is a methyl terminated polyethylene glycol having a molecular weight of about 5 000 X is NH and each Z 2 is hydrogen 26 The compounds of claim 15 wherein Z, is a methyl terminated polyethylene glycol having a molecular weight of about 5 000 X is O and each Z 2 is an acetyl group 27 The compounds of claim 15 wherein Z 1 is hydrogen and each Z 2 is a methyl terminated polyethylene glycol having a molecular weight of about 20 000 attached to the oxygen atom through a group -O-(CH 2 ) 2 -CO- 28 The compounds of claim 15 wherein Z is hydrogen and each Z 2 is an acetyl group 29 The compounds of claim 15 wherein Z λ is a methyl terminated polyethylene glycol having a molecular weight of about 20 000 X is O and each Z 2 is an acetyl group 30 The compounds of claim 15 wherein Z, is a methyl terminated polyethylene glycol having a molecular weight of about 20 000 X is NH and each Z 2 is hydrogen 31 The compounds of claim 15 wherein Z-, is a methyl terminated polyethylene glycol having a molecular weight of about 20 000 X is NH and each Z 2 is an acetyl group 32 The compounds of claim 15 wherein Z1 is a methyl terminated polyethylene glycol having a molecular weight of about 5,000, X is NH and each Z 2 is an acetyl group 33 The compounds of claim 15 wherein Z, is a methyl terminated polyethylene glycol having a molecular weight of about 350, X is NH and each Z 2 is an acetyl group 34 The compounds of claim 15 wherein Z Λ is a methyl terminated polyethylene glycol having a molecular weight of about 350 X is O and each Z 2 is an acetyl group 35 A pharmaceutical composition comprising an effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier 36 A pharmaceutical composition comprising an effective amount of the compound of claim 1 1 and a pharmaceutically acceptable carrier 37 A pharmaceutical composition comprising an effective amount of the compound of claim 15 and a pharmaceutically acceptable carrier I 0 l 38 A method of treating at least one of peripheral vascular disease and pulmonary hypertension comprising administering to a warm-blooded animal the composition of claim 35 39 The method of claim 38 comprising administering said composition in an amount sufficient to provide from about 0 5 to 100 mg/kg/day to said warm¬ blooded animal 40 The method of claim 35 comprising administering said composition intravenously to said warm-blooded animal 41 The method of claim 35 comprising administering said composition subcutaneously to said warm-blooded animal 42 The method of claim 35 comprising administering said composition by inhalation to said warm-blooded animal 43 The method of claim 35 comprising administering said composition orally to said warm-blooded animal

Inventors: BENTLEY MICHAEL D, ROTHBLATT MARTINE, SHORR ROBERT, ZHAO XUAN, BENTLEY, MICHAEL, D., ROTHBLATT, MARTINE, SHORR, ROBERT, ZHAO, XUAN
Applicants: BENTLEY MICHAEL D, ROTHBLATT MARTINE, SHORR ROBERT, UNITED THERAPEUTICS CORP, ZHAO XUAN, BENTLEY, MICHAEL, D., ROTHBLATT, MARTINE, SHORR, ROBERT, UNITED THERAPEUTICS CORPORATION, ZHAO, XUAN
Application year: 2000
Main classification: A01N37
IPC codes: A61K31, A61K47, A61P9, A61P11, C07C69, C07C235, C07C405, C07D307