6-SUBSTITUTED MYCOPHENOLIC AND DERIVATIVES WITH IMMUNOSUPPRESSIVE ACTIVITY

Abstract: The disclosed 6-substituted derivatives of mycophenolic acid of formula (I) are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil.

Description: 6-SUBSTITUTED MYCOPHENOLIC AND DERIVATIVES WITH IMMUNOSUPPRESSIVE ACTIVITY Field of the Invention The present invention relates to mycophenolic acid derivatives where the 6-methoxy substituent has been replaced by other groups, including natural and derivative side chains at the 5-position. The invention is also directed to formulations and methods for treatment. Background Information Mycophenolic acid ("MPA") was initially described as a weakly-active antibiotic found in the fermentation broth of PiM-iicilliiim breviconψactum, having the following structure. Mycopheno l ie Aci MPA and certain related compounds, such as mycophenolate mofetil (the morpholinoethyl ester of MPA) , having the following structure: have more recently been described as having particularly advantageous properties as immunosuppressant drugs. Various derivatives of mycophenolic acid, their synthesis and uses in the treatment of autoimmune disorders, psoriasis, inflammatory diseases, including, in particular, rheumatoid arthritis, tumors, viruses, and for treatment of allograft rejection, are described in U.S. Patents Nos. 4,686,234; 4,725,622; 4,727,069; 4,748,173; 4,753,935; 4,786,637; 4,808,592; 4,861,776; 4,868,153; 4,948,793; 4,952,579; 4,959,387; 4,992,467; 5,247,083; and U.S. Patent Application Serial No. 07/927,260, filed August 7, 1992. As immunosuppressive agents, the previously described esters and derivatives of mycophenolic acid are useful in treating auto-immune related disorders, glomerulonephritis and hepatitis, and in preventing allograft rejection. As anti-inflammatory agents, they are useful in treating rheumatoid arthritis. As anti-tumor agents, they are useful in treating solid tumors and malignancies of lymphoreticular origins. See also U.S. Patents No. 3,825,571 and 3,853,919; Japanese Pat. No. J 01290667; J. tied. Chem. , 33(2), 833-8 (1990) ; Auεtr. J. Chem. , 31(2), 353-64, (1978) ; . and J. JLntibiot . , 29(3), 275-85, 286-91 (1976) . The disclosed compounds are described as having anti-tumor, immunosuppressive, anti-viral, anti-arthritic and/or anti-psoriatic activities. The article by J.W. Patterson and G. Huang, Chemical Communications, 1579 (1991) describes synthetic methodology of interest with respect to such compounds. The above-cited patents, publications, and the references/ publications referenced therein, are all incorporated herein by reference. SUMMARY OF THE INVENTION One aspect of the present invention concerns mycophenolic acid derivatives, i.e., the compounds of Formula A: Formula A wherein: R 1 is H or C(0)R 10 , where R 10 is lower alkyl, aryl or NH-aryl; R 2 is lower alkyl, cycloalkyl, vinyl, fluorovinyl, difluorovinyl, trifluorovinyl, alkenyl, -C≡C-R 11 , allenyl, CHO or CH j OR 12 , where R 11 is H or lower alkyl, and R 12 is H or 4-methoxybenzyl; and Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH: Formula ZA wherein: Z 1 is H, lower alkyl, halo or CF 3 ; Z 2 is H, lower alkyl, lower alkoxy, aryl, or CH-Z 11 , where Z 11 is halo, CN, aryl or heteroaryl; iε H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, or S(0) m -lower alkyl, where m is 0, 1 or 2; is H, lower alkyl, or phenyl; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH 2 ) n -NG 1 G 2 , or O- (CH 2 ) n -N=G 3 , where n is an integer from 1 to 6, G 1 is H or lower alkyl, G 2 is H or lower alkyl, and =G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -O-, -S-, or -N(G 4 ) H or lower alkyl; or Formula ZB wherein: Z 5 is H or lower alkyl; Z 8 is H, .lower alkyl or forms a double bond with D 2 ; D 1 and D 2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and G is as defined above; or Formula ZC wherein: Z 8 is H or lower alkyl; and Z 5 and G are as defined above; or Formula ZD wherein : D 3 is -CH 2 - or -CH 2 -CH 2 - ; and G is as defined above ; or Formula ZE wherein: Z 6 is H, lower alkyl, COOH, NH 2 , azido or halo; Z 7 is H, lower alkyl or halo; and Z 5 and G are as defined above; or Formula ZF wherein: Z 1 and G are as defined above; or wherein: Z and G are as defined above; or Formula ZH wherein: D 4 is -CΑ.- , -CHj-CHj-, -CHj-CHj-CHj-, -0-, or -0-CH 2 -; and Z 1 and G are as defined above; aind the pharmaceutically acceptable salts thereof. In another aspect, the invention relates to a pharmaceutical composition containing a therpeutically effective amount of a compound of Formula A or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. In still another aspect, the invention relates to a method of treating immune, inflammatory, tumor, proliferative, viral and psoriatic disorders in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula A or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION Definitions and General Parameters The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. The term "alkyl" refers to a fully saturated monovalent radical containing only carbon and hydrogen, and which may be a cyclic, branched or straight chain radical. This term is further exemplified by radicals such as methyl, ethyl, t-butyl, pentyl, pivalyl, heptyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, adamantyl, and the like. The term "lower alkyl" refers to a cyclic, branched or straight chain monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl) , cyclopropylmethyl, i-amyl, n-amyl, and hexyl. The term "alkylene" refers to a fully saturated divalent radical containing only carbon and hydrogen, and which may be a branched or straight chain radical. This term is further exemplified by radicals such as methylene, ethylene, n-propylene, t-butylene, i-pentylene, and n-heptylene. The term "lower alkylene" refers to a fully saturated divalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methylene, ethylene, n-propylene, i-propylene, n-butylene, t-butylene, i-butylene (or 2-methylpropylene) , isoamylene, pentylene, and n-hexylene. The term "lower alkenyl" refers to an unsaturated monovalent hydrocarbon radical of one to six carbon atoms. This term is further exemplified by such radicals as vinyl, prop-2-enyl, pent-3-enyl, and hex-5-enyl. The term "lower acyl" refers to the group -C(0)-R', where R 1 is lower alkyl. The term "aryl" refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl) , which can optionally be mono-, di- or tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano. The term "heteroatom" refers to oxygen, sulfur and nitrogen, unless otherwise specified. The term "heteroaryl" refers to a monovalent aromatic carbocyclic radical having at least one heteroatom within the ring, such as quinolyl, benzofuranyl, pyridyl, morpholinyl and indolyl, which can optionally be mono-, di- or tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano. The term "optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms" as used with reference to a side chain of Formula ZB encompases side chains of the following structures: where the line inside each respective ring indicates the optional presence of a double bond and X 1 , X 2 , X 3 , X 4 and X 5 can independently be -CHX"-, -C(O)- , -C(N-X b )-, -C(N-NX d X β ) -, -0-, -S-, -S(O)-, -S(0) 2 - or -NX 0 -, where X" is H, lower alkyl or forms a double bond; X ' bb is acyl, carbamoyl or ureido; X c is lower alkyl, C(0)X d , SfO)^ or C(0)NX d X e ; and X d and C are independently H or lower alkyl; provided that if more than one heteroatom is present such heteroatoms are separated by at least one carbon atom. The term "halo" refers to fluoro, bromo, chloro and iodo, unless otherwise specified. The definition "=G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -0-, -S-, or -N(G 4 )-" means that -N=G 3 represents a heterocyclic derivative such as pyrrolidinyl, piperidinyl, hexamethyleneiminyl, imidazolidino, thiazolidino, morpholino, thiomorpholino, piperazino, thiopentamethyleneimino, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. A "pharmaceutically acceptable salt" is a salt that retains the biological effectiveness and properties of the compounds of formula I and which are not biologically or otherwise undesirable. Salts may be derived from acids or bases. The term "pharmaceutically acceptable anion" refers to the anion of acid addition salts. "Pharmaceutically acceptable cation" refers to the cation of base addition salts. The acid addition salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and biεulfate salts) , nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, salicylic acid, p-toluenesulfonic acid, and the like. The base addition salts may be derived from inorganic bases, and include sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include those formed from primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, hiεtidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosa ine, -alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, and choline. The term "treatment" or "treating" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms. The term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected. "Isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. . "Enantiomerε" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term " (±) " is used to designate a racemic mixture where appropriate. "Diaεtereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line. The compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula A depends upon the number of asymmetric centers present (there are 2 n stereoisomers possible where n is the number of asymmetric centers) .. The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula A by conventional means. The individual stereoisomers (including individual enantiomers and diaεtereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompasεed within the εcope of the present invention, all of which are intended to be depicted by the structures of this specification unlesε otherwise specifically indicated. Specific examples of the separation of isomers are set forth in the Examples. "Structure of Formula A" refers to the generic structure of the compounds of the invention. The chemical bonds indicated as a wavy line, for example for Z 3 and Z 4 in Formula 105 below, indicate a racemic mixture. Nomenclature The naming and numbering of the compounds of the present invention is illustrated below. The isobenzofuranyl nucleuε of the compounds of Formula A iε numbered aε follows: Side chains of Formula ZA are numbered as shown below: Representative compounds of Formula A where the side chain is ZA are as follows: and are named: 1. (E) -6- (l,3-dihydro-4-hydroxy-6,7-dimethyl-3-oxoisobenzofuran-5-yl) - 2- (S) ,4-dimethyl-4-hexenoic acid; 2. (E) -6- (6-cyclopropyl-l,3-dihydro-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2- (S) -ethyl-4-methyl-4-hexenoic acid; 3. 2-morpholinoethyl (E) -4-chloro-6- (1,3-dihydro-6-ethynyl-4-hydroxy-7- methyl-3-oxoisobenzofuran-5-yl) -3-methyl-2-methylsulfonyl-4-hexenoate (where G 3 is - (CH 2 ) 2 -0- ; 4. thiomethyl (E) -2- (R) -chloro-6- (4-benzoyloxy-l,3-dihydro-6- hydroxymethyl-7-methyl-3-oxoisobenzofuran-5-yl) -2-methoxy-3-methyl-4- hexenoate. Side chains of Formula ZB in which D 1 and D 2 do not contain a heteroatom are numbered as shown below: and are named: 1. (E) -2-{2- [2- [l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene] cyclopent-1- (S) -yl}acetic acid; 2. (E) -2-{2- [2- (l,3-dihydro-6- (1-fluorovinyl) -4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] -l-ethylcyclohex-l-yl}acetic acid; 3. (E)-2-{2-[2- (4-acetoxy-l,3-dihydro-7-methyl-3-oxo-6- (prop-2- enyl) isobenzofuran-5-yl)ethylidene] cyclohept-l-yl}propionic acid dimethylamide (where G 1 and G 2 are both methyl) ; 4. (E) -2-{2- [2- (6-but-2-ynyl-l,3-dihydro-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] -5-oxocyclohex-l-yl}acetic acid; 5. thiomethyl (E) -2-{2- [2- (l,3-dihydro-6-formyl-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] cyclobut-1- (R) -yl}octanoate. Side chains of Formula ZB that include a heteroatom are numbered starting with the heteroatom as poεition 1 of the ring, for example, as shown below for a 6-atom heterocycle. Representative compounds of Formula A where the side chain is ZB including a heteroatom are as follows: and are named: 1. (E) -2-{4- [2- (l,3-dihydro-6,7-dimethyl-4-hydroxy-3-oxoisobenzofuran-5- yl)ethylidene] tetrahydrofuran-3-yl}acetic acid; 2. hexyl (E) -2-{4- [2- (4-acetoxy-l,3-dihydro-7-methyl-3-oxo-6- vinylisobenzofuran-5-yl)ethylidene] -3-methylpiperidin-3 (S) - ylJpropionate; 3. (E) -2-{4- [2- (6-allenyl-l,3-dihydro-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl) ethylidene] thiepan-3-yl}heptanoic acid dimethylamide (where G 1 and G 2 are both methyl) . Side chains of Formula ZC are numbered as shown below: Representative compounds of Formula A where the side chain is ZC are as follows: and are named: 1. 3- (1,3-dihydro-4-hydroxy-6-i-propyl-7-methyl-3-oxoisobenzofuran-5- ylmethyl) -2-methylcyclopent-2-enyl-l- (S) -acetic acid; 2. hexyl 3- (4-acetoxy-l,3-dihydro-7-methyl-3-oxo-6- trifluorovinyliεobenzofuran-5-ylmethyl) cyclopent-2-enyl-1-acetate; 3. 2- (S) - [3- (l,3-dihydro-4-hydroxy-6- (4-methoxybenzyloxymethyl) -7- methyl-3-oxoisobenzofuran-5-ylmethyl) -2-methylcyclopent-2-en-l (S) - yl] -1- (S) -3-methylbutyric acid; (2-dimethylamino)ethyl 3- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-ylmethyl) -2-hexylcyclopent-2-enyl-1-acetate (where G 1 and G 2 are both methyl) . Side chains of Formula ZD are numbered as shown below: w h e r e D i s C H . w h e r e D i s C H rx C H Representative compoundε of Formula A where the εide chain is ZD are as follows: are named as follows: 1. (E) -3- [2- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran- 5-yl)ethylidene]cyclopentane-1- (R) -carboxylic acid; 2. hexyl (E) -4- [2- (4-acetoxy-6-cyclopropyl-1,3-dihydro-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclohexane-1-carboxylate; 3. methyl (E) -3- [2- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- vinyliεobenzofuran-5-yl)ethylidene] cyclopentane-1-thiocarboxylate. Side chainε of Formula ZE are numbered aε shown below: Representative compoundε of Formula A where the side chain iε ZE are aε follows: and are named: (E) -2- [3- (l,3-dihydro-6,7-dimethyl-4-hydroxy-3-oxoiεobenzofuran-5- yl) -l-methylprop-l-en-l-yl]benzoic acid; (E) -2- [3- (4-acetoxy-l,3-dihydro-6- (2, 2 -dif luorovinyl) -7-methyl-3- oxoiεobenzofuran-5-yDprop-l-en-l-yl] -6-methylbenzoic acid dimethyl amide (where G 1 and G 2 are both methyl) ; hexyl (E) -6-chloro-2- [3- (1, 3-dihydro-4-hydroxy-7-methyl-6-n-butyl-3- oxoisobenzofuran-5-yl) -1-hexylprop-l-en-l-yl] -6-chlorobenzoate. Side chains of Formula ZF are numbered as shown below: Representative compounds of Formula A where the εide chain is ZF are as follows: and are named: 4- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- ylmethyl) -3-methylcyclopent-3-ene-l- (S) -carboxylic acid; ethyl 4- (4-acetoxy-1,3-dihydro-7-methyl-3-oxo-6-vinyliεobenzofuran-5■ ylmethyl) -3-hexylcyclopent-3-ene-1-carboxylate; thiomethyl 4- (l,3-dihydro-6-ethynyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-ylmethyl) cyclopent-3-ene-1-carboxylate. Side chains of Formula ZG are numbered aε shown below: Repreεentative compounds of Formula A where the εide chain is ZG are aε follows: and are named: 1. 3- [3- (S)'- (1,3-dihydro-6,7-dimethyl-4-hydroxy-3-oxoisobenzo-furan-5- yl) cyclopent-1-en-1-yl] -propionic acid; 2. methyl 3- [3- (R) - (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) cyclopent-1-en-l-yl] -2-chloro-2-methyl propionate; 3. 3- [3- (6-cyclopentyl-l,3-dihydro-7-methyl-3-oxo-4- propionyloxyiεobenzo-furan-5-yl) cyclopent-1-en-l-yl] -3-methyl-2- phenyl propionic acid; 4. methyl 3- [3- (R) - (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- vinyliεobenzofuran-5-yl) cyclopent-1-en-1-yl] propionate; 5. 3- [3- (4-benzoyloxy-l,3-dihydro-6-formyl-7-methyl-3-oxoisobenzofuran- 5-yl) cyclohex-1-en-l-yl] -2(R) ,3-dimethyl-2-methoxy propionic acid. Side chains of Formula ZH are numbered aε εhown below: Representative compounds of Formula A where the side chain is ZH are aε followε: are named as follows: 1. (E) -2- [3- (l,3-dihydro-6,7-dimethyl-4-hydroxy-3-oxoisobenzofuran-5- yl) -1-methylprop-l-en-l-yl] cyclopentane-1-carboxylic acid; 2. Ethyl (E) -2- [3- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl) -1-methylprop-l-en-l-yl] cyclohexane-lR- carboxylate; 3. Thiomethyl (E) -2- [3- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- vinyliεobenzofuran-5-yl)prop-1-en-1-yl] cycloheptane-1-carboxylate. Compounds of Formula A where the side chain is ZH, in which D 4 iε a heteroatom, are numbered differently. For example, the compound where R 2 is ethyl, D 4 iε oxygen, Z 1 iε methyl, and G iε hydroxy, is named aε follows: 4. (E) -2- [3- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -1-methylprop-l-en-l-yl] tetrahydrofuran-3-carboxylic acid. Synthetic Reaction Parameters The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane) , diethyl ether, methanol, pyridine and the like] . Unless specified to the contrary, the solventε uεed in the reactions of the present invention are inert organic solvents. The term "q.s." means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to a desired volume (for example, q.s. to 100%) . unless specified to the contrary, the reactions described herein take place at atmospheric pressure within a temperature range from 5°C to 100°C (preferably from 10°C to 50°C; most preferably at "room" or "ambient" temperature, e.g., 20°C) . Further, unleεε otherwise specified, the reaction times and conditions are intended to be approximate, e.g., taking place at about atmoεpheric preεεure within a temperature range of about 5°C to about 100°C (preferably from about 10°C to about 50°C; moεt preferably about 20°C) over a period of about 1 to about 10 hourε (preferably about 5 hourε) . Parameters given in the Examples are intended to be specific, not approximate. Iεolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedureε can, of course, also be used. Except as specified to the contrary, the compounds and intermediates are isolated and purified by conventional means. As indicated above, compoundε that have one asymmetric center can exist as R or S enantiomers or as mixtures thereof. If desired, the individual R and S enantiomers can be separated by known methods, or can be synthesized individually. For example, an acidic racemic compound can be converted into a salt, ester or amide with a chiral base, alcohol or amine. The resulting mixture of diastereomers can be separated by conventional means εuch as crystallization, distillation or chromatography. The separated compounds can then be subjected to conventional reactions εuch as hydrolysis, to produce the individual enantiomers of the chiral acid. A chiral compound which iε baεic can be resolved analogously. Alternatively, a chiral compound can be separated into enantiomers by selective reaction of one of the enantiomers, or of a derivative. For example, an ester or amide of a racemic compound can be selectively hydrolyzed by chemical or biological (e.g., enzymatic) reactions to produce the individual enantiomers of the racemic compound. Compoundε that have two asymmetric centers exist as two diastereomers. The diastereomers can be separated by conventional methods such aε cryεtallization, distillation or chromatography. Each separate diaεtereomer exists aε a pair of enantiomerε which can be separated by conventional methods such as those described above. Alternatively, the diastereomers or enantiomers can be prepared separately, by means of εtereospecific or diastereoselective reactions known to thoεe εkilled in the art. Alternatively, chiral precursors to chiral compounds of this invention can be prepared using known procedures such as stereoselective or εtereoεpecific reactionε, after which the chiral precursor can be converted into the chiral product. Synthesis of the Compounds of Formula A The compounds of Formula A are εyntheεized starting from the precursorε of Formula I: Formula I where R 1 iε hydrogen and Z has the meaningε εet forth in the Summary of the Invention, where G iε OH or lower alkoxy [designated as the group -Z*-OH or -Z"-lower alkyl in Reaction Schemes A and B, which follow Reaction Schemeε ZA-A-1 through ZH-B (in other words, Z* is any side chain of Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG or ZH without the substituent deεignated aε G) ] . The compoundε of Formula I are prepared aε illuεtrated with reference to Reaction Schemeε ZA-A-1 through ZH-B below, the preparations of which are exemplified in copending application Serial No. 08/???,???, Attorney Docket No. 27960, entitled "5-Substituted Derivatives Of Mycophenolic Acid, " previously incorporated by reference. As those skilled in the art will appreciate, the intermediates synthesized in the preparation of compounds of Formula I, e.g., where R* iε toεyl and/or where G iε lower alkoxy can be substituted in Reaction Scheme A for the compounds of Formula IA and 2 without need for conversion through corresponding compounds where R a is H and G is OH. For example, the compounds of Formula 105 where R a iε aryl or alkylεulfonyl can be used directly as compound of Formula 2 in Reaction Scheme A. Alternatively, when R 2 is lower alkyl or cycloalkyl, by using mycophenolic acid as the starting material and performing the syntheεeε described with reference to Reaction Schemes A and B, the correspondingly obtained 6-substituted derivatives can be further derivatized at the 4- and/or 5-position(ε) , e.g., as described with reference to Reaction Schemes ZA-A through ZH-B. As used in the Reaction Schemeε, the εubstituents (e.g., m, D 1 , G, Z 1 ) have the same meaning as described in the Summary of the Invention unless otherwise specified in a particular instance. Subεtituents introduced for purposes of a particular reaction scheme (e.g., R a in Reaction Scheme ZA-A) are defined in the detailed description of the corresponding synthesis. Starting Materials Mycophenolic acid iε commercially available, e.g., from Sigma Chemical Company, St. Louiε, MO. The mycophenolic acid lower alkyl esters of Formula 1 can be εynthesized, for example, aε described in Synthetic Organic Chemistry by Wagner and Zook (Wiley, New York) 1956, see pages 479- 532. Other reactants, such as methoxyethoxy methyl chloride, t-butyl- dimethylεilyl chloride, and various orthoesters are likewise commercially available or may be readily prepared by those skilled in the art using commonly employed synthetic methodology. Preparation of Compounds of Formula I-ZA One method of preparing compoundε of Formula I where Z is sidechain of Formula ZA, illustrated aε compoundε of Formula I-ZA, is shown below in Reaction Schemes ZA-A to ZA-M. REACTION SCHEME ZA-A Formula 101 Formula 102 Formula 1D2 Formu I a 103 F Formula 104 Formula 103a Fo Fo r mula 104a Formula 105 For ula -ZA-A Preparation of Formula 102 As illustrated in Reaction Scheme ZA-A, Step 1, the phenolic hydroxyl group of a mycophenolic acid lower alkyl ester iε protected. A mycophenolic acid lower alkyl ester of Formula 101, in a solvent (such as ether, ethyl acetate, DMF or preferably dichloromethane) , iε reacted with an equimolar amount of a halogenated protecting group (εuch aε: methoxyethoxymethyl chloride; a εulfonyl chloride, e.g., toεyl chloride, mesyl chloride; or a silyl chloride, e.g., trimethylsilyl chloride, diphenylmethylsilyl chloride, or preferably tert-butyldimethyl- silyl chloride) in presence of an equimolar amount of an organic base (such as diisopropylethylamine, triethylamine or imidazole) . The reaction takes place at -20 to 35°C (preferably at 25°C) for 1 to 24 hours (preferably 16 hourε) to give the correεponding compound of Formula 102 (where R" is the protecting group) . Preparation of Formula 103 Aε illustrated in Reaction Scheme ZA-A, Step 2, the εide chain double bond of a protected mycophenolic acid lower alkyl eεter iε ozonized to yield an aldehyde. A εtream of ozonized oxygen is passed through a solution of a protected compound of Formula 102 in a solvent (such as an alcohol, a halocarbon, or preferably a mixture of methanol and dichloromethane) . The reaction takes place at -100 to -40°C (preferably at -80 Q C) , and continues until the presence of excesε ozone is detected by the development of a blue color, indicating the formation of an intermediate α-alkoxyhydroperoxide, which is reduced without further purification, by the addition of a reducing agent (εuch aε zinc and acetic acid, dimethyl εulfide, or preferably thiourea) . The reaction takeε place at -80°C to 25°C (preferably 0°C) over a period of 12 to 24 hours (preferably 16 hours) , to give the corresponding aldehyde of Formula 103. Preparation of Formula 104 As illustrated in Reaction Scheme ZA-A, Step 3, the aldehyde is converted to a carbinol by addition of an organometallic compound of Formula 103a [where M is MgBr or lithium, preferably MgBr (a Grignard reagent) ; Z 1 is H, lower alkyl or CF 3 , and Z 2 is H or lower alkyl] . An organolithium reagent iε formed by reaction of a halovinyl (preferably bromovinyl) compound of Formula 103a (where M is halo) with an alkyllithium (preferably n-butyllithium) in an ethereal solvent (such as ether, or preferably tetrahydrofuran) . The reaction takeε place at -100 to 0°C (prefereibly -40°C) over a period of 0.5 to 5 hourε (preferably 1 hour) . Alternatively the halovinyl compound of Formula 103a iε reacted with magneεium metal in an ethereal solvent (such as ether or preferably tetrahydrofuran) . The reaction takeε place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hourε (preferably 2 hours) . The organometallic compound of Formula 103a where M iε zinc or cadmium may be prepared by reaction of 103a where M iε Li or MgBr w.ith a zinc or cadmium halide, preferably chloride. The compound of Formula 103a where M is tin may be prepared by reaction of 103a where M is Li or MgBr with a trialkyl chlorostannane, preferably tributyltin chloride. The compound of Formula 103a where M iε tin may also be prepared by reaction of 103a where M is trifluoromethanesulfonate by reaction with a compound of formula (R 3 Sn) 2 , where R iε alkyl, preferably methyl, in the presence of a palladium catalyst, preferably tetrakis(triphenylphosphine)palladium. The compound of Formula 103a where M is trifluoromethanesulfonate may be prepared from a ketone of the formula: by reaction with a strong base (such as sodium hydride or potasεium hexamethyldisilazide) , followed by reaction of the anion thus produced with trifluoromethaneεulfonic anhydride. Alternatively, the compound of Formula 103a where M iε tin may be prepared by reacting a trialkyl tin hydride (preferably tributyl tin hydride) with an acetylene of the formula Z'-O≡C-Z 2 . One molar equivalent of the reεultant organometallic reagent iε added to a solution of an aldehyde of Formula 103 (in the same solvent system used to make the organometallic reagent) . The reaction takeε place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minutes (preferably 10 minutes) to give the corresponding carbinol of Formula 104. Preparation of Formula 105 Aε illustrated in Reaction Scheme ZA-A, Step 4, an alkyl ester of Formula 105 is formed by a Claiεen ortho ester rearrangement reaction of a carbinol of Formula 104 and an orthoester of Formula 104a (where Z 3 is H, halo, lower alkyl, lower alkenyl, phenyl, alkoxy or -thio lower alkyl; and Z 4 iε H or lower alkyl; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl) . A carbinol of Formula 104 is heated at 50 to 140°C (prefereibly about 130°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalentε (preferably 0.10 molar equivalents) of an organic acid catalyst (such aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hours (preferably 3 hourε) to give the corresponding alkyl ester of Formula 105. Preparation of Formula I-ZA-A Formula I-ZA-A is prepared aε described below with reference to Reaction Scheme ZA-M, Step 1 (in which the compound of Formula I-ZA-A iε named Formula I-ZA-M1) . The compoundε of Formula I-ZA-A are alεo employed aε starting materials in Step 1 of Reaction Scheme ZA-K. Preparation of Enantiomers of Formula I-ZA where Z z is Lower Alkyl One method of preparing individual enantiomers of compounds of Formula I where Z is sidechain ZA, illustrated as compounds of Formula I-ZA, is from chiral compounds of Formula 104b, the preparation of which is shown below in Reaction Scheme ZA-A-1. REACTION SCHEME ZA-A-1 Formula 103 Formu la 103f Formula 03f Formula 103g where Y is chloro or bromo. Formu l a 103g Formu l a 103a Formu la 103 Formula 104b Preparation of Formula 103f As illustrated in Reaction Scheme ZA-A-1, Step 1, an aldehyde of Formula 103 is oxidized to the corresponding carboxylic acid of Formula 103f. An aldehyde of Formula 103 iε reacted with about two molar equivalentε of an oxidizing agent (for example, chromic acid, εilver oxide, bleach, or preferably sodium periodate) , in an inert solvent (εuch as toluene, or preferably ethyl acetate) , in the presence of water [and, when using sodium periodate or bleach as the oxidizing agent, a catalytic amount (for example, about 0.01 molar equivalents) of ruthenium oxide, or preferably ruthenium trichloride] . The reaction takes place at 0 to 40°C (preferably 25°C) for 30 minutes to 8 hours (preferably 2 hours) , to give the corresponding carboxylic acid of Formula 103f. Preparation of ' Formula 103g As illustrated in Reaction Scheme ZA-A-1, Step 2, a carboxylic acid of Formula 103f iε converted to the correεponding acyl halide of Formula 103g. A carboxylic acid of Formula 103f iε reacted with about one molar equivalent, preferably 1.1 molar equivalents, of a thionyl or oxalyl halide (for example, thionyl chloride, thionyl bromide, or preferably oxalyl chloride) , in an inert solvent (such aε dichloromethane, or preferably ethyl acetate) , in the presence of a catalytic amount (for example, about 0.05 molar equivalents) of dimethylformamide. The reaction takes place at 0 to 40°C (preferably 25°C) for 30 minutes to 8 hours (preferably 2 hours) , to give the correεponding acyl halide of Formula 103g. Preparation of Formula 103h As illustrated in Reaction Scheme ZA-A-1, Step 3, an acyl halide of Formula 103g iε converted to the correεponding keto olefin of Formula 103h by addition of an organometallic compound of Formula 103a. An acyl halide of Formula 103g is reacted with about one molar equivalent of a organometallic compound of Formula 103a (where M iε cadmium, zinc, tin, or the like, prepared aε shown in the preparation of compounds of Formula 104) , in an inert solvent (εuch aε dichloromethane, ether or preferably tetrahydrofuran) , optionally in the preεence of a catalytic amount (for example, about 0.05 molar equivalentε) of a palladium catalyst [preferably tetrakis (triphenylphosphine)palladium] . The reaction takes place at -10 to 20°C (preferably 0°C) for 30 minutes to 8 hours (preferably 4 hours) , to give the corresponding keto olefin of Formula 103h. Preparation of Formula 104b Aε illustrated in Reaction Scheme ZA-A-l, Step 4, a keto olefin of Formula 103h iε reduced stereospecifically to the corresponding carbinol of Formula 104b by reduction with borane methyl sulfide in the presence of a catalytic amount of (R) -tetrahydro-1-methyl-3,3-diphenyl-lH,3H-pyrrolo- [1,2-c] [l,3,2]oxazabprole. A keto olefin of Formula 103h is stereospecifically reduced with about one molar equivalent of borane methyl sulfide in the presence of a catalytic amount (0.05-0.3 molar equivalents) of (R) -tetrahydro-1-methyl- 3,3-diphenyl-lH,3H-pyrrolo- [1,2-c] [1,3,2] oxazaborole in an inert solvent (preferably a mixture of toluene and dichloromethane) . The reaction takes place at -30 to 40°C (preferably -20°C) for 1-24 hours (preferably 12 hours) , to give the corresponding carbinol of Formula 104b. Preparation of Enantiomers of Compounds of Formula I-ZA The chiral carbinol of Formula 104b is then converted to an enantiomer of a compound of Formula I-ZA in the same manner as shown above in Reaction Scheme ZA-A (conversion of compounds of Formula 104 to 105 to I-ZA) . REACTION SCHEME ZA-B Formula 10B Formula 103b Formula 106 Formula 107 Formula 106a Preparation of Formula 106 As illustrated in Reaction Scheme ZA-B, Step 1, an aldehyde of Formula 103 iε tranεformed into an unεaturated aldehyde of Formula 106 by a Wittig reaction with an ylid of Formula 103b (where Z 1 is H or lower alkyl) . An aldehyde of Formula 103 is reacted with one molar equivalent of an ylid of Formula 103b, in an organic solvent (such as dichloromethane, dimethylformamide or preferably toluene) . The reaction takes place at 0 to 110°C (preferably 80°C) for 1 to 24 hours (preferably 8 hours) to give the corresponding unεaturated aldehyde of Formula 106. Preparation of Formula 107 As illustrated in Reaction Scheme ZA-B, Step 2, an unsaturated aldehyde of Formula 106 is condensed with the anion of an ester of Formula 106a (where Z 3 is H, lower alkyl, lower alkenyl, or phenyl and Z 4 is H, lower alkyl, or phenyl) to give a beta-hydroxy ester of Formula 107. An ester of Formula 106a iε converted to an alkali metal salt by reacting a solution of the ester in an ethereal solvent (such aε ether or preferably tetrahydrofuran) with an equimolar amount of an alkali metal hydride, hexamethyldiεilazide or amide (preferably lithium diiεopropylamide) at a temperature of -100 to 0°C (preferably -80°C) , for 30 minutes to 2 hourε (preferably 30 minuteε) to give a solution of the corresponding ester anion. The ester anion solution (1.0 to 1.5 molar equivalentε, preferably 1.0 molar equivalentε) iε added to a solution of an unεaturated aldehyde of Formula 106 in the εame ethereal εolvent. The condensation reaction takeε place at a temperature of -100°C to 0°C (preferably -80°C) for 1 to 6 hours (preferably 2 hourε) to give the corresponding beta-hydroxy ester of Formula 107. REACTION SCHEME ZA-C Formula 107 Formu la 108 Preparation of Formula 108 Aε illustrated in Reaction Scheme ZA-C, Step 1, the beta-hydroxy group of an ester of Formula 107 iε O-alkylated to give the corresponding beta-alkoxy ester (R) of Formula 108. An ester of Formula 107 is reacted with 1 to 3 (preferably 1.5) molar equivalents of an alkyl halide (preferably an alkyl iodide, εuch aε methyl iodide or n-butyl iodide, preferably methyl iodide) and 1 to 3 (preferably 1.25) molar equivalentε of εilver oxide, in a polar organic solvent (such as dioxane, dimethylformamide or preferably acetonitrile) . The reaction takes place at 25 to 100°C (preferably 70°C) for 1 to 24 hours (preferably 4 hourε) to give the corresponding beta-alkoxy ester of Formula 108. REACTION SCHEME ZA-E Formula 106 Formula 109 Formula 109 Formula 110 Formula 109a Formula 110 Formula I-ZA-E Preparation of Formula 109 Aε illuεtrated in Reaction Scheme ZA-E, Step 1, an unεaturated aldehyde of Formula 106 iε reduced and then converted to the corresponding compound of Formula 109 in which R b is a leaving group (a sulfonate or halide, preferably a bromide) . An unεaturated aldehyde of Formula 106 iε reacted with from 0.5 to 2 (preferably 1) molar equivalentε of a reducing agent (such as sodium cyanoborohydride or preferably sodium borohydride) in an alcoholic solvent (such as ethanol, isopropanol or preferably methanol) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 12 hours (preferably 2 hourε) to give the correεponding allylic alcohol (not εhown) which is used without isolation or further purification. The allylic alcohol is reacted with from 1 to 1.5 (preferably 1.25) molar equivalents of a εulfonating agent (such aε p-tolueneεulfonyl chloride) and an organic baεe, or preferably reacted with a halogenating reagent (εuch aε carbon tetrachloride/triphenylphosphine or preferably N-bromosuccinimide/triphenylphosphine) in an inert organic εolvent (εuch as ether or preferably dichloromethane) . The reaction takes place at a temperature of -40 to 40°C (preferably -10°C) for 1 to 12 hours (preferably 2 hours) to afford the corresponding compound of Formula 109. Preparation of Formula 110 An allylic halide or sulfonate of Formula 109 iε alkylated with a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a to give the correεponding chiral εubstituted acyl oxazolidinone of Formula 110. An alkali metal (preferably. lithium) salt of a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a (the alkyl group preferably being 4- isopropyl) by reaction of the N-acyl oxazolidinone with 1 to 1.25 (preferably 1.05) molar equivalentε of an alkali metal hydride, hexamethyldisilazide or dialkylamide (preferably lithium diisopropylamide) in an inert organic εolvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takeε place at -100 to -20°C (preferably -80°C) for 5 to 120 minuteε (preferably 30 minuteε) . The solution of the allylic compound of Formula 109 in the same solvent is added to the salt (1 to 3, preferably 3 molar equivalents) . The alkylation reaction takeε place at -100 to 0°C (preferably -10°C) for 30 minuteε to 6 hourε (preferably 1 hour) to afford the correεponding chiral εubεtituted acyl oxazolidinone of Formula 110. Preparation of Formula I-ZA-E Aε illustrated in Reaction Scheme ZA-E, Step 3, a chiral εubεtituted acyl oxazolidinone of Formula 110 is hydrolyzed to the corresponding chiral acid of Formula I-ZA-E. Use of an acyl oxazolidinone of Formula 109a having a 4-alkyl substituent of the opposite configuration in Reaction Scheme ZA-E, Step 2, followed by hydrolyεis aε deεcribed in Step 3 reεultε in the correεponding chiral acid where Z 3 has the opposite configuration. An acyl oxazolidinone of Formula 110 is reacted with from 1.25 to 3.5 (preferably 3.0) molar equivalentε of lithium hydroxide, in a mixture of water and a water-miεcible organic solvent (such as dioxane or preferably tetrahydrofuran) containing from 6 to 10 (preferably 8) molar equivalents of 30% aqueous hydrogen peroxide. The reaction takes place at -20 to 40°C (preferably 20°C) for 1 to 24 hours (preferably 12 hours) to afford the corresponding chiral acid of Formula I-ZA-E. REACTION SCHEME ZA-H Formula 109 lkyl Formula 112 Formula 109b Preparation of Formula 112 As illuεtrated in Reaction Scheme ZA-H, Step 1, an allylic compound of Formula 109 in which R iε a leaving group (a sulfonate or halide, preferably a bromide) is condensed with an ester of Formula 109b to give the mono- or di-alkyl ester of Formula 112 (where Z 3 is H, lower alkyl, lower alkenyl, or phenyl and Z 4 is H, lower alkyl, or phenyl) . An ester of Formula 109b iε converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal amide (such as sodium hexamethyldisilazide, potassium tetramethylpiperidide or preferably lithium diisopropylamide) in an organic solvent (such aε ether, dioxane or preferably tetrahydrofuran) . The reaction takes place at -40 to 30°C (preferably 0°C) for 15 minutes to 3 hours (preferably 30 minutes) . Without isolation or further purification, the resulting solution of the alkali metal salt of the ester of Formula 109b (1.2 to 1.6, preferably about 1.3 molar equivalents) is then reacted with an allylic compound of Formula 109, in the same solvent, optionally in the presence of from 2% to 10% (preferably about 5%) by volume of hexamethyl phosphoric tria ide. The reaction takeε place at -100 to -40°C (preferably -80°C) for 30 minuteε to 6 hourε (preferably 1 hour) to afford the corresponding alkyl ester of Formula 112. REACTION SCHEME ZA-K lkyl Formula l-ZA-A Formula l-ZA-K Preparation of Formula -ZA-K Aε illuεtrated in Reaction Scheme ZA-K, Step 1, a 2- (alkylthio) -4- hexenoic acid eεter of Formula I-ZA-A (where Z 3 iε S-lower alkyl, and Z 4 is H or lower alkyl) is oxidized to give the corresponding 2- (alkylsulfinyl) - or 2- (alkylsulfonyl) -4-hexenoic acid ester of Formula I-ZA-K (where m is 1 or 2) . Alternatively, the reaction can be performed with an acid of Formula I-ZA-M2 where Z 3 is S-lower alkyl, to give the correεponding acid where Z 3 iε 2- (alkylsulfinyl) or 2- (alkylsulfonyl) . An alkylthio-4-hexenoic acid eεter of Formula I-ZA-A iε reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of an oxidizing agent (εuch as Oxone ® ) optionally in the presence of an inert support (εuch as alumina) , in a solvent (εuch aε chloroform or preferably dichloromethane) . The reaction takeε place at 0 to 55°C (preferably 35°C) for 1 to 10 hourε (preferably 2 hourε) to afford the correεponding 2- (alkylεulfinyl) -4- hexenoic acid eεter of Formula I-ZA-K (where m iε 1) . By repeating the foregoing procedure under the εame conditions [starting with the 2- (alkylsulfinyl) -4-hexenoic acid ester so-produced] , or by conducting the reaction with the 2- (alkylthio) -4-hexenoic acid ester starting material [and using 2.0 to 2.5 (preferably 2.25) molar equivalentε of oxone] the correεponding 2-alkylεulfonyl-4-hexenoic acid esters are produced. A 2- (alkylsulfinyl) - or 2- (alkylεulfonyl) -4-hexenoic acid eεter of Formula I-ZA-K iε hydrolyzed to give the corresponding acid as described with reference to Reaction Scheme ZA-M, Step 2. Alternatively, the acid can be obtained by substituting the correεponding 2- (alkylthio) -4-hexenoic acid for the ester starting material as described in Reaction Scheme ZA-K, Step 1. REACTION SCHEME ZA-L Formu l a 103c f ormu l a 114 Formu l a 115 Preparation of Formula 114 As illustrated in Reaction Scheme ZA-L, Step 1, a protected aldehyde of Formula 103 and a triphenylphoεphoranylideneacetate of Formula 103c are combined in a Wittig reaction to give the correεponding alkyl-2-halo- butenoate eεter of Formula 114. An aldehyde of Formula 103 is reacted with 1.0 to 1.5 (preferably 1.1) molar equivalents of an alkyl 2-halo-2-triphenylphosphoranylidene- acetate of Formula 103c (the halo group preferably being chloro) in an organic εolvent (such as acetonitrile, or preferably dimethylformamide or toluene) . The reaction takes place at 0 to 120°C (preferably 110°C) for 4 to 48 hours (preferably 24 hourε) to afford the correεponding alkyl 2-halo-4-aryl-2-butenoate eεter of Formula 114. Preparation of Formula 115 As illustrated in Reaction Scheme ZA-L, Step 2, a protected alkyl 2- halo-4-aryl-2-butenoate ester of Formula 114 iε converted to the correεponding bromide of Formula 115 via converεion to the corresponding acid (not shown) and reduction to the corresponding alcohol (not εhown) . A 2-halo-4-aryl-2-butenoate ester of Formula 114 (preferably a t- butyl ester) is . converted to the correεponding acid (preferably by dissolution in trifluoroacetic acid at room temperature for 1 to 2 hours) . The acid is isolated and purified by conventional means, then reacted with 0.5 to 3 (preferably 1.6) molar equivalents of a reducing agent (εuch aε εodium cyanoborohydride, sodium borohydride, or preferably borane dimethyl disulfide complex) in a solvent (such aε methanol, ethanol, isopropanol or preferably THF) . The reaction takeε place at 0 to 50°C (preferably 25°C) for l to 48 hourε (preferably 24 hours) to give the correεponding alcohol (not εhown) which iε used after purification. The allylic alcohol so-produced iε reacted with from 1 to 1.5 (preferably 1.25) molar equivalentε of a sulfonating agent (such as p-toluenesulfonyl chloride) and an organic base, or preferably reacted with a halogenating reagent (εuch as carbon tetrachloride/triphenylphoεphine or preferably N-bromosuccinimide/triphenylphosphine) in an inert organic solvent (such as ether or preferably dichloromethane) . The reaction takeε place at a temperature of -40 to 40°C (preferably -10°C) for 1 to 12 hourε (preferably 2 hourε) to afford the corresponding 2-halo-4-aryl-2-butenyl bromide compound of Formula 115. Preparation of Formula I-ZA-L Aε illuεtrated in Reaction Scheme ZA-L, Step 3, a protected 2-halo-4- aryl-2-butenyl bromide compound of Formula 115 is condensed with a dialkyl malonate of Formula 116, subεtituted by Z 4 (where Z 4 iε hydrogen, lower alkyl, or phenyl) , which iε hydrolyzεed and decarboxylated to give the correεponding 4-halo-4-hexenoic acid derivative of Formula I-ZA-L. An eεter of Formula 116 (where Z 4 iε H, lower alkyl, or phenyl) is converted to an alkali metal εalt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal hydride (preferably sodium hydride) in an organic solvent (such aε ether, dioxane or preferably tetrahydrofuran) . The reaction takeε place at -40 to 30°C (preferably 0°C) for 15 minuteε to 3 hourε (preferably 30 minuteε) . Without iεolation or further purification, the resulting solution of the alkali metal salt of the ester of Formula 116 (1.2 to 1.6, preferably about 1.3 molar equivalentε) is then reacted with an allylic bromo compound of Formula 115 in the same solvent. The reaction takes place at -20 to 50°C (preferably 25°C) for 30 minuteε to 6 hourε (preferably 2 hours) to afford the corresponding dialkyl ester derivative. The dialkyl ester thus produced is then hydrolyzsed conventionally, using a strong base, preferably aqueouε sodium hydroxide, in a protic solvent, preferably ethanol, heating to reflux. The dicarboxylic acid thus produced is separated conventionally, and then decarboxylated by heating, preferably in a high-boiling inert solvent, most preferably 1,2- dichlorobenzene, to give the corresponding 4-halo-4-hexenoic acid derivative of Formula I-ZA-L. REACTION SCHEME ZA-M lkyl Formula 117 Formula I-ZA- 1 Formula I-ZA- 1 Formula I-ZA-M2 Preparation of Formula I-ZA-M1 As illuεtrated in Reaction Scheme ZA-M, Step 1, an alkyl ester of Formula 117 (which can be any of the corresponding protected eεterε of Reaction Schemeε ZA-A to ZA-L, such as Formulae 105, 107, 108, and 112) iε deprotected to give the correεponding alkyl eεter of Formula I-ZA-M1. An alkyl eεter of Formula 117 (having either an acetal-type or a εilyl-type protecting group) is treated with from 0.05 to 0.2 molar equivalents (preferably 0.1 molar equivalents) of an aqueouε mineral acid (εuch aε εulfuric, perchloric, or preferably hydrochloric acid) , in a water-miscible organic εolvent (εuch as methanol, acetone, or preferably ethanol) . The reaction takes place at 0 to 50°C (preferably 25°C) over a period of 1 to 6 hours (preferably 2 hours) to give the correεponding free phenol of Formula I-ZA-M1. Alternatively, to remove acetal-type protecting groups (εuch as MEM) a compound of Formula 117 iε treated with 0.05 to 0.25 molar equivalents (preferably 0.1 molar equivalentε) of a Lewiε acid (such as zinc chloride or preferably zinc bromide) , in a εolvent (εuch aε benzene, chloroform, or preferably dichloromethane) . The reaction takeε place at 0 to 50°C (preferably 25°C) over a period of 1 to 12 hours (preferably 3 hourε) to give the corresponding free phenol of Formula I-ZA-M1. Alternatively, to remove silyl-type protecting groupε (such as t- butyldimethylsilyl) a compound of Formula 117 is reacted with 1.0 to 1.5 (preferably 1.25) moles of a tetraalkyl ammonium fluoride (preferably tetrabutylammonium fluoride) in an ethereal solvent (εuch as dioxane or preferably tetrahydrofuran) . The reaction takes place at -10 to 25°C (preferably 0°C) over a period of 0.1 to 2 hours (preferably 0.5 hourε) to give the corresponding free phenol of Formula I-ZA-M1. Preparation of Formula I-ZA-M2 As illuεtrated in Reaction Scheme ZA-M, Step 2, an alkyl eεter of Formula I-ZA-M1 (prepared as described above, or which can.be any of previouεly described deprotected esterε, εuch aε Formulae I-ZA-A, I-ZA-G, I-ZA-I, I-ZA-J, and I-ZA-K) iε hydrolyzed to give the correεponding acid of Formula I-ZA-M2. An alkyl ester of Formula I-ZA-M1 iε reacted with from 1.5 to 4 molar equivalentε (preferably 2 molar equivalentε) of an inorganic hydroxide (εuch aε potassium, sodium, or preferably lithium hydroxide) in a mixture of water and an organic solvent (such as tetrahydrofuran, methanol, or preferably dimethoxyethane) . The reaction takes place at 0 to 60°C (preferably 40°C) over a period of 1 to 12 hourε (preferably 3 hourε) . The reεulting anion iε acidified with an aqueous mineral acid (such as hydrochloric acid) . The acidification takeε place at 0 to 40°C (preferably 25°C) over a period of 1 to 10 minuteε (preferably 2 minuteε) to give the corresponding acid of Formula I-ZA-M2. Preparation of Compounds of Formula I-ZB One method of preparing compounds of Formula I where Z is sidechain of Formula ZB, illustrated as compoundε of Formula I-ZB, is shown below in Reaction Schemes ZB-A to ZB-A-1. REACTION SCHEME ZB-A Formu I a 103 + Formu la 201 Formu la 202 where M iε Li or MgBr. Formu la 202 Formu la 203 Formu la 203 Formula I-ZB-A Preparation of Formula 202 Aε illuεtrated in Reaction Scheme ZB-A, Step 1, the aldehyde of Formula 103 iε converted to a carbinol of Formula 202 by addition of an unεaturated cyclic organometallic compound of Formula 201 where M is Li or MgBr, prepared for example aε deεcribed above with reference to Reaction Scheme ZA-A, Step 3. One molar equivalent of the organometallic reagent 201 iε added to a solution of an aldehyde of Formula 103 (in the εame εolvent εyεtem uεed to make the organometallic reagent) . The reaction takes place at -80 to -20°C (preferably -40°C) over a period of 5 to 60 minutes (preferably 15 minutes) to give the correεponding carbinol of Formula 202. Resolution of Formula 202 The racemic compound of Formula 202 may be separated into its two enantiomerε by conventional means, for example by conversion into two diastereoisomerε that are then εeparated by crystallization, chromatography, or by any conventional separation technique. Preferably, the carbinol is reacted with a chiral iεocyanate to give a mixture of diaεtereoiεomeric carbamateε, which are separated by chromatography and cleaved to give the pure enantiomers. A carbinol of Formula 202 is heated at 30 to 100°C (preferably about 60°C) with 2 to 6 molar equivalentε (preferably 4 molar equivalentε) of a chiral iεocyanate in the presence of 1 to 1.5 molar equivalents (preferably 1.2 molar equivalents) of a strong organic base, for example 4-dimethylaminopyridine, in a hindered tertiary amine (for example diisopropylethylamine) as a solvent. The reaction takes place over a period of 1 to 24 hourε (preferably 7 hours) to give the corresponding carbamate as a mixture of diastereoiεomerε. The mixture of diaεtereoisomeric carbamateε is separated by conventional means, preferably chromatography. The individual diastereoiεomerε are then εeparately cleaved by treatment with 1 to 1.5 molar equivalents (preferably 1.2 molar equivalents) of a trihalosilane, for example trichloroεilane, in the preεence of an exceεε of a tertiary amine, for example triethylamine, in an inert εolvent, for example toluene. The reaction takeε place at a temperature of 90-120°C (preferably 110°C) over a period of 5 minuteε to 2 hours (preferably 15 minutes) to give the corresponding enantiomer of the carbinol of Formula 202. Preparation of Formula 203 As illustrated in Reaction Scheme ZB-A, Step 2, an alkyl ester of Formula 203 is formed by a Claiεen ortho eεter reaction of a carbinol of Formula 201 (or an enantiomer thereof) with an appropriately substituted orthoester. A carbinol of Formula 202 is heated at 50 to 140°C (preferably 130°C) with a large exceεε of an orthoeεter of Formula 104a (εee Reaction Scheme ZA-A, εtep 4), in the presence of from 0.05 to 0.25 molar equivalentε (preferably 0.10 molar equivalents) of an organic acid catalyst (such aε propionic, butyric, or trimethylacetic acid, preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 24 hourε (preferably 2.5 hourε) to give the corresponding alkyl ester of Formula 203. Preparation of Formula I-ZB-A Compounds of Formula I-ZB-A are prepared aε deεcribed above with reference to Reaction Scheme ZA-M, Step 1 (deprotection to afford the corresponding alkyl ester) , and Step 2 (hydrolysiε to afford the correεponding acid of Formula I-ZB-A) . Alternative Preparation of Enantiomers of Compounds of Formula I-ZB Another method of preparing individual enantiomers of compoundε of Formula I where Z iε εidechain ZB, illuεtrated as compounds of Formula I-ZB, is from chiral compoundε of Formula 202b, the preparation of which iε shown below in Reaction Scheme ZB-A-1. REACTION SCHEME ZB-A-1 For ula 103g + Formula 201 Formu la 202a Formula 202a Formu la 202b Preparation of Formula 202a Compounds of Formula 202a are prepared aε deεcribed above with reference to Reaction Scheme ZA-A-1, Step 3 (converεion of 103g to 103h) . Preparation of Formula 202b Compoundε of Formula 202b are prepared as described above with reference to Reaction Scheme ZA-A-1, Step 4 (conversion of 103h to 104b) . Preparation of Enantiomers of Compounds of Formula I-ZB The chiral carbinol of Formula 202b iε then converted to an enantiomer of a compound of Formula I-ZB in the εame manner aε shown above in Reaction Scheme ZB-A (converεion of Formula 202 to 203 to I-ZB-A) . Preparation of Compounds of Formula I-ZC One method of preparing compounds of Formula I where Z is sidechain of Formula ZC, illustrated as compoundε of Formula I-ZC, iε εhown below in Reaction Scheme ZC-A. REACTION SCHEME ZC-A Formu la 302 Formu la 301 Formula 302 Formula 303 F rmula 303 Formula 304 Formu la 304 For ula 305 Formula 306 Formula 306 Formu I a 307 For u la 307 Formu la 308 Formu la 308 For ula 309 Formu la 309 For u la I-ZC Preparation of Formula 302 Aε illuεtrated in Reaction Scheme ZC-A, Step 1, an aldehyde of Formula 103 (prepared, for example aε deεcribed above with reference to Reaction Scheme ZA, Steps 1 and 2) iε transformed into an unsaturated aldehyde of Formula 302.by a Wittig reaction with an ylid of Formula 301 (where Z 5 iε H or lower alkyl) . An aldehyde of Formula 103 iε reacted with one molar equivalent of an ylid of Formula 301, in an organic εolvent (such as dichloromethane, dimethylformamide or preferably toluene) . The reaction takeε place at 0 to 110°C (preferably 80°C) for 1 to 24 hourε (preferably 8 hourε) to give the correεponding unεaturated aldehyde of Formula 302. Preparation of Formula 303 As illustrated in Reaction Scheme ZC-A, Step 2, an unεaturated aldehyde of Formula 302 is converted to the corresponding vinyl carbinol of Formula 303. An aldehyde of Formula 302 is reacted with from 1.0 to 1.25 (preferably 1.1) molar equivalentε of an organovinyl compound (preferably vinylmagneεium bromide) in a solvent (such aε ether or preferably tetrahydrofuran) . The reaction takes place at -30 to 20°C (preferably at 0°C) for 0.1 to 4 hours (preferably 0.5 hourε) to give the corresponding vinyl carbinol of Formula 303. Preparation of Formula 304 As illustrated in Reaction Scheme ZC-A, Step 3, a vinyl carbinol of Formula 303 is oxidized to give the corresponding dienone of Formula 304. A vinyl carbinol of Formula 303 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of an oxidizing agent (εuch aε manganeεe dioxide, pyridinium chlorochromate or preferably pyridinium dichromate) in a solvent (such as pyridine or preferably dichloromethεine) . The reaction takes place at 0 to 30°C (preferably 25°C) for 30 minutes to 4 hours (preferably 1 hour) to give the correεponding dienone of Formula 304. Preparation of Formula 305 Aε illustrated in Reaction Scheme ZC-A, Step 4, a dienone of Formula 304 is cyclized to give the corresponding cyclopentenone of Formula 305. A dienone of Formula 304 reacted with 0.3 to 1.5 (preferably 1.0) molar equivalentε of a Lewiε acid (εuch as boron trichloride, tin (IV) chloride or preferably boron trifluoride etherate) in a solvent (such aε tetrachloroethane or preferably dichloromethane) . The reaction takeε place at 0 to 30°C (preferably 25°C) for 1 to 6 hourε (preferably 2 hourε) to give the corresponding cyclopentenone of Formula 305. Preparation of Formula 306 As illustrated in Reaction Scheme ZC-A, Step 5, a cyclopentenone of Formula 305 is reduced to give the corresponding cyclopentenol of Formula 306. A cyclopentenone of Formula 305 is reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of a reducing agent (εuch aε lithium tri-tert-butoxyaluminium hydride or prefereibly sodium borohydride in the presence of an equimolar amount of cerium trichloride) in a mixture of an ethereal solvent (preferably tetrahydrofuran) and a lower alkanol (preferably methanol) . The reaction takes place at 0 to 40°C (preferably at 25°C) for 1 to 6 hours (preferably 2 hours) to give the cyclopentenol of Formula 306. Preparation of Formula 307 Aε illuεtrated in Reaction Scheme ZC-A, Step 6, a cyclopentenol of Formula 306 iε tranεformed to the correεponding vinyl ether of Formula 307. A cyclopentenol of Formula 306 is reacted with from 10 to 100 (preferably 50) molar equivalentε of a 1-alkenyl ether, optionally in the presence of a co-solvent (such as ether or tetrahydrofuran) , in the presence of from 0.1 to 0.5 (preferably 0.3) molar equivalentε of a mercury (II) εalt (preferably mercury (II) acetate) . The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 5 days (preferably 2 days) to give the corresponding vinyl ether of Formula 307. Preparation of Formula 308 Aε illuεtrated in Reaction Scheme ZC-A, Step 7, a vinyl ether of Formula 307 iε rearranged to the correεponding acetaldehyde of Formula 308. A vinyl ether of Formula 307 iε reacted with from 10 to 100 (preferably 50) molar equivalents of a lithium εalt (such as the tetrafluoroborate or preferably the perchlorate) in a solvent (such as tetrahydrofuran or preferably ether) . The reaction takeε place at 0 to 35°C (preferably 25°C) for 0.1 to 2 hourε (preferably 0.5 hourε) to give the corresponding acetaldehyde of Formula 308. Preparation of Formula 309 Aε illuεtrated in Reaction Scheme ZC-A, Step 8, an acetaldehyde of Formula 308 iε oxidized to give the corresponding acid of Formula 309. An acetaldehyde of Formula 308 is reacted with 1 to 3 (preferably 1.5) molar equivalents of a suitable oxidizing agent [such as silver oxide, Jones reagent or sodium chlorite, preferably sodium chlorite in the presence of an equimolar amount of a phenol (such aε quinol. or preferably reεorcinol)] . The reaction iε conducted in a mixture of water and a water- miεcible organic solvent (such as tetrahydrofuran or preferably dioxane) at a pH of from 4 to 6 (preferably 5) at -10 to 25°C (preferably 0°C) for 10 minutes to 2 hourε (preferably 30 minutes) to give the corresponding acid of Formula 309. Preparation of Formula I-ZC As illuεtrated in Reaction Scheme ZC-A, Step 9, an acid of Formula 309 iε deprotected to give the correεponding acid of Formula I-ZC. An acid of Formula 309 where R" is a εulphonyloxy protecting group hydrolyzed under baεic conditionε, using from 1 to 5 (preferably 3) molar equivalents of an alkali metal hydroxide (preferably lithium hydroxide) in a mixture of water and a water-miscible organic solvent (such as dioxane or preferably methanol) . The reaction takeε place at 40 to 100°C (preferably 60°C) for 1 to 48 hourε (preferably 12 hourε) to afford the correεponding cyclopentene carboxylic acid of Formula I-ZC. Alternatively, for other protecting groups, the deprotection reaction takes place aε described above with reference to Reaction Scheme ZA-M, Step 1. Preparation of Compounds of Formula I-ZD One method of preparing compoundε of Formula I where Z iε sidechain of Formula ZD, illuεtrated aε compounds of Formula I-ZD, iε εhown below in Reaction Scheme ZD-A. REACTION SCHEME ZD-A Formula 40 Fo u la 03d I ky For u I a 104a Fo u la 402 Formu la 402 For u la 403 Formu la 403 Formu la I - ZD- A 1 For u la I - ZD- A1 Formu la I - ZD- A2 Preparation of Formula 401 As illustrated in Reaction Scheme ZD-A, Step 1, an aldehyde of Formula 103 (where R a iε a εilyl protecting group) is converted to a carbinol by addition of an organometallic compound of Formula 103d (εuch aε a substituted vinyl organolithium, or preferably a Grignard reagent where: M is MgBr or Li; Z 2 is H or lower alkyl; and TBS iε a tert- butyldimethy1silyl protecting group) . The aldehyde of Formula 103 iε reacted with from 1.1 to 1.5 (preferably 1.25) molar equivalents of an organometallic, preferably organolithium, derivative of a protected 2-halo (2-bromo or preferably 2-iodo) but-l-en-4-ol. The reaction is performed at from -100 to -40°C (preferably at -78°C) for from 30 minuteε to 6 hours (preferably 1 hour) to afford the corresponding compound of Formula 401. Preparation of Formula 402 As illustrated in Reaction Scheme ZD-A, Step 2, an alkyl ester of Formula 402 is formed by a Claisen ortho ester rearrangement reaction of a carbinol of Formula 401 and a trialkyl orthoacetate of Formula 104a. A carbinol of Formula 401 is heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 (preferably 0.10) molar equivalentε of an organic acid catalyst (such aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hourε (preferably 8 hours) to give the corresponding alkyl ester of Formula 402. Preparation of Formula 403 As illustrated in Reaction Scheme ZD-A, Step 3, an alkyl ester of Formula 402 is reacted with a tetraalkylammonium fluoride and then halogenated to give a protected eεter of Formula 403. A compound of Formula 402 iε reacted with from 2.0 to 3.0 (preferably 2.0) molar equivalents of a tetraalkylammonium (preferably tetrabutylammonium) fluoride, in a solvent (such as dioxane or preferably tetrahydrofuran or dichloromethane) at from 0 to 25°C (preferably 10°C) , for from 30 minutes to 4 hourε (preferably 1 hour) . The product εo obtained iε reacted with from 1.0 to 1.5 (preferably 1.25) molar equivalentε of a halogenating agent (preferably a brominating agent, εuch aε triphenylphoεphine/carbon tetrabromide or preferably triphenylphoεphine/N-bromosuccinimide) in a solvent εuch aε ether or preferably dichloromethane. The reaction takes place at from -40 to 0°C (preferably -10°C) for from 1 to 6 hours (preferably 4 hours) to give the correεponding halogenated ester of Formula 403. Preparation of Formula I-ZD-A1 As illustrated in Reaction Scheme ZD-A, Step 4, a halogenated ester of Formula 403 is cyclized to give a protected cycloalkyl ester of Formula I-ZD-A1. A compound of Formula 403 is reacted with from 2.0 to 2.5 (preferably 2.25) molar equivalentε of a εtrong base (such as lithium diisopropylamide, sodium hydride or preferably sodium hexamethyldisilazide) in an ethereal solvent (εuch aε ether, dioxane or preferably tetrahydrofuran) The reaction takeε place at from -100 to -60°C (preferably -78°C) for 1 to 12 hourε (preferably 4 hours) to give the protected cycloalkyl ester of Formula I-ZD-A1. Preparation of Formula I-ZD-A2 Aε illuεtrated in Reaction Scheme ZD-A, Step 6, a cycloalkyl eεter of Formula I-ZD-A1 iε hydrolyzed to give the correεponding acid of Formula I- ZE-D2. The hydrolyεiε reaction takeε place aε described above with reference to Reaction Scheme ZA-M, Step 2. Preparation of Compounds of Formula I-ZE One method of preparing compounds of Formula I where Z iε sidechain of Formula ZE, illustrated as compounds of Formula I-ZE, is shown below in Reaction Schemes ZE-A to ZE-E. REACTION SCHEME ZE-A Formula 501 Formula 502 yl Formula 502 Formula 503 Formula 503 Formula 504 Formula 504 Formula 103 Formula 505 Formula 505 Formula 506 Preparation of Formula 502 As illustrated in Reaction Scheme ZE-A, Step 1, the 2-methyl group of an alkyl 2-methylbenzoate of Formula 501 (where Z 6 and Z 7 are selected from H, lower alkyl, halo and nitro) is brominated to give the corresponding compound of Formula 502. An ester of Formula 501 is reacted with 1.0 to 1.2 (preferably 1.05) molar equivalents of a brominating agent (such aε N-bromoacetamide or preferably N-bromoεuccinimide) , optionally in the preεence of an initiator (such as visible light) or from 0.001 to 0.01 (preferably 0.005) molar equivalentε of a chemical initiator (such as azobisisobutyronitrile or preferably benzoyl peroxide) in a solvent (εuch as ethyl formate or preferably carbon tetrachloride) . The reaction takeε place at 40 to 80°C (preferably 75°C) for 30 minuteε to to 6 hourε (preferably 2 hourε) to afford the correεponding alkyl 2-bromomethylbenzoate of Formula 502, which can be purified by conventional means or preferably used directly for the next step. Preparation of Formula 503 As illustrated in Reaction Scheme ZE-A, Step 2, a 2-bromomethyl group of Formula 502 iε converted to the correεponding phosphonium salt of Formula 503. A 2-bromomethylbenzoate of Formula 502 iε reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of a triaryl phosphine (preferably triphenyl phosphine) in a εolvent (such as dimethylformamide or preferably acetonitrile) . ' The reaction takeε place at 25 to 90°C (preferably 50°C) for 1 to 24 hours (preferably 2 hours) to afford the corresponding phoεphonium εalt of Formula 503. Preparation of Formula 504 Aε illuεtrated in Reaction Scheme ZE-A, Step 3, a phosphonium salt of Formula 503 iε converted to the correεponding substituted benzylidenetriphenylphoεphorane ylid of Formula 504. A phoεphonium εalt of Formula 503 iε diεεolved or εuεpended in a solvent (εuch as dioxane, ether or preferably dimethylformamide) and reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of a baεe (εuch aε sodium hydride, triethylamine or preferably 1,5-diazabicyclo- [4.3.0]non-5-ene) . The reaction takes place at 0 to 60°C (preferably 25°C) for 1 to 6 hourε (preferably 2 hours) to afford the correεponding ylid of Formula 504, which can be iεolated by conventional means or its solution can be used directly for the next step. Preparation of Formulae 505 and 506 As illustrated in Reaction Scheme ZE-A, Step 4, an ylid of Formula 504 and a protected aldehyde of Formula 103 (prepared, for example, as described in connection with Reaction Scheme ZA-A, Step 2) are employed in a Wittig reaction to give the corresponding protected subεtituted benzoic acid alkyl eεter of Formula 505 aε a mixture of E and Z isomers, from which the desired E isomer of Formula 506 iε isolated, as illustrated in Reaction Scheme ZE-A, Step 5. A solution of 0.8 to 1.0 (preferably 0.95) molar equivalents of a protected aldehyde of Formula 103 in a εolvent (such aε ether, dioxane or preferably dimethylformamide) iε added to a solution of an ylid of Formula 504 in the same solvent. The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 24 hours (preferably 12 hours) to afford the correεponding protected substituted benzoic acid alkyl ester of Formula 505 aε a mixture of E and Z isomers, from which the desired E-isomer of Formula 506 can be isolated by conventional means (such as diεtillation, chromatography or preferably fractional cryεtallization) . REACTION SCHEME ZE-B kyl Formula 507 Formula 508 Formula 508 Formula 509 Formula 509 Formula 103 Formula 510 Formula 510 Formula 511 Preparation of Formula 508 Aε illuεtrated in Reaction Scheme ZE-B, Step 1, the alpha carbon of an alkyl 2-alkylbenzoate of Formula 507 (where Z 5 is H or lower alkyl, and Z 6 and Z 7 are εelected from H, lower alkyl, halo and nitro) is brominated to give the corresponding compound of Formula 508. The reaction takeε place under conditionε deεcribed with reference to Reaction Scheme ZE-A, Step 1. Preparation of Formula 509 As .illustrated in Reaction Scheme ZE-B, Step 2, an alkyl 2-bromo- alkylbenzoate of Formula 508 and a trialkyl phosphite are combined in an Arbuzov reaction to give the corresponding phosphonate of Formula 509. A compound of Formula 508 iε reacted with from 5 to 20 (preferably 10) molar equivalentε of a trialkyl phosphite (preferably triethyl phosphite) . The reaction takes place at 100 to 200°C (preferably 150°C) for 1 to 24 hours (preferably 6 hours) to afford the corresponding phoεphonate of Formula 509. Preparation of Formulae 510 and 511 Aε illuεtrated in Reaction Scheme ZE-B, Step 3, a phoεphonate of Formula 509 and a protected aldehyde of Formula 103 (prepared, for example, aε deεcribed in connection with Reaction Scheme ZA-A, Step 2) are reacted to give the correεponding protected εubεtituted benzoic acid alkyl eεter of Formula 510 as a mixture of E and Z iεomers, from which the desired E iεomer of Formula 511 iε isolated, aε illustrated in Reaction Scheme ZE-B, Step 4. A phosphonate of Formula 509 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalents of a base εuch (aε εodium amide, potassium tert-butoxide or preferably εodium hydride) for from 1 to 4 hourε (preferably 2 hourε) at 0 to 50°C (preferably 25°C) in a solvent (such aε dioxane, dimethylformamide or preferably dimethoxyethane) , to give a εolution or εuεpenεion of the corresponding alkali metal εalt of Formula 509, which iε employed without iεolation or further purification. The alkali metal εalt is reacted with from 0.9 to 1.1 (preferably 1.0) molar equivalentε of a protected aldehyde of Formula 103, diεεolved in the εame solvent. The reaction takes place at 0 to 60°C (preferably 40°C) for 1 to 6 hours (preferably 2 hourε) to afford the corresponding protected optionally subεtituted benzoic acid alkyl eεter of Formula 510 aε a mixture of E and Z iεomers, from which the desired E-isomer of Formula 511 can be isolated by conventional meanε (εuch aε distillation, chromatography or preferably fractional crystallization) . REACTION SCHEME ZE-C F B Formu l a 513 Formu l a 512 Formu la 513 Formula 514 Formu la 514 Formula 515 where R° is TBDMS where R° is acy Formula 515 Formula 511 Formula 516 Preparation of Formula 513 Aε illustrated in Reaction Scheme ZE-C, Step 1, a protected aldehyde of Formula 103 is converted to a trialkylεilylcarbinol of Formula 513 in a Grignard reaction. An aldehyde of Formula 103 iε reacted with from 1.0 to 1.25 (preferably 1.1) molar equivalents of a trialkylsilylalkylmagnesium bromide (such aε trimethylεilylpropylmagneεium bromide, or preferably trimethylεilylmethylmagneεium bromide) of Formula 512, in an ethereal εolvent (such as ether, dimethoxyethane or preferably tetrahydrofuran) . The reaction takes place at -40 to 40°C (preferably 0°C) for 30 minuteε to 4 hourε (preferably 1 hour) to give the corresponding trialkylsilylcarbinol of Formula 513. Preparation of Formula 514 Aε illuεtrated in Reaction Scheme ZE-C, Step 2, a protected trialkylεilylcarbinol of Formula 513 iε dehydrated to give the corresponding protected alkene as a mixture of E and Z isomers, from which the desired Z isomer of Formula 514 is isolated. A carbinol of Formula 513 is reacted with from 1.0 to 1.5 (preferably 1.05) molar equivalents of a εulphonyl chloride (such aε p-tolueneεulphonyl chloride or preferably methanesulphonyl chloride) in the presence of the same molar proportion of a tertiary organic base (such as N-methyl- pyrrolidine or preferably triethylamine) . The reaction takes place at 0 to 40°C (preferably 15°C) for 30 minutes to 4 hours (preferably 2 hours) to afford the corresponding protected alkene of Formula 514 aε a mixture of E and Z iεomers, from which the desired Z-isomer of Formula 514 can be isolated by conventional means (such aε distillation, chromatography or preferably fractional crystallization) . Preparation of Formula 515 As illuεtrated in Reaction Scheme ZE-C, Step 3, an alkene of Formula 514 where R" iε a εilyl protecting group iε converted to an alkene of Formula 515 where R* is an acyl group. An alkene of Formula 514 is heated at 50-130°C (preferably about 118°C) with a large exceεε of a mixture (preferably about equimolar) of a carboxylic acid of Formula ROH and an anhydride of Formula (R") 2 0 (where R* iε the desired acyl group) , preferably a mixture of acetic acid and acetic anhydride. The reaction takes place over a period of 6 to 48 hours (preferably 18 hourε) to give the correεponding alkene of Formula 515 where R" is the acyl group. Preparation of Formula 511 Aε illustrated in Reaction Scheme ZE-C, Step 4, a protected alkene of Formula 515 is converted to a protected optionally subεtituted benzoic acid alkyl eεter of Formula 511 in a Heck reaction with an alkyl-2-halo-benzoate of Formula 515. An alkene of Formula 515 is reacted with 1.0 to 2.0 (preferably 1.25) molar equivalents of an alkyl 2-halobenzoate (such aε an alkyl 2-bromobenzoate or prefereibly 2-iodobenzoate) . The reaction is conducted in the presence of from 0.001 to 0.1 (preferably 0.05) molar equivalents of a palladium catalyst [εuch aε tetrakiε(tri-o-tolylphoεphine) palladium, or tetrakis(triphenylphosphine)palladium or preferably palladium (II) acetate] optionally in the presence of from 1.0 to 1.25 (preferably 1.05) molar equivalentε of a baεe (such silver carbonate, sodium bicarbonate or preferably triethylamine) , in a solvent (such as acetonitrile or preferably dimethylformamide) . The reaction is conducted at from 0 to 120°C (preferably 60°C) for 1 to 48 hours (preferably 6 hourε) to yield the correεponding protected optionally substituted benzoic acid alkyl ester of Formula 511. REACTION SCHEME ZE-D kyl Form Form Formula I-ZE-D1 Formula I-ZE-D1 Formula I-ZE-D2 Preparation of Formula I-ZE-Dl As illustrated in Reaction Scheme ZE-D, Step 1, a protected optionally subεtituted benzoic acid eεter of Formula 506 or Formula 511 iε deprotected to give the correεponding eεter of Formula I-ZE-Dl. The deprotection reaction takeε place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 1. Preparation of Formula I-ZE-D2 As illuεtrated in Reaction Scheme ZE-D, Step 2, a deprotected optionally εubεtituted benzoic acid ester of Formula I-ZE-Dl is hydrolyzed to give the corresponding acid of Formula I-ZE-D2. The hydrolization reaction takeε place aε described above with reference to Reaction Scheme ZA-M, Step 2. The compounds of Formula I-ZE-D2 where Z 6 is nitro are employed as precurεorε to the correεponding compoundε of Formula I-ZE-E where Z 6 iε amino (aε illustrated in Reaction Scheme ZE-E, Step 1) ; the nitro compounds are also active as IMPDH inhibitors when teεted aε deεcribed below. REACTION SCHEME ZE-E Formula l-ZE-D2a Preparation of Formula I-ZE-E Aε illuεtrated in Reaction Scheme ZE-E, Step 1, a benzoic acid of Formula I-ZE-D2a (a compound of Formula I-ZE-D2 where Z 6 is N0 2 ) is reduced to the corresponding amino-substituted benzoic acid of Formula I-ZE-E. A nitrobenzoic acid of Formula I-ZE-D2a iε reacted with 1.0 to 3.0 (preferably 2.0) molar proportions of a reducing agent (such as sodium hydrosulfite or preferably tin (II) chloride) in hydrochloric acid εolution, optionally in the preεence of a water-miscible co-solvent (such as methanol or preferably acetic acid) . The reaction takes place at 25 to 100°C (preferably 75°C) for 1 to 24 hours (preferably 4 hours) to afford the correεponding amino-substituted benzoic acid of Formula I-ZE-E. REACTION SCHEME ZE-F Formula 509 + Formu la 517 Formu la 51 i Formula 520 Formu l a I-ZE-D1 Formula I-ZE-D2 Step 5 Step 6 Preparation of Formula 517 As illuεtrated in Reaction Scheme ZE-F, Step 1, a phosphonate of Formula 509 undergoes a base catalyzed condensation (e.g., using l molar equivalent of sodium hydride) with tetrahydropyranyloxyacetaldehyde, in a solvent εuch as dimethylformamide. The reaction takeε place at 25°C over a period of 1 to 4 hourε, to give E/Z mixture from which the deεired product of Formula 517 can be iεolated by conventional meanε, such as chromatography. Preparation of Formula 518 As illustrated in Reaction Scheme ZE-F, Step 2, the tetrahydropyranyloxy group of a compound of Formula 517 is hydrolyzed in the presence of a catalytic amount of a dilute acid (e.g., HC1) in aqueous tetrahydrofuran. The reaction takes place at 25°C over a period of 1 to 4 hours, to give the corresponding carbinol of Formula 518. Preparation of Formula 519 As illustrated in Reaction Scheme ZE-F, Step 3, a carbinol of Formula 518 is converted to the halo (e.g., chloro or bromo) derivative of Formula 519 using 1 molar equivalent of triphenylphosphine and either carbon tetrachloride or carbon tetrabromide, in dichloromethane. The reaction takes place at 25°C over a period of 2 hours. Preparation of Formula 520 Aε illuεtrated in Reaction Scheme ZE-F, Step 4, a halo derivative of Formula 519 undergoes a base-catalyzed ether formation with the indicated phenol, using 5 molar equivalents of potassium carbonate, in dimethylformamide. The reaction takes place at 25°C over a period of 4 hours. Preparation of Formula I-ZE-Dl and Formula I-ZE-D2 Aε illuεtrated in Reaction Scheme ZE-F, Step 5, an ether of Formula 520 is rearranged to give the correεponding eεter of Formula I-ZE-Dl (εhown in Reaction Scheme ZE-D) by a thermal rearrangement catalyzed by Floriεil ® . The rearrangement takes place in toluene at 110°C over a period of one to four days. As illustrated in Reaction Scheme ZE-F, Step 6, the ether so-produced iε hydrolyzed to the correεponding acid of Formula I-ZE-D2 as described with reference to Reaction Scheme ZA-M, Step 2. Preparation of Compounds of Formula I-ZF One method of preparing compoundε of Formula I where Z iε εidechain of Formula ZF, illuεtrated aε co poundε of Formula I-ZF, iε εhown below in Reaction Scheme ZF-A. REACTION SCHEME ZF-A C Formula BD1 Formula B02 Formu la 604 Formula 605 Formula 606 Preparation of Formula 602 Aε illuεtrated in Reaction Scheme ZF-A, Step 1, an aldehyde of Formula 601, prepared for example aε shown in J. Org. Chem. , 3408 (1977), is reduced to a carbinol of Formula 602. An aldehyde of Formula 601 iε reacted with a reducing agent capable of εelectively reducing an aldehyde in the preεence of ester groups, preferably from 1 to 2 (preferably 1.5) molar equivalents of sodium borohydride in the preεence of from 1 to 2 (preferably 1.5) molar equivalents of cerium chloride trihydrate, in an alcoholic/ethereal εolvent mixture (preferably 4:1 tetrahydrofuran:methanol) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 10 minuteε to 2 hourε (preferably 30 minutes) to give the corresponding carbinol of Formula 602. Preparation of Formula 604 As illustrated in Reaction Scheme ZF-A, Step 2, a phenol of Formula 603 is alkylated with a carbinol of Formula 602 by means of the Mitsonobu reaction to give an ether of Formula 604. A carbinol of Formula 602 iε reacted with an equimolar amount of a phenol of Formula 603 in the preεence of from 1 to 3 (preferably 2) molar equivalents of a triarylphosphine, preferably triphenylphosphine, plus from 1 to 3 (preferably 1.5) molar equivalentε of diethyl azodicarboxyl te in an ethereal solvent (preferably tetrahydrofuran) . •' The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 10 hours (preferably 3 hours) to give the corresponding ether of Formula 604. Preparation of Formula 605 As illustrated in Reaction Scheme ZF-A, Step 3, a phenol of Formula 604 iε thermally rearranged to give a dieεter of Formula 605. An ether of Formula 604 iε heated in an inert εolvent (preferably toluene) in the preεence of about 10 parts by weight of an activated magnesium silicate, preferably Florisil ® . The reaction takes place at reflux temperature for 1 to 10 days (preferably 4 dayε) to give the correεponding dieεter of Formula 605. Preparation of Formula 606 Aε illuεtrated in Reaction Scheme ZF-A, Step 4, a diester of Formula 605 is hydrolyzed to give a dicarboxylic acid of Formula 606. A diester of Formula 605 iε reacted with an excess of an inorganic base, preferably about 50 molar equivalents of lithium hydroxide, in an aqueouε solvent (preferably 5:1 methanol: ater) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 10 dayε (preferably 2 dayε) to give the corresponding dicarboxylic acid of Formula 606. Preparation of Formula I-ZF As illustrated in Reaction Scheme ZF-A, Step 5, a dicarboxylic acid of Formula 606 is decarboxylated to give a monocarboxylic acid of Formula I-ZF. A dicarboxylic acid of Formula 606 is heated (optionally in the presence of a high boiling inert εolvent, for example tetramethylbenzene, but preferably in the abεence of any εolvent) . The reaction takes place at 160 to 240°C (preferably 195°C) for about 5 minutes to give the corresponding monocarboxylic acid of Formula I-ZF. Preparation of Compounds of Formula I-ZG One method of preparing compounds of Formula I where Z is sidechain of Formula ZG, illustrated aε compoundε of Formula I-ZG, iε εhown below in Reaction Scheme ZG-A. REACTION SCHEME ZG-A Formu la 701 Formu la 702 Formu la 703 Formu la 703 Formu la 704 Formula 704 Formu la 705 Formu la 705 Formu la 706 Formu la 706 For mu I a 707 Formu la 707 Formula 70E Formu la 708 Fo mu l 709 Formu la 710 Formula 710 For ula 711 Formu la 711 Formu la I - ZG-A Preparation of Formula 703 As illustrated in Reaction Scheme ZG-A, Step 1, the phenol of Formula 701 is alkylated with 3-hydroxycyclohexene to give the correεponding ether of Formula 703, by means of the Mitsonobu reaction. The Mitsonobu reaction takes place as described with reference to Reaction Scheme ZF-A, Step 2. Similarly, by substituting 3-hydroxy-cyclohexene with 3-hydroxy- cycloheptene, and carrying out the procedures of Reaction Scheme ZG-A, the corresponding compounds where Z is a side chain of Formula ZG where D 3 is -CH--CH 2 - are obtained. Preparation of Formula 704 As illustrated in Reaction Scheme ZG-A, Step 2, a Claisen rearrangement of the ether of Formula 703 gives the alkylated phenol of Formula 704. The reaction takes place, e.g., at 200°C for 12 to 16 hours in the presence of N,N-diethylaniline. Preparation of Formula 705 Aε illuεtrated in Reaction Scheme ZG-A, Step 3, the alkylated phenol of Formula 704 iε protected to give a protected phenol of Formula 705 (where R a iε εilyl or toεyl) . An alkylated phenol of Formula 704 is reacted with an equimolar amount of t-butyl dimethylsilyl chloride or p-toluenesulfonyl chloride, in the presence of an equimolar amount, respectively, of imidazole or 4- dimethylaminopyridine. The reaction takeε place in dichloromethane at a temperature of 25°C for 1 to 4 hourε to give the correεponding protected phenol of Formula 705. Preparation of Formula 706 Aε illuεtrated in Reaction Scheme ZG-A, Step 4, a protected phenol of Formula 705 iε converted to the corresponding dialdehyde of Formula 706 by ozonolysiε. The ozonolyεiε reaction takeε place aε described with reference to Reaction Scheme ZA-A, Step 2. Preparation of Formula 707 As illustrated in Reaction Scheme ZG-A, Step 5, an intramolecular baεe-catalyzed aldol reaction with a dialdehyde of Formula 706 produceε the corresponding formyl cyclopentene of Formula 707. The reaction is conducted with 0.1 moles of dibenzylamine or N-methylaniline trifluoroacetate in benzene, taking place at 50°C for 30 minuteε. Preparation of Formula 708 Aε illustrated in Reaction Scheme ZG-A, Step 6, a formyl cyclopentene of Formula 707 is reduced to the correεponding carbinol. The reaction employε εodium borohydride/cerium chloride, aε described with reference to Reaction Scheme ZF-A, Step 1. Preparation of Formula 709 As illustrated in Reaction Scheme ZG-A, Step 7, a carbinol of Formula 708 is converted to the corresponding acetate of Formula 709. The reaction is conducted with equimolar amounts of acetyl chloride and triethylamine, taking place in methylene chloride at 0°C for 1 hour. Preparation of Formula 710 Aε illuεtrated in Reaction Scheme ZG-A, Step 8, an acetate of Formula 709 iε converted to the corresponding dieεter of Formula 710. The reaction iε conducted as described in J. Am. Chem. Soc , 102:4730 (1980), with 4 moles of εodium dimethylmalonate, 0.5 moleε triphenylphosphine and 0.25 moles of tetrakis triphenylphosphine palladium at 50°C in tetrahydrofuran. Preparation of Formula 711 As illuεtrated in Reaction Scheme ZG-A, Step 9, a diester of Formula 710 is converted to give the corresponding ester of Formula 711, by reaction with cesium acetate in hexamethylphoεphoric triamide at 120°C for 1 to 3 hourε. Similarly, by use in Step 8 of an alternative for sodium dimethylmalonate suitably substituted to introduce Z 3 or Z 4 , the correspondingly substituted ester of Formula 711 is obtained in Step 9. Preparation of Formula I-ZG-A As illustrated in Reaction Scheme ZG-A, Step 10, an eεter of Formula 711 is hydrolyzed to give the corresponding compound of Formula I-ZG-A. The reactions take place as deεcribed with reference to Reaction Scheme ZA- M, Steps 1 and 2 respectively. Preparation of Compounds of Formula I-ZH One method of preparing compounds of Formula I where Z is ' sidechain of Formula ZH, illuεtrated as compounds of Formula I-ZH, is shown below in Reaction Scheme ZH-A. REACTION SCHEME ZH-A -0TBΞ For ula 03e Formu la 801 Formula i01 Formu la 802 Formu la 802 Formu l a 803 Formu la B03 Formu l a 804 Formu 'a 804 Formu la 805 Formu la 805 Formu I a I -ZH- A1 Formu l a -ZH-A1 Formu la I - ZH- A2 Preparation of Formula 801 As illustrated in Reaction Scheme ZH-A, Step 1, an aldehyde of Formula 103 is converted to a carbinol by addition of an organometallic compound of Formula 103e (such aε a εubstituted vinyl organolithium, or preferably a Grignard reagent where: M iε MgBr; TBS iε a tert- butyldimethylεilyl protecting group; and D 4 iε preferably lower alkylene) . A halovinyl (preferably bromovinyl) compound of Formula 103e (where M is halo) iε reacted with magnesium metal in an ethereal solvent (such aε ether or preferably tetrahydrofuran) . The reaction takeε place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hourε (preferably 2 hourε) . One moiar equivalent of the resultant organometallic reagent is added to a solution of an aldehyde of Formula 103 (in the εame solvent system used to make the organometallic reagent) . The reaction takes place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minutes (preferably 10 minutes) to give the corresponding silyl-protected carbinol of Formula 801. Preparation of Formula 802 As illustrated in Reaction Scheme ZH-A, Step 2, an alkyl eεter of Formula 802 iε formed by a Claiεen ortho ester rearrangement reaction of a carbinol of Formula 801 and an orthoester compound of Formula 104a (as illustrated in Reaction Scheme ZA-A, where Z 3 and Z 4 are H) . A silyl-protected carbinol of Formula 801 is heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalentε of an orthoester of Formula 104a, in the preεence of from 0.05 to 0.25 molar equivalentε (preferably 0.10 molar equivalentε) of an organic acid catalyst (such as propionic, butyric, or preferably trimethylacetic acid) . The reaction takes place over a period of 1 to 48 hours (preferably 8 hourε) to give the corresponding alkyl ester of Formula 802. Preparation of Formula 803 As illustrated in Reaction Scheme ZH-A, Step 3, the silyl-protected carbinol of an alkyl ester of Formula 802 is deprotected. A compound of Formula 803 iε reacted with from 5 to 30 (preferably 20) molar equivalents of hydrogen fluoride, in a mixture of water and a water-miscible organic solvent (preferably acetonitrile) . The reaction takeε place at -20 to 40°C (preferably 25°C) for 5 to 60 minuteε (preferably 30 minuteε) to afford the corresponding unprotected carbinol/alkyl eεter of Formula 803. Preparation of Formula 804 Aε illuεtrated in Reaction Scheme ZH-A, Step 4, a carbinol of Formula 803 iε converted to a halide (preferably a bromide) of Formula 804, by meanε of a one-εtep or a two-step procedure. In the one-step procedure, a carbinol of Formula 803 is reacted with from 1.0 to 1.3 (preferably 1.1) molar equivalents of a triaryl (preferably triphenyl) phosphine, and from 1.0 to 1.3 (preferably 1.1) molar equivalents of a halogen source (such as N-bromoεuccinimide or preferably carbon tetrabromide) . The reaction iε conducted in an inert solvent (εuch as ether or preferably tetrahydrofuran) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 12 hourε (preferably 3 hourε) to afford the corresponding halide of Formula 804. Alternatively, in the two-step procedure, which is preferred, a carbinol of Formula 803 iε converted first into a εulphonate eεter (εuch aε a p-tolueneεulphonate or preferably a methaneεulphonate) by reaction with from 1.0 to 1.5 (preferably 1.3) molar equivalentε a εulphonyl halide (preferably methaneεulphonyl chloride) in the preεence of an equimolar amount of a tertiary organic baεe (preferably diiεopropylethylamine) in a solvent (such as chloroform or preferably dichloromethane) . The reaction takes place at -20 to 30°C (preferably 0°C) for 10 to 60 minutes (preferably 30 minutes) . The so-obtained εulphonate ester iε then reacted with from 5 to 20 (preferably 20) molar equivalentε of an alkali metal halide (preferably lithium bromide) in a εolvent (such as 2-butanone or preferably acetone) . The reaction takes place at 0 to 56°C (preferably at reflux) for 30 to 180 minutes (preferably 90 minuteε) to afford the corresponding halide of Formula 804. Preparation of Formula 805 Aε illuεtrated in Reaction Scheme ZH-A, Step 5, a halogenated carbinol/alkyl eεter of Formula 804 iε deprotected at the phenolic group to give the correεponding halogenated carbinol/alkyl eεter of Formula 805. The deprotection reaction takes place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 1. Preparation of Formula I-ZH-A1 As illuεtrated in Reaction Scheme ZH-A, Step 6, a halogenated carbinol/alkyl eεter of Formula 805 iε subjected to a base-induced cyclization reaction to afford the product of Formula I-ZH-A1. A compound of Formula 805 is reacted with from 2.0 to 2.5 (preferably 2.3) molar equivalentε of a strong base (εuch aε lithium diiεopropy1amide, εodium hydride or preferably εodium hexamethyldiεilazide) in a solvent (εuch as dioxane or preferably tetrahydrofuran) . The reaction takes place at -20 to 30°C (preferably at 0°C) for 5 to 60 minutes (preferably 15 minutes) to afford the corresponding cycloalkylester of Formula I-ZH-A1. Preparation of Formula I-ZH-A2 As illustrated in Reaction Scheme ZH-A, Step 7, a cycloalkyl eεter of Formula I-ZH-A1 is hydrolyzed to give the correεponding acid of Formula I-ZH-A2. The hydrolysis takes place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 2. Compoundε of Formula I where Z iε a εidechain of Formula ZH in which D 4 iε O or 0-CH 2 are preferably prepared aε described below in Reaction Scheme ZH-B. REACTION SCHEME ZH-B For u la 806 Formu l a 807 For u I a 807 For u l a 80£ q -Br Formu la 80B Formu I a B09 Formu l a B09 Fo u l a 8 0 For u la 10 Formu I a I -ZH-B1 Formu l a I - Z H- B 1 F or m u l a I - Z H- B 2 Preparation of Formula 807 As illustrated in Reaction Scheme ZH-B, Step 1, an aldehyde of Formula 302 (where Z 5 is methyl) undergoes an aldol reaction with the bromo-alkyl oxazolidinone of Formula 806 (where q iε 1 or 2) , which can be prepared by analogy with the reactionε deεcribed in J. Am. Chem. Soc , 103:2127 (1981), to give the acyloxazolidinone of Formula 807. An oxazolidinone of Formula 806 iε reacted with an equimolar amount of a baεe (εuch aε lithium diisopropylamide or preferably di-n-butylboryl trifluoromethane sulphonate/triethylamine) , and then with an aldehyde of Formula 302. The reaction takeε place at -78°C to 0°C (preferably -40°C) for 1 to 12 hourε (preferably 3 hourε) to afford the corresponding acyloxazolidinone of Formula 807. Preparation of Formula 808 Aε illustrated in Reaction Scheme ZH-B, Step 2, an acyloxazolidinone of Formula 807 iε hydrolyzed to the carboxylic acid of Formula 808. An acyloxazolidinone of Formula 807 is reacted with 1-5 (preferably 3) molar equivalents of lithium hydroxide in 3:1 tetrahydrofuran containing 5-20 (preferably 12) molar equivalents of hydrogen peroxide. The reaction takes place at -10 to 25°C (preferably 0°) for 5 to 60 minutes (preferably 30 minutes) to give the correεponding carboxylic acid of Formula 808. Preparation of Formula 809 Aε illuεtrated in Reaction Scheme ZH-B, Step 3, a carboxylic acid of Formula 808 iε deprotected to give the correεponding phenol of Formula 809, using the method deεcribed with reεpect to Reaction Scheme ZA-M, Step 1. Preparation of Formula 810 A phenol of Formula 809 iε esterified to give the corresponding ester of Formula 810. A phenol of Formula 809 iε treated with methanol in the presence of 0.05 to 0.2 (preferably 0.1) molar equivalents of an acid catalyst (preferably p-tolueneεulphonic acid) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 12 hourε) to give the corresponding methyl ester of Formula 810. Preparation of Formula I-ZH-B1 A methyl ester of Formula 810 undergoes an intramolecular cyclization reaction to give the corresponding cyclized ester of Formula I-ZH-B1. A methyl ester of Formula 810 iε treated with 1.9 to 2.5 (preferably 2.0) molar equivalentε of a εtrong baεe (εuch aε lithium diisopropylamide or preferably εodium hydride) in tetrahydrofuran (or preferably dimethylformamide) . The reaction takeε place at -10 to 25°C (preferably 0°) for 1-12 hours (preferably 2 hours) to give the corresponding cyclized ester of Formula I-ZH-B1. Preparation of Formula I-ZH-B2 Aε ill ' uεtrated in Reaction Scheme ZH-B, Step 6, a cyclized eεter of Formula I-ZH-B1 iε hydrolyzed to give the corresponding acid of Formula I- ZH-B2, using the method deεcribed with respect to Reaction Scheme ZA-M, Step 2. Preparation of Esters of Formula I The esters of Formula I (compoundε where G iε not OH) can be prepared aε deεcribed in U.S. Patentε Nos. 4,727,069 and 4,753,935, incorporated herein by reference, by deprotection of a precursor (e.g., as described with reference to Reaction Scheme ZA-M, Stepε 1) or aε described below by attachment of a leaving group and its replacement by the desired ester. Attachment of Leaving Group A carboxylic acid of Formula I is reacted with from 1.0 to 3.0, preferably about 1.5, molar equivalents of oxalyl chloride or preferably thionyl chloride, in a εolvent (εuch aε chloroform or preferably dichloromethane) optionally containing from 0.01 to 0.05 (preferably 0.03) molar equivalentε of dimethylformamide. The reaction takeε place at -10 to 30°C (preferably 0°C) for 1 to 12 hours (preferably 2 hours) to give the corresponding acid chloride (where the leaving group is Cl) . Alternatively, a carboxylic acid of Formula I iε reacted with 1.0 to 1.5 (preferably 1.25) molar equivalents of carbonyldiimidazole, in a solvent (εuch as tetrahydofuran or preferably dichloromethane) . The reaction takes place at 0 to 40°C (preferably 25°C) for 1 to 12 hours (prefereibly 2 hours) to give the corresponding acyl imidazole (where the leaving group iε 1-imidazolyl) . Esterification A compound of Formula I where G has been replaced by a halide or imidazolide iε reacted with from 1.0 to 5.0 (preferably 2) molar equivalentε of a lower alkanol, optionally in the preεence of from 1.0 to 1.5 (preferably 1.25) molar equivalentε of a tertiary organic baεe (εuch aε 4-dimethylaminopyridine or preferably triethylamine) in an organic εolvent (such as dioxane, tetrahydrofuran or preferably dichloromethane) . The reaction takeε place at -10 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 4 hours) to afford the correεponding lower alkyl eεter of Formula I, which iε employed in synthesis of the compoundε of Formula A. PREPARATION OF FORMULA A The compoundε of Formula A [where R 2 iε lower alkyl, cycloalkyl, vinyl, fluorovinyl, difluorovinyl, trifluorovinyl, alkenyl, -C≡C-R π , allenyl or CH 2 -0- (4-methoxybenzyl) , collectively designated as Formula AA] are prepared aε deεcribed with reference to Reaction Scheme A. REACTION SCHEME A Formu la I A Formu I a 2 Formu I a 2 Formula 3 Formula 3 Fo mula 4 Formula 4 Formu la 5 lower a l yl For u I a 5a Formula 6 Formu I a 6 Formula AA Preparation of Formula 2 Aε illuεtrated in Reaction Scheme A, Step 1, a lower alkyl ester of Formula IA, prepared aε deεcribed above, iε protected at the phenolic hydroxyl with an arylsulfonyl or alkylsulfonyl group. A compound of Formula IA is reacted with 1.0 to 1.1 (preferably 1.05) molar equivalents of an arylsulfonyl or alkylεulfonyl halide (preferably p-toluenesulfonyl chloride) in pyridine. The reaction takes place at -10°C to 30°C (preferably room temperature) for 1 to 24 hours (preferably 12 hours) . The protected correεponding compound of Formula 2 iε isolated by conventional means (εuch as evaporation) . Preparation of Formula 3 As illuεtrated in Reaction Scheme A, Step 2, a protected lower alkyl eεter of Formula 2 is demethylated in a cleavage reaction with 5 moles of anhydrous lithium iodide in a pyridine solvent (preferably collidine) . The reaction takes place at 60 to 75°C (preferably 60°C) for 10 hours to 8 dayε (preferably 4 ' days) . The correεponding protected 6-hydroxy acid of Formula 3 iε isolated by conventional means (such as evaporation) . Preparation of Formula 4 As illustrated in Reaction Scheme A, Step 3, a protected 6-hydroxy acid of Formula 3 is eεterified in an acid-catalyzed eεterification. The reaction takeε place in a lower alkanol εolvent (correεponding to the desired lower alkyl ester, such aε methanol) with an acid (such aε p-tolueneεulfonic acid) at room temperature for 12 to 24 hourε (preferably 18 hourε) . The correεponding protected 6-hydroxy lower alkyl eεter of Formula 4 is isolated and purified by conventional means (such aε chromatography) . Preparation of Formula 5 As illustrated in Reaction Scheme A, Step 4, a protected 6-hydroxy lower alkyl ester of Formula 4 is converted to the corresponding 6-triflate. The reaction takes place with the addition of 1.05 to 1.3 (preferably 1.2) molar equivalentε of trifluoromethaneεulfonic anhydride in a solvent (such aε methylene chloride and/or pyridine) at -10°C to 10°C (preferably 0°C) for 15 minuteε to 10 hourε (preferably 30 minutes) . The correεponding protected 6-triflate iε iεolated by conventional means (εuch aε evaporation) . Preparation of Trialkylstannanes of Formula 5a The trialkylstannanes of Formula 5a, which are used in Step 5 of Reaction Scheme A, are prepared as illustrated below, by reaction of an organolithium or organomagneεium (Grignard) reagent with a trialkyl (preferably tributyl) tin chloride. The organolithium or organomagneεium reagents are either commercially available, or are made by conventional methods such as halogen-metal exchange. Compoundε in which R 2 containε a terminal triple bond, (e.g., where R 2 iε -C≡CH or -C≡C-CH 3 ) can be reacted directly with butyllithium to afford the organolithium compound R 2 -Li. Bu I C- Iky l 3 ,- SnC ,! Ca I ky I 3 3 -Sn- Mg -»■ R -MgHa I o Formu I a 5a The butyl lithium reaction takeε place at -100°C to 0°C (preferably -78°C) for 1 to 8 hourε (preferably 2 hourε) to give the correεponding lithium derivative. The halide εtarting material iε reacted with magneεium metal in a solvent (preferably THF) under standard Grignard reaction conditions to give the magnesium halide derivative. The lithium or magneεium halide derivative iε reacted with a trialkylchlorostannane (preferably tributylchlorostannane) in an ethereal solvent (preferably THF) . The reaction takes place at -78°C to 0°C for 1 to 4 hours (preferably 2 hourε) to give the corresponding trialkylstannane of Formula 5a, which iε iεolated and used in Reaction Scheme A, Step 5 without further purification. Tetramethyl, vinyltributyltin and phenyltributyl are all commercially available, e.g., from Aldrich. Preparation of Formula 6 Aε illuεtrated in .Reaction Scheme A, Step 5, a protected 6-triflate of Formula 5 iε converted to the corresponding compound of Formula 6 where R 2 iε methyl, cycloalkyl, vinyl, fluorovinyl, difluorovinyl, trifluorovinyl, alkenyl, -C≡C-R π , allenyl or CH 2 -0- (4-methoxybenzyl) by reaction with a trialkylεtannane of Formula 5a in the preεence of 6 moleε of lithium chloride and a palladium catalyεt [such as triε(dibenzylidine- acetone)dipalladium (O) chloroform adduct, or preferably tetrakis- (triphenylphosphine)palladium] . The reaction takeε place in a polar aprotic εolvent (preferably N-methylpyrrolidinone) at 50°C to 100°C (preferably 80°C) for 3 to 10 hourε (preferably 6 hourε) . The 6-substituted protected lower alkyl eεter of Formula 6 iε iεolated and purified by conventional methodε. The compoundε of Formula 6 where R 2 iε lower alkyl of 2 or more carbon atoms can be made by hydrogenation of the corresponding alkenyl compoundε of Formula 6, e.g., aε deεcribed below in Example 7. Preparation of Formula AA Aε illustrated in Reaction Scheme A, Step 6, a 6-εubεtituted protected lower alkyl eεter of Formula 6 iε deprotected and converted to the correεponding acid by baεe hydrolysis. The compound of formula 6 is reacted with 5 moles of a strong base (preferably lithium hydroxide) in an aqueouε/lower alkanol εolvent (εuch as methanol:water) . The reaction takeε place at 50 to 70°C (preferably 60°C) for 10 to 24 hours (preferably 16 hourε) followed by acidification. The 6-substituted acid of Formula AA is isolated and purified by conventional means. Preparation of Formula A where R 2 is CHjOH and CHO The compounds of Formula A where R 2 iε CH 2 OH and CHO (respectively designated Formulae AB-1 and AB-2) are prepared aε deεcribed with reference to Reaction Scheme B. REACTION SCHEME B Formula AB- 1 Fo mu I a AB- 1 Formu I a AB- 2 Preparation of Formula AB-1 As illuεtrated in Reaction Scheme B, Step 1, a 6- (4-methoxy)benzyl- oxymethyl subεtituted compound of Formula AA (εhown as Formula AA-1) is debenzylated by reaction with 1 mole of a Lewis acid (such as boron tribromide or preferably boron trifluoride etherate) or 20 moles of trifluoroacetic acid. The reaction takes place in dichloromethane at -10°C to 5°C (preferably 0°C) for 30 minuteε to 2 hourε (preferably 1 hour) . Alternatively, when uεing trifluoroacetic acid, the reaction takeε place at room temperature. The correεponding 6-hydroxymethyl compound of Formula AB-1 iε iεolated and purified by conventional means. Preparation of Formula AB-2 As illustrated in Reaction Scheme B, Step 2, a 6-hydroxymethyl compound of Formula AB-1 is oxidized (using magneεium dioxide or preferably one mole of pyridine chlorochromate) . The reaction takeε place in methylene chloride at -10°C to 5°C (preferably 0°C) for 8 to 24 hourε (preferably 12 hourε) . The correεponding 6-formyl compound of Formula AB-2 iε iεolated and purified by conventional means. Alternative Preparation of Formula A where R 2 is Lower Alkyl A compound of Formula A where R 2 is vinyl or alkenyl in converted to the corresponding lower alkyl compound by catalytic reduction in the presence of 0.01 to 0.10 (preferably 0.02) moles of triε(triphenyl- phoεphine)rhodium chloride. The reaction takes place in an inert organic εolvent (preferably 1:1 ethanol:benzene) at 20°C to 30°C (preferably 25°C) for 1 to 12 hours (preferably 2 hourε) . The corresponding compound of, Formula A where R 2 is lower alkyl (other than methyl) iε iεolated and purified by conventional meanε. Preparation of Formula A where R 1 is Acyl. A compound of Formula A, e.g., prepared as described above, iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of an acylating agent [εuch aε an acyl halide (e.g., benzoyl chloride) or an acyl anhydride (e.g., acetic anhydride)] in a εolvent (εuch aε ether, tetrahydrofuran, or preferably pyridine) optionally in the preεence of from 1.0 to 2.0 (preferably 1.25) molar equivalentε of an inorganic or organic baεe (εuch aε εodium carbonate, cesium carbonate or dimethylaminopyridine) . The reaction takeε place at 0 to 60°C (preferably 25 °C) for 1 to 12 hourε (preferably 2 hours) to afford the corresponding compound of Formula A where R 1 is acyl. Preparation of Formula A where R 1 is C(0)-NH-aryl The compounds of Formula A where R 1 iε C(0)-NH-aryl are prepared, e.g., aε described in previously incorporated U.S. Patent No. 3,853,919. Preparation of Esters of Formula A The esters of Formula A (compounds where G is not OH) can be prepared as deεcribed in U.S. Patentε Noε. 4,727,069 and 4,753,935, incorporated herein by reference, or aε deεcribed below by attachment of a leaving group and itε replacement by the deεired eεter. Attachment of Leaving Group A carboxylic acid of Formula A iε reacted with from 1.0 to 3.0, preferably about 1.5, molar equivalentε of oxalyl chloride or preferably thionyl chloride, in a εolvent (εuch aε chloroform or preferably dichloromethane) optionally containing from 0.01 to 0.05 (preferably 0.03) molar equivalents of dimethylformamide. The reaction takeε place at -10 to 30°C (preferably 0°C) for 1 to 12 hourε (preferably 2 hourε) to give the correεponding acid chloride (where the leaving group iε Cl) . Alternatively, a carboxylic acid of Formula A iε reacted with 1.0 to 1.5 (preferably 1.25) molar equivalents of carbonyldiimidazole, in a εolvent (such as tetrahydofuran or preferably dichloromethane) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 12 hours (preferably 2 hours) to give the correεponding acyl imidazole (where the leaving group iε 1-imidazolyl) . Esterification A compound of Formula A where G has been replaced by a halide or imidazolide is converted to the corresponding alkyl (where G is O-alkyl) , thioalkyl (where G is S-alkyl) , aminoalkyl (where G is 0- (CH 2 ) n -NG'G 2 ) or heterocyclic aminoalkyl (where G iε 0- (CH^-NsG 3 ) compoundε, or to the corresponding amides (where G iε NG'G 2 ) . A compound of Formula A where G haε been replaced by a halide or imidazolide is reacted with from 1.0 to 5.0 (preferably 2) molar equivalentε of an alkanol, a thiol or ammonia, a monoalkyl or dialkylamine, or a heterocyclic aminoalkanol, optionally in the preεence of from 1.0 to 1.5 (preferably 1.25) molar equivalents of a tertiary organic base (such aε 4-dimethylaminopyridine or preferably triethylamine) in an organic εolvent (εuch aε dioxane, tetrahydrofuran or preferably dichloromethane) . The reaction takes place at -10 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 4 hourε) to afford the correεponding compound of Formula A where G iε other than OH. Preparation of the Salts of Formula A Some of the compoundε of Formula A can be converted to correεponding acid addition salts. The conversion iε accompliεhed by treatment with a εtoichiometric amount of an appropriate acid, εuch aε hydrochloric acid (e.g., 3 molar equivalentε to form the trihydrochloride salt) . Typically, the free base is dissolved in a polar organic εolvent, εuch aε methanol or ethanol, and the acid iε added in methanol or ethanol. The temperature iε maintained at 0°C to 50 °C. The correεponding salt precipitates spontaneously or can be brought out of solution with a leεε polar solvent. The acid addition salts of the compounds of Formula A can be decomposed to the corresponding free bases by treatment with an exceεε of a suitable baεe, such aε ammonia or εodium bicarbonate, typically in the preεence of an aqueouε εolvent, and at a temperature between 0°C and 50°C. The free baεe form iε iεolated by conventional meanε, εuch aε extraction with an organic εolvent. Some of the compoundε of Formula A can be converted to correεponding baεe addition εaltε. The conversion is accompliεhed by treatment with a εtoichiometric amount of an appropriate baεe, εuch aε εodium carbonate, potaεεium bicarbonate, lithium hydroxide, ethanolamine, tromethamine, and the like. Typically, the free acid is disεolved in a polar organic solvent, εuch aε methanol or ethanol, and the baεe iε added in water, methanol or ethanol. The temperature iε maintained at 0°C to 50 °C. The correεponding εalt precipitates spontaneouεly or can be brought out of εolution with a leεε polar εolvent, or the εalt can be iεolated by evaporation of all εolventε, and optionally recryεtallizing the reεidue thus obtained from a suitable εolvent, or a mixture of solvents, for example, methanol, ethanol, propanol, ethyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, and the like. Preferred Processes and Last Steps A compound of Formula A where R 1 is replaced by a protecting group is deprotected. A compound of Formula A where G is lower alkoxy is hydrolyzed to the corresponding acid where G is OH. A compound of Formula A where G is OH iε eεterified to give the correεponding compound where G iε lower alkoxy, lower thioalkyl, NG'G 2 , 0- (CH 2 ) n -NG'G 2 , or 0- (CH 2 ) n -N=G 3 . A compound of Formula A is contacted with a pharmaceutically acceptable acid or base to form the corresponding acid or base addition salt. A pharmaceutically acceptable acid addition salt of Formula A is contacted with a base to form the corresponding free base of Formula A. Preferred Compounds Generally preferred are the compoundε of Formula A where R 1 is H, G iε OH, and Z iε a εide chain of Formulae ZA, ZB, ZE, or ZH, particularly thoεe where R 2 is lower alkyl, cycloalkyl or vinyl (especially methyl, ethyl, cyclopropyl and vinyl) . Of the compoundε of Formula A where Z iε a εide chain of Formula ZA, preferred are thoεe compoundε where Z 1 iε methyl, Z 2 iε H or methyl, Z 3 iε methyl or ethyl, and Z 4 iε H; particularly the compounds where Z 2 and Z 3 are methyl, and where Z 2 is H and Z 3 is methyl or ethyl especially in the (S) configuration.. Of the compoundε of Formula A where Z is a side chain of Formula ZB, preferred are those compounds where D'-D 2 is -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -,' and Z 5 is H, methyl or ethyl; particularly the compounds where Z 5 iε methyl or ethyl, especially methyl in the (S) configuration. At present, the moεt preferred compoundε are: (E) 6- (l,3-dihydro-4-hydroxy-6,7-dimethyl-3-oxoiεobenzofuran-5-yl) -4- methyl-4-hexenoic acid; (E) 6- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- yl) -4-methyl-4-hexenoic acid; (E) 6- (6-cyclopropyl-l,3-dihydro-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; (E) 6- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinylisobenzofuran-5- yl) -4-methyl-4-hexenoic acid; (E) 6- (1,3-dihydro-6-ethyl- -hydroxy-7-methyl-3-oxoiεobenzofuran-5- yl) -3,4-dimethyl-4-hexenoic acid; and (E) -2- [2- [2- [1,3-dihydro-6-ethyl 4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] cyclopent-1-yl]acetic acid. Utility, Testing and Administration General Utility The compoundε of the preεent invention, the pharmaceutically acceptable εaltε thereof and pharmaceutical compositions therewith (collectively the "compoundε" for purpoεeε of the following deεcription) are uεeful aε immunoεuppreεεive agents, anti-inflammatory agents, anti- tumor agents, anti-proliferative agents, anti-viral agents and anti- pεoriatic agents in mammals, whether domestic (cattle, pigs, sheep, goats, horses), pets (cats, dogε) , or preferably humanε. The compoundε are inhibitorε of inoεine monophosphate dehydrogenaεe (IMPDH) and thuε inhibit de novo purine syntheεiε; they have anti-proliferative effectε (e.g., againεt εmooth muεcle cells and both B and T lymphocytes) and inhibit antibody formation and the glycosylation of cell adheεion moleculeε in lymphocyteε and endothelial cellε. Aε immunosuppresεive agentε, the compoundε are uεeful in treating auto-immune related diεorders, for example: Type I Diabetes Mellitus; Inflammatory Bowel Disease (e.g., Crohn's Diεeaεe and ϋlcerative Colitis); Syεtemic Lupuε Erythematosus; Chronic Active Hepatitiε; Multiple Sclerosis; Grave's Diseaεe; Haεhimoto'ε Thyroiditiε; Behcet'ε Syndrome; Myasthenia Gravis; Sjogren'ε Syndrome; Perniciouε Anemia; Idiopathic Adrenal Inεufficiency; and Polyglandular Autoimmune Syndromeε Type I and II. The compoundε are alεo useful as therapeutic immunosuppreεεive agents in the treatment of Asthma, Immunohemolytic Anemia, Glomerulonephritiε, and Hepatitiε. Preventative uses of the compoundε aε immunoεuppreεsive agentε include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, εkin and corneal allograftε, and prevention of Graft vε. Host Diseaεe. The compounds are uεeful for inhibiting proliferative reεponεes to vascular injury, for example, stenoεis following an insult to a blood veεεel wall in poεt-angioplaεty reεtenoεiε, and poεt-cardiac by-paεε εurgery reεtenoεis. The compounds are useful aε anti-inflammatory agentε, for example, in treating Rheumatoid Arthritiε, Juvenile Rheumatoid Arthritiε and Uveitiε. Aε anti-tumor agentε, the compounds are useful in treating solid tumors and malignancies of lymphoreticular origin. For example, the compounds' utility for treatment of εolid tumorε includeε: cancerε of the head and neck, including εquamouε cell carcinoma; lung cancer, including εmall cell and non-small cell lung carcinoma; mediaεtinal tumors; esophageal cancer, including εquamouε cell carcinoma and adenocarcinoma; pancreatic cancer; cancer of the hepatobiliary system, including hepatocellular carcinoma, cholangiocarcinoma, gall bladder carcinoma and biliary tract carcinoma; small intestinal carcinoma, including adenocarcinoma, sarcoma, lymphoma and carcinoids; colorectal cancer, including colon carcinoma and rectal carcinoma; metaεtatic carcinoma; cancers of the genitourinary system, including ovarian cancer, uterine sarcoma, and renal cell, ureteral, bladder, prostate, urethral, penile, testicular, vulvar, vaginal, cervical, endometrial, and fallopian tube carcinoma; breast cancer; endocrine εyεtem cancer; εoft tiεsue sarcomas; malignant mesotheliomaε; εkin cancer, including εquamouε cell carcinoma, baεal cell carcinoma and melanoma; cancer of the central nervouε system; malignant bone tumors; and plasma cell neoplasmε. Aε anti-tumor agents for the treatment of malignancies of lymphoreticular origin, the compounds are useful in treating, for example: Lymphomaε and Leukemiaε, including B, T and promonocyte cell line malignancieε. Mycoses Fungoideε, Non-Hodgkinε Lymphoma, Malignancieε of Burkitt Lymphoma Cellε and other EBV-transformed B-lymphocytes, Lymphomas resulting from Epstein-Barr viral infectionε in allograft recipients, Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and Hairy Cell Leukemia. Aε anti-viral agentε, the compoundε are useful in treating, for example: retroviruses, including Human T-leukemia Viruseε, Typeε I and II (HTLV-l and HTLV-2) , Human Immuno Deficiency Viruseε, Typeε I and II (HIV-1, HIV-2) and, Human Naεopharyngeal Carcinoma Viruε (NPCV) and in treating Herpeε Viruεeε, including EBV infected B-lymphocytes, CMV infection, Herpeε Virus Type 6, Herpes Simplex, Typeε 1 and 2, (HSV-1, HSV-2) and Herpeε Zoεter. Aε anti-psoriatic agents, the compounds are useful in treating, for example, psoriaεiε and pεoriatic arthritiε. Testing Activity testing is conducted as described in the following references, and by modifications thereof. General anti-inflammatory, anti-viral, anti-tumor, anti-psoriatic and/or immunoεuppreεεive activity iε aεsociated with the inhibition of Inosine 5' -Monophoεphate Dehydrogenase ("IMPDH"). In vitro aεεayε meaεuring the inhibition of IMPDH, for example, by determining the level of NADH formation according to the method of Anderεon, J.H. and Sartorelli, A.C., J " . Biol . Chem. , 243:4762-4768 (1968) are predictive of εuch activity. Initial animal screening tests to determine anti-inflammatory activity potential include the adjuvant arthritis aεεay, e.g., according to the method of Pearεon, Proc. Soc. Exp. Biol . Med. , 91:95-101 (1956). Alεo, in vitro teεts, for example those using synovial explantε from patientε with rheumatoid arthritis, Dayer, et al., J. Exp. Med., 145:1399-1404 (1977) , are useful in determining whether compoundε exhibit anti- inflammatory activity. Autoimmune activity iε determined, for example, utilizing experimental allergic encephalomyelitiε, by a modification of a procedure initially described by Grieg, et. al., JO Pharmacol . Exp. Ther. , 173:85 (1970) . Human clinical trials for efficacy in the treatment of asthma are conducted, e.g., as deεcribed by Erzurum, Leff, Cochran, et al. "Lack of benefit of methotrexate in εevere, steroid-dependent asthma. A double- blind, placebo controlled study." Ann. Int. Med. , 114:353-360 (1991). Activity to prevent the rejection of organ or tiεεue allografts in experimental animals iε determined, for example, aε described by Hao, et al., J. Immunol . , 139:4022-4026 (1987). In addition, U.S. Patent No. 4,707,443 and EP 226062, incorporated herein by reference, alεo deεcribe aεεayε for activity in prevention of allograft rejection by detection of IL-2R levelε. Human clinical trialε to eεtabliεh efficacy in preventing rejection of solid organ transplantε (such aε renal) are conducted, e.g., as deεcribed by Lindholm, Albrechtεen, Tufveson, et al. , "A randomized trial of cyclosporin and prednisolone verεuε cycloεporin, azathioprine and predniεolone in primary cadaveric renal tranεplantation, " Transplantation, 54:624-631 (1992). Human clinical trialε for graft vε. hoεt disease are conducted, e.g., as deεcribed by Storb, Deeg, Whitehead, et al. , "Methotrexate and cyclosporin compared with cyclosporin alone for prophylaxis of acute graft verεuε host diseaεe after marrow transplantation for leukemia." New England J. Med. , 314:729-735 (1986). Immunosuppresεive activity iε determined by both in vivo and in vitro procedureε. In vivo activity iε determined, e.g., utilizing a modification of the Jerne hemolytic plaque aεsay, [Jerne, et al., "The agar plaque technique for recognizing antibody producing cells," Cell -bound Antibodies, Amos, B. and Kaprowεki, H. editorε (Wiεtar Inεtitute Preεε, Philadelphia) 1963, p. 109] . In vitro activity iε determined, e.g., by an adaptation of the procedure deεcribed by Greaves, et al. , "Activation of human T and B lymphocytes by polyclonal mitogens," Nature, 248:698-701 (1974). Anti-viral activity is determined, for example, by the procedure described by Smee, et al. ["Anti-Herpeεviruε Activity of the Acyclic Nucleoside 9- (i,3-Dihydroxy-2-Propoxymethyl)Guanine, " Antimicrobial Agents and Chemotherapy, 23 (5) :676-682 (1983)], or aε described by Planteroεe ["Antiviral and cytotoxic effectε of mycophenolic acid, " Journal of General Virology, 4:629 (1969)] . Anti-viral activity can likewise be determined by measurement of reverse transcriptaεe activity, for example, according to the method deεcribed by Chen et al., Biochem. Pharm. , 36:4361 (1987). Human clinical trialε for anti-HIV efficacy (together with clinical treatment εcenarios) are deεcribed and cited, for example, by Sande, et al. , "Antiretroviral Therapy for Adult HIV-Infected Patientε," JAMA, 270 (21) :2583-2589 (1993). A large εcale clinical trial can be conducted, e.g., aε deεcribed by Volberding, P.A., et al. "Zidovudine in aεymptomatic human immunodeficiency viruε infection: a controlled trial in perεons with fewer than 500 CD4 poεitive cells per cubic millimeter, " New England J. Med. , 322 (14) :941-949 (1990). A smaller scale (Phase I) clinical trial can be conducted, e.g., as described by Browne, et al. , "2' ,3' -Didehydro-3' - deoxythymidine (d4T) in Patients with AIDS or AIDS-Related Complex: A Phaεe I Trial," J. Infectious Diseases, 167:21-29 (1993). Teεtε for εystemic activity in psoriaεiε can be carried out, for example, aε deεcribed by Spatz, et al. , "Mycophenolic acid in pεoriaεis," British Journal of Dermatology, 98:429 (1978) . Teεtε for anti-tumor activity can be performed, for example, as described by Carter, et al. ["Mycophenolic acid: an anticancer compound with unusual propertieε," Mature, 223:848 (1969)] . In vitro activity for treating εtenosis iε demonstrated, for example, by inhibiting the proliferation of smooth muscle cellε, aε eεtabliεhed by the following human arterial εmooth muεcle cell proliferation aεεay. Human smooth muscle cellε are grown in culture. A teεt group is treated with the test compound added at selected concentrationε in freεh media. Both groupε receive 2μCi tritiated thymidine ( 3 HTdR) , a radioiεotope label. After 24 hourε, the cellε are harvested and the amount of label incorporated into DNA is counted by scintillation; this iε compared for the teεt and control groupε, the amount being proportional to cell proliferation. Inhibition of εmooth muεcle proliferation iε eεtabliεhed when the teεt group haε a lower radioisotope count than the control group. The concentrations of test compound required to inhibit proliferation by 50% (the ICy,) , and to inhibit proliferation by more than 95% are determined. In vivo activity for treating stenoεiε iε demonεtrated, for example, in rat and pig modelε for arterial εtenoεiε. In the rat model, a teεt group iε treated with the teεt compound, εtarting 6 dayε before and continuing for 14 days after injury to the left carotid artery; the test group is compared to a control group receiving vehicle without the teεt compound. Injury iε achieved by a gentle perfuεion of air through a 10 mm long section of the left artery. The right artery is left intact. Arterial croεε-εections (10 μm) are taken from both the left and right arteries of each subject, and the area of the vesεel wall (endothelium, intima, media) iε measured, The amount of vascular proliferation iε calculated by εubtracting the mean area of the intact, right carotid artery from the mean area of the injured, left carotid artery. Reduction in vaεcular proliferation iε eεtabliεhed when the teεt group εhows lesε proliferation than the control group. Human clinical trialε for restenosiε after coronary angioplaεty are conducted, e.g., aε deεcribed by Serruyε, Rutεch, Heyndrickx, et al. , "prevention of reεtenoεiε after percutaneouε tranεluminal coronary antioplaεty with thromboxane Aj-receptor blockade: a randomozed, double- blind, placebo-controlled trial." Circulation, 84:1568-80 (1991). Administration The compoundε of Formula A are adminiεtered at a therapeutically effective doεage, e.g., a dosage sufficient to provide treatment for the diseaεe εtates previously described. Administration of the compounds of the invention or the pharmaceutically acceptable εaltε thereof can be via any of the accepted modeε of administration for agents that serve similar utilities. The compoundε can be used both prophylactically (e.g., to prevent allograft rejection) and therapeutically. While human dosage levels have yet to be optimized for the compoundε of the invention, generally, a daily dose iε from about 0.01 to 100.0 mg/kg of body weight, preferably about 0.1 to 64.3 mg/kg of body weight, and moεt preferably about 0.3 to 43.0 mg/kg of body weight. Thuε, for adminiεtration to a 70 kg person, the dosage range would be about 0.7 mg to 7 g per day, preferably about 7.0 mg to 4.5 g per day, and moεt preferably about 21 mg to 3.0 g per day. The amount of active compound administered will, of courεe, be dependent on the εubject and diεease state being treated, the severity of the affliction, the manner and schedule of administration (e.g., oral administration one day prior to cancer chemotherapy and intravenous administration during cancer chemotherapy) and the judgment of the prescribing physician. In employing the compoundε of thiε invention for treatment of the above conditionε, any pharmaceutically acceptable mode of administration can be used. The compounds of Formula A can be administered either alone or in combination with other pharmaceutically acceptable excipientε, including εolid, semi-solid, liquid or aerosol dosage forms, εuch as, for example, tabletε, capεules, powders, liquids, injectables, suεpenεions, suppoεitorieε, aeroεolε or the like. The compounds of Formula A can also be administered in εustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotranεport) patcheε, and the like, for the prolonged adminiεtration of the compound at a predetermined rate, preferably in unit dosage forms εuitable for εingle adminiεtration of precise dosages. The compositions will typically include a conventional pharmaceutical carrier or excipient and a compound ' of Formula A or a pharmaceutically acceptable salt thereof. In addition, these compoεitionε may include other medicinal agentε, pharmaceutical agentε, carrierε, adjuvantε, etc., εuch aε multidrug resistance modifying agentε, εteroidε, immunoεuppreεεantε εuch aε cycloεporine A, azathioprene, rapamycin, FK-506, brequinar, leflunomide and vineryεtine. Generally, depending on the intended mode of adminiεtration, the pharmaceutically acceptable compoεition will contain about 0.1% to 90%, preferably about 0.5% to 50%, by weight of a compound or εalt of Formula A, the remainder being εuitable pharmaceutical excipientε, carriers, etc. One preferred manner of administration for the conditionε detailed above iε oral, uεing a convenient daily doεage regimen which can be adjuεted according to the degree of affliction. For εuch oral adminiεtration, a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, εuch aε, for example, mannitol, lactoεe, εtarch, povidone, magneεium εtearate, εodium εaccharine, talcum, celluloεe, croεcarmellose εodium, glucose, gelatin, εucroεe, magneεium carbonate, and the like. Such compoεitionε take the form of solutions, εuspenεionε, tabletε, dispersible tabletε, pills, capεuleε, powdez-s, εuεtained releaεe formulations and the like. Preferably the compoεitionε will take the form of a pill or tablet and thuε the composition will contain, along with the active ingredient, a diluent such as lactoεe, εucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; a diεintegrant such as croscarmellose sodium or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like. Liquid pharmaceutically adminiεtrable compoεitionε can, for example, be prepared by dissolving, diεperεing, etc. an active compound aε defined above and optional pharmaceutical adjuvantε in a carrier, such as, for example, water, εaline, aqueouε dextrose, glycerol, glycols, ethanol, and the like, to thereby form a εolution or εuspension. If desired, the pharmaceutical composition to be administered may also contain minor amountε of nontoxic auxiliary εubεtanceε εuch as wetting agents, suspending agents, emulεifying agentε, or solubilizing agents, pH buffering agentε and the like, for example, εodium acetate, εodium citrate, cyclodextrine derivativeε, polyoxyethylene, εorbitan monolaurate or εtearate, etc. Actual methodε of preparing εuch doεage formε are known, or will be apparent, to thoεe εkilled in thiε art; for example, εee Remington's Pharmaceutical Sciences, Mack Publishing Company, Eaεton, Pennsylvania, 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a quantity of the active compound in em amount effective to alleviate the symptoms of the subject being treated. Dosage formε or compoεitionε containing active ingredient in the range of 0.005% to 95% with the balance made up from pharmaceutically acceptable carrier may be prepared. For oral administration, a pharmaceutically acceptable composition iε formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactoεe, εtarch, magneεium stearate, talcum, povidone, cellulose derivatives, croεcarmellose sodium, glucose, εucroεe, magneεium carbonate, sodium saccharin, talcum and the like. Such compoεitionε take the form of εolutionε, suspensions, tabletε, capsules, powders, sustained release formulations and the like. Such compoεitionε may contain 0.01%-95% active ingredient, preferably 0.1-50%. For a solid dosage form containing liquid, the εolution or suεpenεion, in for example propylene carbonate, vegetable oilε or triglycerideε, is preferably encapsulated in a gelatin capεule. Such eεter εolutions, and the preparation and encapsulation thereof, are discloεed in U.S. Patentε Noε. 4,328,245; 4,409,239; and 4,410,545. For a liquid doεage form, the εolution, e.g. in a polyethylene glycol, may be diluted with a εufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be eaεily meaεured for adminiεtration. Alternatively, liquid or semi-solid oral formulations may be prepared by diεεolving or diεperεing the active compound or εalt in vegetable oilε, glycols, triglycerideε, propylene glycol eεters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suεpenεionε in hard or soft gelatin capsule shells. Other useful formulations include thoεe εet forth in U.S. Patentε Noε. Re. 28,819 and 4,358,603. Parenteral administration is generally characterized by injection, either εubcutaneouεly, intramuscularly or intravenously. Injectables can be prepared in conventional formε, either aε liquid solutions or suεpensionε, εolid formε εuitable for εolution or suspenεion in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, εaline, dextroεe, glycerol, ethanol or the like. In addition, if deεired, the pharmaceutical compoεitionε to be adminiεtered may alεo contain minor amountε of non-toxic auxiliary εubεtances such aε wetting or emulεifying agentε, pH buffering agentε, solubility enhancers, and the like, εuch aε for example, sodium acetate, polyoxyethylene, εorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc. A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-releaεe syεtem, εuch that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795. The percentage of active compound contained in such parenteral compositionε iε highly dependent on the εpecific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the composition is a solid which will be subεequently diluted to the above percentages. Preferably the composition will comprise 0.2-2% of the active agent in solution. Formulations of the active compound or a εalt may alεo be adminiεtered to the reεpiratory tract aε an aerosol or εolution for a nebulizer, or aε a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation have diameters of lesε than 50 micronε, preferably leεε than 10 microns. EXAMPLES The following preparations and exa pleε are given to enable thoεe εkilled in the art to more clearly underεtand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely aε being illuεtrative and repreεentative thereof. EXAMPLE 1 IA. Formula 2 where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, R b is Tosyl and Lower Alkyl is Methyl p-Tolueneεulfonyl chloride (30g) waε added to a εolution of methyl (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4- methyl-4-hexenoate (40g) in pyridine (200ml) at 0°C. After 6 hourε the solution waε poured on to ice and acidified to pH 3 with dilute hydrochloric acid. The εolution waε extracted with ethyl acetate and the extract was dried and evaporated to afford methyl (E) 6- (1,3-dihydro-6- methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxyiεobenzofuran-5-yl) -4-methyl- 4-hexenoatg. IB. Formula 2 varying Z" By following the procedure of part A and εubstituting methyl (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4- methyl-4-hexenoate with: methyl (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] cyclopent-1-yl] acetate; methyl 3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ylacetate; ethyl (E) -3- [2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclopentane-1-carboxylate; methyl (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -prop-1-en-l-yl] -3-methylbenzoate; methyl 4- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzo- furan-5-yl) cyclopent-1-en-l-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the compounds of Formula IA where Z* correεpondε to the εide chainε identified in the following tableε: there are obtained methyl (E) -2- [2- [2- [l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyisobenzofuran-5-yl]ethylidene]cyclopent-1- yl]acetate; methyl 3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyl- oxy-5-isobenzofuranylmethyl) -2-methylcyclopent-2-en-1- ylacetate; ethyl (E) -3- [2- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylate; methyl (E) -2- [3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-l-yl] -3- methylbenzoate; methyl 4- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyisobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-l- carboxylate; methyl 3- [3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-tolueneεulfony- loxyiεobenzo-furan-5-yl)cyclopent-1-en-l-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other correεponding compoundε of Formula 2. EXAMPLE 2 2A. Formula 3 where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, and R b is Tosyl A εolution of methyl (E) 6- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate (28g) in 2,4,6- collidine (100ml) waε heated to 65°C and lithium iodide (50g) waε added. After 3 days the solution was added to ethyl acetate and dilute hydrochloric acid. The organic layer waε dried and evaporated to afford (E) 6- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy- iεobenzofuran-5-yl) -4-methyl-4-hexenoic acid. 2B. Formula 3 Varying Z" By following the procedure of part A and substituting methyl (E) 6- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran- 5-yl) -4-methyl-4-hexenoate with: methyl (E) -2- [2- [2- [l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-1- yl]acetate; methyl 3- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyl- oxy-5-isobenzofuranylmethyl) -2-methylcyclopent-2-en-l- ylacetate; ethyl (E) -3- [2- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzofuran-5-yl)ethylidene]cyclopentane-1- carboxylate; methyl (E) -2- [3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-l-yl] -3- methylbenzoate; methyl 4- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyl- oxyisobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyisobenzo-furan-5-yl)cyclopent-1-en-1-yl] - propionate; methyl (E) -2- [-3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyiεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compoundε of Formula 2 correεponding to thoεe liεted in the tables in Example IB, there are obtained: (E) -2- [2 ; - [2- [l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-1- yl]acetic acid; 3- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyl-oxy-5- isobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ylacetic acid; (E) -3- [2- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylic acid; (E) -2- [3- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-l-yl] -3- methylbenzoic acid; 4- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyiεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylic acid; 3- [3- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzo-furan-5-yl)cyclopent-1-en-l-yl] - propionic acid; (E) -2- [-3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -l-methylpropenyl] - cyclopentanecarboxylic acid; and the other compoundε of Formula 3 correεponding to thoεe liεted in the tables in Example IB. EXAMPLE 3 3A. Formula 4 where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , 7?, and Z 4 are H, and R b is Tosyl and Lower Alkyl is Methyl A solution of (E) 6- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid (23g) and p-toluenesulfonic acid (0.8g) in methanol (150ml) waε εtirred for 18 hourε then added to water and ethyl acetate. The organc layer waε dried and evaporated and the reεidue waε chromatographed on silica gel, eluting with hexane:ethyl acetate: methanol 40:58:2, to afford methyl (E) 6- (1,3- dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyloxyiεobenzofuran-5-yl) - 4-methy1-4-hexenoate. 3B. Formula 4 Varying Z" By following the procedure of part A and subεtituting (E) 6- (1,3- dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxyiεobenzofuran-5-yl) - 4-methyl-4-hexenoic acid with: (E) -2- [2- [2- [l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-1- yl]acetic acid; 3- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyl-oxy-5- isobenzofuranylmethyl) -2-methylcyclopent-2-en-l-ylacetic acid; (E) -3- [2- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylic acid; (E) -2- [3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofurein-5-yl) -prop-1-en-1-yl] -3- methylbenzoic acid; 4- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyiεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylic acid; 3- [3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyiεobenzofuran-5-yl)cyclopent-1-en-1-yl] -propionic acid; (E) -2- [-3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylic acid; and the other compoundε of Formula 3 correεponding to thoεe listed in the tables in Example IB, there are obtained: methyl (E) -2- [2- [2- [l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-1- yl]acetate; methyl 3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyl- oxy-5-isobenzofuranylmethyl) -2-methylcyclopent-2-en-1- ylacetate; methyl (E) -3- [2- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluene- εulfonyloxyisobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylate; methyl (E) -2- [3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-1-yl] -3- methylbenzoate; methyl 4- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyiεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzo-furan-5-yl)cyclopent-1-en-1-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compoundε of Formula 4 correεponding to thoεe listed in the tables in Example IB. EXAMPLE 4 4A. Formula 5 where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, and R b is Tosyl and Lower Alkyl is Methyl Trifluoromethanesulfonic anhydride (10.57g) was added to a εolution of methyl (E) 6- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyl- oxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate in methylene chloride (500ml) amd pyridine (5ml) at 0°C. After 6 hours the reaction was added to excesε aqueous sodium bicarbonate. The organic εolution waε dried and evaporated to afford methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- 6-trifluoromethaneεulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate. 4B. Formula 5 Varying Z* By following the procedure of part A and εubεtituting methyl (E) 6- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxyiεobenzofuretn- 5-yl) -4-methyl-4-hexenoate with: methyl (E) -2- [2- [2- [1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-l- yl]acetate; methyl 3- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluenesulfonyl- oxy-5-isobenzofuranylmethyl) -2-methylcyclopent-2-en-1- ylacetate; methyl (E) -3- [2- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylate; methyl (E) -2- [3- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-l-yl] -3- methylbenzoate; methyl 4- (1,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyisobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyisobenzo-furan-5-yl)cyclopent-1-en-1-yl] - propionate; methyl (E) -2- [-3- (l,3-dihydro-6-hydroxy-7-methyl-3-oxo-4-p- toluenesulfonyloxyiεobenzofurem-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compoundε of Formula 4 correεponding to those listed in the tableε in Example IB, there are obtained: methyl (E) -2- [2- [2- [1,3-dihydro-7-methyl-3-oxo-4-p- toluenesulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran- 5-yl]ethylidene] cyclopent-1-yl]acetate; methyl 3- (1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyl-oxy-6- trifluoromethaneεulfonyloxy-5-isobenzofuranylmethyl) -2- methylcyclopent-2-en-l-ylacetate; methyl (E) -3- [2- (l,3-dihydro-7-methyl-3-oxo-4-p-toluene-sulfonyloxy- 6-trifluoromethanesulfonyloxyiεobenzofuran-5-yl) - ethylidene] cyclopentane-1-carboxylate; methyl (E) -2- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- trifluoromethaneεulfonyloxyisobenzofuran-5-yl) -prop-1-en-l-yl] - 3-methylbenzoate; methyl 4- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl-oxy-6- trifluoromethaneεulfonyloxyiεobenzofuran-5-ylmethy1) -3- methylcyclopent-3-ene-1-carboxylate; methyl 3- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- tirifluoromethaneεulfonyloxyiεobenzo-furan-5-yl)cyclopent-1-en- 1-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- 6-trifluoromethaneεulfonyloxyisobenzofuran-5-yl) -1- methylpropenyl] -cyclopentanecarboxylate; and the other compounds of Formula 5 corresponding to those liεted in the tables in Example IB. EXAMPLE 5 5A. Formula 6 where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, and R b is Tosyl, R 2 is Vinyl and Lower Alkyl is Methyl A mixture of lithium chloride (4.8g), triε(dibenzylideneacetone) - dipalladium (0) chloroform adduct (0.65g), triphenylarεine (1.6g) and methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- trifluoromethaneεulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate (24.2g) in N-methylpyrrolidinone (220ml) was heated to 55°C. Vinyltributyltin (15g) waε added. After 3 hourε the mixture waε added to water (500ml) , potaεεium fluoride (16g) and ethyl acetate. The organic εolution waε dried, filtered through celite and evaporated to afford methyl (E) 6- (l,3-dihydro-7-methyl- 3-oxo-4-p-tolueneεulfonyloxy-6-vinyliεobenzofuran-5-yl) -4-methyl-4- hexenoate. 5B. Formula 6 Varying Z" By following the procedure of part A and substituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoromethane- sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate with: methyl (E) -2- [2- [2- [1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl¬ oxy-6-trifluoromethanesulfonyloxyisobenzofuran-5- yl]ethylidene]cyclopent-1-yl]acetate; methyl 3- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyl-oxy-6- trifluoromethaneεulfonyloxy-5-iεobenzofuranylmethyl) -2- methylcyclopent-2-en-1-ylacetate; methyl (E) -3- [2- (l,3-dihydro-7-methyl-3-oxo-4-p-toluene-sulfonyloxy- 6-trifluoromethaneεulfonyloxyiεobenzofurεin-5-yl) - ethylidene]cyclopentane-1-carboxylate; methyl (E) -2- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- trifluoromethanesulfonyloxyisobenzofuran-5-yl) -prop-1-en-l-yl] - 3-methylbenzoate; methyl 4- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl-oxy-6- trifluoromethaneεulfonyloxyiεobenzofuran-5-ylmethyl) -3- methylcyclopent-3-ene-1-carboxylate; methyl 3- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- trifluoromethaneεulfonyloxyiεobenzo-furan-5-yl)cyclopent-1-en- 1-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- 6-trifluoromethaneεulfonyloxyiεobenzofuran-5-yl) -1- methylpropenyl] -cyclopentanecarboxylate; and the other compounds of Formula 5 corresponding to those liεted in the tableε in Example IB, there are obtained: methyl (E) -2- [2- [2- [l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxy-6-vinylisobenzofuran-5-yl]ethylidene] cyclopent-1-yl] - acetate; methyl 3- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl-oxy-6-vinyl- 5-iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ylacetate; methyl (E) -3- [2- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- vinyliεobenzofuran-5-yl)ethylidene] cyclopentane-1-carboxylate; methyl (E) -2- [3- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- vinyliεobenzofuran-5-yl) -prop-1-en-l-yl] -3-methylbenzoate; methyl 4- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyl-oxy-6- vinyliεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- vinyliεobenzo-furan-5-yl) cyclopent-1-en-l-yl] -propionate; methyl (E) -2- [-3- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- 6-vinyliεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compounds of Formula 6 corresponding to thoεe liεted in the tableε in Example IB. 5C. Formula 6 Varying R 2 By following the procedure of part A and substituting vinyltributyltin with: methyltributyltin; cyclopropyltributyltin; fluorovinyltributyltin; trifluorovinyltributyltin; prop-2-enyltributyltin; ethynyltributyltin; pent-2-ynyltributyltin; allyltributyltin; and 4-methoxybenzyloxymethyltributyltin; there are obtained: methyl (E) 6- (1,3-dihydro-6,7-dimethyl-3-oxo-4-p-tolueneεulfonyloxy- iεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (6-cyclopropyl-l,3-dihydro-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (1,3-dihydro-6-fluorovinyl-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- trifluorovinyliεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- (p'irop-2-enyl) iεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (1,3-dihydro-6-ethynyl-7-methyl-3-oxo-4-p-toluene¬ sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- (pent-2-ynyl) isobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (6-allyl-l,3-dihydro-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate; and methyl (E) 6- (1,3-dihydro-6- (4-methoxybenzyloxymethyl) -7-methyl-3- oxo-4-p-tolueneεulfonyloxyiεobenzofuran-5-yl) - -methyl-4- hexenoate. 5D. Formula 6 Varying R 2 By following the procedure of part A and εubstituting vinyltributyl¬ tin with ethyltributyltin, and substituting methyl (E) 6- (l,3-dihydro-7- methyl-3-oxo-4-p-tolueneεulfonyloxy-6-trifluoromethaneεulfonyloxyiεobenzo- furan-5-yl) -4-methyl-4-hexenoate with methyl (E) 6- (1,3-dihydro-7-methyl-3- oxo-4-p-tolueneεulfonyloxy-6-trifluoromethanesulfonyloxyisobenzofuran-5- yl) -3,4-dimethyl-4-hexenoate, there iε obtained methyl (E) 6- (1,3-dihydro- 6-ethyl-7-methyl-3-oxo-4-p-tolueneεulfonyloxyiεobenzofuran-5-yl) -3,4- dimethyl-4-hexenoate. EXAMPLE 6 6A. Formula AA where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, and R 2 is Vinyl A solution of methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-6-vinyliεobenzofuran-5-yl) -4-methyl-4-hexenoate (0.37g) and lithium hydroxide (0.4g) in methanol (6ml) and water (6ml) was heated at 62°C for 15 hours. The reaction waε acidified with aqueouε sodium hydrogen sulfate and extracted with ethyl acetate. The extract waε dried and evaporated and the reεidue chromatographed on εilica gel, eluting with ethyl acetate/hexane/acetic acid to give (E) 6- (1,3-dihydro-4-hydroxy-7- methyl-3-oxo-6-vinyliεobenzofuran-5-yl) -4-methyl-4-hexenoic acid, m.p. 148-149°C (tert-butylmethyl ether/hexane) . 6B. Formula AA Varying Z" By following the procedure of part A and εubstituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6-vinylisobenzofuran-5- yl) -4-methyl-4-hexenoate with: methyl (E) -2- [2- [2- [1,3-dihydro-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-6-vinyliεobenzofuran-5- yl]ethylidene] cyclopent-1-yl]acetate; methyl 3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl-oxy-6-vinyl- iεobenzofurein-5-ylmethyl) -2-methylcyclopent-2-en-1-ylacetate; methyl (E) -3- [2- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- vinyliεobenzofuran-5-yl)ethylidene] cyclopentane-1-carboxylate; methyl (E) -2- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- vinyliεobenzofuran-5-yl) -prop-1-en-l-yl] -3-methylbenzoate; methyl 4- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyl-oxy-6- vinyliεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- vinylisobenzofuran-5-yl)cyclopent-1-en-l-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy- 6-vinyliεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compoundε of Formula 6 corresponding to those listed in the tables in Example IB, there are obtained: (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- vinylisobenzofuran-5-yl]ethylidene] cyclopent-1-yl]acetic acid; 3- (1,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinyl-isobenzofuran-5- ylmethyl) -2-methylcyclopent-2-en-l-ylacetic acid; (E) -3- [2- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinyliεobenzofuran- 5-yl)ethylidene] cyclopentane-1-carboxylic acid; (E) -2- [3- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinyliεobenzofuran- 5-yl) -prop-1-en-l-yl] -3-methylbenzoic acid; 4- (1,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinyliεobenzofuran-5- ylmethyl) -3-methylcyclopent-3-ene-1-carboxylic acid; 3- [3- (1,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinyliεobenzofuran-5- yl)cyclopent-l-en-l-yl] -propionic acid; (E) -2- [-3- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6-vinyliεobenzofuran- 5-yl) -1-methylpropenyl] -cyclopentanecarboxylic acid; and the other compoundε of Formula AA where R 2 iε vinyl, corresponding to those listed in the tables that follow: 6C. Formula AA Varying R 2 By following the procedure of part A and εubεtituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6-vinyliεobenzofuran-5- yl) -4-methyl-4-hexenoate with: methyl (E) 6- (1,3-dihydro-6,7-dimethyl-3-oxo-4-p-tolueneεulfonyloxy- iεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (6-cyclopropyl-l,3-dihydro-7-methyl-3-oxo-4-p-toluene- εulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-6-fluorovinyl-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- trifluorovinyliεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- (prop-2-enyl)isobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-6-ethynyl-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- (pent-2-ynyl)iεobenzofuran-5-yl) -4-methyl-4-hexenoate; methyl (E) 6- (6-allyl-l,3-dihydro-7-methyl-3-oxo-4-p-toluene- sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate; and methyl (E) 6- (1,3-dihydro-6- (4-methoxybenzyloxymethyl) -7-methyl-3- oxo-4-p-tolueneεulfonyloxyisobenzofuran-5-yl) -4-methyl-4- hexenoate, there are obtained: (E) 6- (1,3-dihydro-4-hydroxy-6,7-dimethyl-3-oxoiεobenzofuran-5-yl) -4- methyl-4-hexenoic acid, m.p. 167-170°C (ethyl acetate) ; (E) 6- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- yl) -4-methyl-4-hexenoic acid, m.p. 141-142°C (t-butylmethyl ether) ; (E) 6- (6-cyclopropyl-1,3-dihydro-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl) -4-methyl-4-hexenoic acid, m.p. 172-174°C (t-butylmethyl ether) ; (E) 6- (1,3-dihydro-6-fluorovinyl-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl) -4-methyl-4-hexenoic acid; (E) 6- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- trifluorovinyliεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; (E) 6- (l ' ,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- (prop-2- enyl) iεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; (E) 6- (1,3-dihydro-6-ethynyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- yl) -4-methyl-4-hexenoic acid; (E) 6- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- (pent-2-ynyl) - iεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; (E) 6- (6-allyl-l,3-dihydro-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- yl) -4-methyl-4-hexenoic acid; and (E) 6- (l,3-dihydro-4-hydroxy-6- (4-methoxybenzyloxymethyl) -7-methyl-3- oxoisobenzofuran-5-yl) -4-methyl-4-hexenoic acid. 6D. Formula AA Varying Z a and R 2 By following the procedure of part A and subεtituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6-vinylisobenzofuran-5- yl) -4-methyl- -hexenoate with methyl (E) 6- (l,3-dihydro-6-ethyl-7-methyl-3- oxo-4-p-tolueneεulfonyl-oxyiεobenzofuran-5-yl) -3, -dimethyl-4-hexenoate, there iε obtained (E) 6- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3,4-dimethyl-4-hexenoic acid, m.p. 180-182°C (acetone/hexane) . EXAMPLE 7 7A. Formula 6 where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, and R b is Tosyl, R 2 is Ethyl and Lower Alkyl is Methyl A solution of methyl (E) 6- (l,3-dihydro-7-methyl-3-oxo-4-p- toluenesulfonyloxy-6-vinylisobenzofuran-5-yl) -4-methyl-4-hexenoate (17.7g) and tris(triphenylphosphine) rhodium chloride (1.2g) in benzene (180ml) and ethanol (180ml) waε hydrogenated for 11 hourε. The εolventε were removed under vacuum and the residue waε crystallized from ethyl acetate/tert-butyl methyl ether to afford methyl (E) 6- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4- p-tolueneεulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate, m.p. 101.3- 102.8°C. 7B. Formula 6 Varying Z a By following the procedure of part A and substituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6-vinyliεobenzofuran-5- y1) -4-methy1-4-hexenoate with: methyl (E) -2- [2- [2- [1,3-dihydro-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-6-vinyliεobenzofuran-5- yl]ethylidene] cyclopent-1-yl]acetate; methyl 3- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyl-oxy-6-vinyl- iεobenzofuran-5-ylmethyl) -2-methylcyclopent-2-en-1-ylacetate; methyl (E) -3- [2- (1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- vinylisobenzofuran-5-yl)ethylidene] cyclopentane-1-carboxylate; methyl (E) -2- [3- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6- vinylisobenzofuran-5-yl) -prop-1-en-l-yl] -3-methylbenzoate; methyl 4- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- vinyliεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6- vinyliεobenzofuran-5-yl)cyclopent-1-en-l-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy- 6-vinylisobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compounds of Formula 6 corresponding to those liεted in the tableε in Example IB, there are obtained: methyl (E) -2- [2- [2- [l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-1- yl]acetate; methyl 3- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- iεobenzofuran-5-ylmethyl) -2-methylcyclopent-2-en-1-ylacetate; methyl (E) -3- [2- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyisobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylate; methyl (E) -2- [3- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-1-yl] -3- methylbenzoate; methyl 4- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- iεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-l- carboxylate; methyl 3- [3- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- toluenesulfonyloxyisobenzofuran-5-yl)cyclopent-1-en-l-yl] - propionate; methyl (E) -2- [-3- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- " tolueneεulfonyloxyisobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compounds of Formula 6 where R 2 is ethyl, corresponding to those liεted in the tableε in Example IB. EXAMPLE 8 8A. Formula AA where Z" is a Side Chain of Formula ZA and Z 1 is Methyl, Z 2 , Z 3 , and Z 4 are H, and R 2 is Ethyl A solution of methyl (E) 6- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyliεobenzofuran-5-yl) -4-methyl-4-hexenoate (3.16g) and lithium hydroxide (1.2g) in 1:1 aqueouε methanol (40ml) waε heated at 62°C for 18 hourε. The εolution waε acidified and extracted with ethyl acetate. The extract waε dried and evaporated and the reεidue chromatographed on silica gel, eluting wth ethyl acetate/hexane/acetic acid to afford (E) 6- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl) -4- methyl-4-hexenoic acid, m.p. 141-142°C (t-butylmethylether) . 8B. Formula AA Varying Z" By following the procedure of part A and substituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-6-ethylisobenzofuran-5- yl) -4-methyl-4-hexenoate with: methyl (E) -2- [2- [2- [1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluene¬ εulfonyloxyiεobenzofuran-5-yl]ethylidene] cyclopent-1-yl] - acetate; methyl 3- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-tolueneεulfonyloxy- 5-isobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ylacetate; methyl (E) -3- [2- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylate; methyl (E) -2- [3- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -prop-1-en-l-yl] -3- methylbenzoate; methyl 4- (1,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-tolueneεulfonyloxy¬ iεobenzofuran-5-ylmethyl) -3-methylcyclopent-3-ene-1- carboxylate; methyl 3- [3- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p-toluenesulfonyl- oxyiεobenzofuran-5-yl) cyclopent-1-en-l-yl] -propionate; methyl (E) -2- [-3- (l,3-dihydro-6-ethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -1-methylpropenyl] - cyclopentanecarboxylate; and the other compoundε of Formula 6 where R 2 iε ethyl, correεponding to -97- those listed in the tεdaleε in Example IB, there are obtained: (E) -2- [2- [2- [l,3-dihydro-6-ethyl 4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1-yl] acetic acid, m.p. 168-169°C (t-butylmethylether) ; 3- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- ylmethyl) -2-methylcyclopent-2-en-l-ylacetic acid; (E) -3- [2- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran- 5-yl)ethylidene] cyclopentane-1-carboxylic acid; (E) -2- [3- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -prop-1-en-l-yl] -3-methylbenzoic acid; 4- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5- ylmethyl) -3-methylcyclopent-3-ene-l-carboxylic acid; 3- [3- (1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofurεui-5- yl) cyclopent-1-en-l-yl] -propionic acid; (E) -2- [-3- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoiso- benzofuran-5-yl) -1-methylpropenyl] -cyclopenteuiecarboxylic acid; and the other coiipounds of Formula AA where R 2 iε ethyl, correεponding to thoεe liεted in the tableε that follow: RΞCΪSΓ- ' .E :- : ΞΞT (RIJL≡ 91) ISA RECTIFIED SHEET (RULE 91 ISA/EP RECTIFIED SHEET (RULE 91) ISA/EP RECTIFIED SHEET (RULE 91) ISA/EP EXAMPLE 9 9A. Methyl (E) 6- (l,3-dihydro-6- (p-methoxybenzyloxymethyl) -7-methyl-3- oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate A mixture of lithium chloride (1.6g), tris (dibenzylideneacetone) - dipalladium (0) chloroform adduct (0.22g), triphenylarsine (0.53g), methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoro- methaneεulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate (8.0g) and N-methylpyrrolidinone (70ml) iε heated to 55°C. p-Methoxybenzyloxy- methyltributyltin (7.5g) is added. After 3 hours the solution iε added to water (200ml) , potaεεium fluoride (5g) and ethyl acetate (200ml) . The organic εolution iε dried, filtered through celite and evaporated, and the reεidue is chromatographed on εilica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6- (1,3-dihydro-6- (p-methoxybenzyloxymethyl) - 7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl) -4-methyl-4- hexenoate. 9B. Methyl (E) 6- (1,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo- - p-toluenesulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate Methyl ' (E) 6- (l,3-dihydro-6- (p-methoxybenzyloxymethyl) -7-methyl-3- oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate (0.5g) iε diεεolved in trifluoroacetic acid (10ml) at 0°C. After 30 minutes the εolvent iε removed under vacuum and the reεidue iε chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6- (1,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4-p-toluenesulfonyl- oxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate. 9C. Methyl (E) 6- (l,3-dihydro-6-formyl-7-methyl-3-oxo-4- p-toluenesulfonyloxyisobenzofuran-5-yl) -4-methyl- -hexenoate Methyl (E) 6- (l,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4- p-toluenesulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate (0.2g) iε diεεolved in dichloromethane (10ml) and pyridinium chlorochromate (0.15g) is added. After one hour water (25ml) is added. The organic solution iε dried and evaporated and the reεidue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6- (1,3-dihydro-6- formyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl) - -methyl-4- hexenoate. 9D. Formula A where R 2 is p-Methoxybenzyloxymethyl, Hydroxymethyl and Formyl By following the procedure of Example 6 and substituting methyl (E) 6- (1,3-dihydro-7-methyl-3-oxo-4-p-toluenesulfonyloxy-6-trifluoro- methanesulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate with: methyl (E) 6- (1,3-dihydro-6- (p-methoxybenzyloxymethyl) -7-methyl-3- oxo-4-p-tolueneεulfonyloxyiεobenzofuran-5-yl) -4-methyl-4- hexenoate; methyl (E) 6- (l,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4-p- tolueneεulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoate; and methyl (E) 6- (1,3-dihydro-6-formyl-7-methyl-3-oxo-4-p-toluene¬ sulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoate, there are obtained: (E) 6- (1,3-dihydro-6- (p-methoxybenzyloxymethyl) -7-methyl-3-oxo-4-p- tolueneεulfonyloxyisobenzofuran-5-yl) -4-methyl-4-hexenoic acid; (E) 6- (l,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4-p-toluene- εulfonyloxyiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; and (E) 6- (l,3-dihydro-6-formyl-7-methyl-3-oxo-4-p-tolueneεulfonyl- oxyisobenzofuran-5-yl) -4-methyl-4-hexenoic acid. EXAMPLE 10 (E) -2-{2- [2- [1,3-dihydro-6-ethyl-4-hydroxy-7-methyl- 3-oxoisobenzofuran-5-yl]ethylidene] cyclopent-1- (S) -yl}acetic acid 10A. Methyl (E) -6- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl) - -methyl-4-hexenoate A solution of (E) -6- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid in methanol (200 ml) waε treated with p-tolueneεulfonic acid (0.8 g) and εtirred at 25°C for 16 hourε. The reaction mixture waε cooled to 0°C. Methyl (E) -6- (1,3-dihydro- 6-ethyl-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate, m.p. 116.5-117.6, waε collected by filtration. 10B. Methyl (E) -6- (4-t-butyldimethylsilyloxy-l,3-dihydro-6-ethyl-7-methyl- 3-oxoisobenzofuran-5-yl) - -methyl- -hexenoate A εolution of methyl (E) -6- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate (8.61 g) and imidazole (3.5 g) in dimethyl formamide (40 ml) was treated with t-butyldimethylεilyl chloride (4.50 g) and stirred at 25°C for 14 hourε. The reaction mixture was then poured into ice water and extracted with ether. Drying over magneεium εulfate and evaporation gave methyl (E) -6- (4-t-butyldimethyl- silyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4- hexenoate. 10C. 2- (4-1-Butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3- oxoisobenzofuran-5-yl) -acetaldehyde A solution of methyl (E) -6- (4-t-butyldimethylεilyloxy-l,3-dihydro-6- ethyl-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate (10.6 g) in methylene chloride (150 ml) , methanol (150 ml) and pyridine (5 ml) waε treated with an exceεε of Oxone ® at -70°C. The reaction waε quenched with dimethylεulfide (20 ml) and εtirred for 5 hours at 25°C. The reaction mixture waε poured into IN aqueouε sodium hydrogen εulfate. Extraction with 1:1 ethyl acetate:hexane gave an oil which on purification by εilica gel chromatography gave 2- (4-t-butyldimethylεilyloxy-l,3-dihydro-6-ethyl-7- methyl-3-oxoisobenzofuran-5-yl) -acetaldehyde, m.p. 90.9-91.6°C. 10D. dl-1- [2- { -t-Butyldimβthylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3- oxoisobenzofuran-5-yl) -1-hydroxy-1-yl]cyclopent-1-ene A εolution of 1-bromocyclopentene (21.4 g) in tetrahydrofuran (100 mi) waε added over 30 minuteε to magnesium (3.62 g) in tetrahydrofuran (30 ml) . The reaction mixture was refluxed for 15 minuteε and then diluted with tetrahydrofuran εo that the final volume waε 200 ml. Thiε Grignard reagent (31 ml) waε then added to a εolution of 2- (4-t-butyldimethyl- εilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoiεobenzofuran-5-yl) -acetaldehyde in tetrahydrofuran (100 ml) at -65°C. After 40 minuteε the reaction mixture waε poured into aqueouε ammonium chloride. Extraction with ether gave an oil which waε recryεtalized from t-butylmethyl ether/hexane to give dl-1- [2- (4-1-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3- oxoiεobenzofuran-5-yl) -1-hydroxy-1-yl] cyclopent-1-ene, m.p. 129.5-132°C. 10E. Cyclopentyl (4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl- 3-oxoisobenzofuran-5-yl methyl) methanone A solution of dimethyl εulfoxide (3 ml) in methylene chloride (100 ml) was cooled to -60°C and treated with trifluoroacetic anhydride (4 ml), dl-1- [2- (4-t-Butyldimethylεilyloxy-l,3-dihydro-6-ethyl-7-methyl-3- oxoiεobenzofuran-5-yl) -1-hydroxy-1-yl] cyclopent-1-ene (4.1 g) in methylene chloride (14 ml) waε added over 5 minuteε and the reaction mixture waε εtirred at -60°C for 1 hour. Triethylamine (11 ml) waε added and the reaction mixture waε allowed to warm to 20°C. Aqueouε workup and extraction with methylene chloride gave an oil which was crystalized from t-butylmethyl ether to give cyclopentyl (4-t-butyl-dimethylsilyloxy-l,3- dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl methyl) methanone, m.p. 128.2-129.4°C. 10F. (S) -2- (4-t-Butyldimethylsilyloxy-l,3-dihydro-6-ethyl-7-methyl-3- oxoisobenzofuran-5-yl) -l-cyclopβntenyl-l-hydroxyβthanβ Cyclopentyl (4-1-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl- 3-oxoisobenzofuran-5-yl methyl) methanone (4.2 g) was treated with a 1M toluene εolution of (R) -tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo- [1,2-c] [1,3,2]oxazaborole (3 ml) . The toluene waε evaporated in vacuo and methylene chloride added (2 ml) . The reaction mixture was cooled to -30°C and borane/dimethyl sulfide (0.33 ml) waε added three timeε at 45 minute intervals. The reaction mixture waε εtirred 16 hourε at -30°C and quenched by addition of 1M hydrogen chloride/ether (3 ml) . Toluene waε added (10 ml) and the solution filtered, diluted with ether (200 ml) , washed with aqueouε hydrochloric acid, aqueouε εodium bicarbonate and brine. Drying and evaporation gave an oil which waε purified by εilica gel chromatography to give (S) -2- (4-t-butyldimethylεilyloxy-l,3-dihydro-6-ethyl-7-methyl-3- oxoiεobenzofuran-5-yl) -1-cyclopentenyl-l-hydroxyethane. Further purification by cryεtallization from t-butylmethyl ether gave material with an enantiomeric excesε of 97.8% (Chiracel OD-H, 85:15 hexane:i-propanol, 0.8 ml/minute, minor 8.3 minuteε, major 9.2 minutes). 10G. Ethyl (S) (E) -2-{2- [2- (4-t-butyldimethylsilyloxy-l,3-dihydro-6-ethyl- 7-mβthyl-3-oxoisobβnzofuran-5-yl)ethylidene]cyclopent-1-yl} acetate A mixture of (S) -2- (4-t-butyldimethylεilyloxy-l,3-dihydro-6-ethyl-7- methyl-3-oxoisobenzofuran-5-yl) -1-cyclopentenyl-l-hydroxyethane (2.8 g) , pivalic acid (0.1 g) and triethyl orthoacetate (125 ml) waε heated to 138°C. After 2.5 hourε, more pivalic acid (65 mg) was added and the reaction was continued 1 hour more. The reaction mixture was cooled, the excess triethyl orthoacetate removed in vacuo, εmd the residue chromatographed on εilica gel (20% ethyl acetate/hexane) to give ethyl (S) (E) -2-{2- [2- (4-t-butyldimethylεilyloxy-l,3-dihydro-6-ethyl-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1-yl} acetate. 10H. Ethyl (S) (E) -2-{2- [2- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]cyclopent-1-yl} acetate A solution of ethyl (S) (E) -2-{2- [2- (4-t-butyldimethylεilyloxy-l,3- dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene] cyclopent-1-yl} acetate (1.24 g) in tetrahydrofuran (8 ml) waε cooled to 0°C and treated with 1M tetrabutylammonium fluoride in tetrahydrofuran (3 ml) . After 5 minuteε, the reaction mixture waε poured into ice water and extracted with ethyl acetate. The extractε were dried, evaporated and the residue chromatographed on silica gel (20% ethyl acetate/hexane) to give ethyl (S) (E) -2-{2- [2- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran- 5-yl)ethylidene]cyclopent-1-yl} acetate, m.p. 95.0-95.7 Q C. 10 . (S) (E) -2-{2- [2- (l,3-Dihydro-6-ethyl-4-hydroxy-7-mβthyl-3- oxoisobenzofuran-5-yl)ethylidene]cyclopent-1-yl} acetic acid A mixture of ethyl (S) (E) -2-{2- [2- (1,3-dihydro-6-ethyl-4-hydroxy-7- methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1-yl} acetate (0.4 g) in methanol (20 ml) and water (20 ml) waε treated with lithium hydroxide (1.6 g) . The reaction mixture waε heated at 65°C for 2 hourε and then cooled. The methanol waε removed in vacuo and the reεidue treated with excess 1M sodium hydrogen sulfate. Extraction with ethyl acetate followed by drying and evaporation gave a residue which was recrystalized from t-butylmethyl ether to give (S) (E) -2-{2- [2- (1,3-dihydro-6-ethyl-4-hydroxy- 7-methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1-yl} acetic acid, m.p. 168.2-169.3°C with an enantiomeric exceεε of 96.4% (Chiracel AD, 85:15 hexane:i-propanol, 0.1% trifluoroacetic acid, 0.8 ml/minute, minor 12.6 minutes, major 13.5 minuteε). EXAMPLES 11 • 16 Theεe exampleε illuεtrate the preparation of a representative pharmaceutical formulations containing an Active Compound of Formula A, e.g. , (E) -6- (1,3-dihydro-4-hydroxy-6-vinyl-7-methyl-3-oxoiεobenzofuran-5- yl) -4-methyl-4-hexenoic acid. Other compoundε of Formula A, εuch aε those prepared in accordance with Exampleε 1 through 10, can be uεed aε the Active Compound in preparation of the formulationε of theεe exampleε. EXAMPLE 11 This example illustrateε the preparation of a representative pharmaceutical formulation for oral administration. Quantity per Ingredients capεule. mσs. Active compound 200 lactose, spray-dried 148 magnesium stearate 2 The above ingredients are mixed and introduced into a hard-shell gelatin capsule. EXAMPLE 12 This example illustrates the preparation of another representative pharmaceutical formulation for oral adminiεtration. Quantity per Ingredients tablet, mαε. Active compound 400 cornεtarch 50 croscarmelloεe sodium 25 lactose 120 magneεium εtearate 5 The above ingredientε are mixed intimately and pressed into single scored tablets. EXAMPLE 13 A εuεpeήsion for oral administration iε prepared having the following composition: Ingredients Amount Active compound 1.0 g fumaric acid 0.5 g εodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated εugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml EXAMPLE 14 An injectable preparation buffered to a εuitable pH iε prepared having the following compoεition: Ingredients Amount Active compound 0.2 g Sodium Acetate Buffer Solution (0.4 M) 2.0 ml HC1 (IN) or NaOH (IN) q.ε. to εuitable pH water (diεtilled, εterile) q.s. to 20 ml EXAMPLE 15 This example illustrateε the preparation of a representative pharmaceutical formulation for topical application. Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy aniεole) 0.01 Water q.ε. to 100 All of the above ingredientε, except water, are combined and heated to 60°C - 70°C with stirring. A sufficient quantity of water at 60°C iε then added with vigorouε εtirring to emulεify the ingredientε, and water then added q.ε. 100 g. EXAMPLE 16 A εuppoεitory totalling 2.5 gramε iε prepared having the following compoεition: Active compound 500 mg witepεol H-15* balance ( ♦ triglycerideε of εaturated vegetable fatty acid; a product of HOLS, Inc., New Jerεey) . ' EXAMPLE 17 In Vitro Determination of Therapeutic Activity (Aε an Anti-Inflammatory, Anti-Viral, Anti-Tumor, Anti-Pεoriatic and/or Immunosuppressive Agent) Utilizing the Inhibition of IMP Dehydrogenase Assay Thiε aεεay iε a modification of the method of Anderεon, J.H. and Sartorelli, A.C., Jour. Biol . Chem, 243:4762-4768 (1968). It measures the formation of NADH {λ ^ . = 340 nm, e340 = 6,220 M " 'cm"') as Inosine 5' -monophoεphate ("IMP") iε converted to Xanthoεine 5' -monophoεphate ("XMP") by the human Type II IMP dehydrogenase ("IMPDH") . Compounds are dissolved and diluted in DMSO, and reaction solutionε containing compoundε at 0, 0.01, 0.10, 1.0, 10, and lOOμM are prepared in diεpoεable methacrylic plaεtic microcuvetε ('UV-tranεparent' plastic, 1 cm pathlength, 1.5 ml capacity). The solutionε (0.5-1 ml) contain the following: 0.1 M TriεHCL, pH 8.0; 0.1 M KCL; 3.0 mM EDTA; 100 μg/ml BSA; 0.05 mM IMP; 0.10 mM NAD; 10% DMSO; 5-15 nM IMPDH (0.003-0.010 units/ml; one unit of enzyme catalyzeε the formation of one μmol NADH per minute at 40°C at εaturating εubεtrate concentrationε - 200 μM IMP and 400 μM NAD) . Reactionε are performed at 40°C and initiated by the addition of enzyme. Mycophenolic acid (IC J Q - 0.02μM) εerveε aε the positive control. The reactions are monitored at 340 run for 10 minuteε in a UV/VIS spectrophotometer, and rate data are collected. The 50% inhibitory value ("ICy,") is determined by fitting the fractional activities relative to control to the following equation on a Macintosh computer by the program Systat: Fractional activity = MAX/( (X/ICjo) n +l) . X iε the concentration of the compound, and the term n accountε for deviationε of the data from a simple competitive inhibition model. The compoundε of the present invention inhibit IMPDH when tested by this method, indicating their activity aε anti-inflammatory, anti-viral, anti-tumor, anti-psoriatic and/or immunoεuppreεεive agentε, aε εhown in the below table. R 1 R 2 Z Z 1 Z 2 Z 3 Z 4 G ICjo tμM) H ethyl ZA methyl methyl H H H 0.0084 EXAMPLE 18 In Vitro Determination of Immunosuppreεεive Activity Utilizing Reεponεeε of Human Peripheral Blood Lymphocyteε to Phytohemagglutinin (PHA) This procedure is a modification of a procedure initially described by Greaves, et al. ["Activation of human T and B lymphocyteε by polyclonal mitogenε," Nature, 248:698-701 (1974)]. Human mόnonuclear cellε ("PBL") are εeparated from heparinized whole blood by denεity gradient centrifugation in Ficoll-Plaque (Pharmacia) . After waεhing, 2 x 10 5 cellε/well are cultured in microtiter plateε with RPMI 1640 εupplemented with 5% fetal calf εerum, penicillin and εtreptomycin. PHA (Sigma) at 10 μg/ml iε then added. Teεt materials are teεted at concentrationε between 10 4 and lO'M, by addition to the culture at time 0. Cultureε are εet up in quadruplicate and incubated at 37°C in a humidified atmoεphere with 7% CO, for 72 hourε. A pulεe of 0.5 μCi/well of ^-thymidine iε added for the laεt 6 hourε. Cellε are collected on glaεs fiber filters with an automatic harvester and radioactivity is measured by standard scintillation procedures. The 50% inhibitory concentration ("ICjo") for mitogenic stimulation iε determined graphically. To evaluate differential effectε on T- and B-lymphocytes, different mitogens are used: PWM (Sigma) at 20 μg/ml and Staphylococcuε Protein A bound to Sepharoεe (SPA) (Sigma) 2 mg/ml or 14 μg/ml of Protein A. The compoundε of the present invention show immunosuppressive activity when tested by this method. EXAMPLE 19 In Vivo Determination of Immunoεuppreεεive Activity Utilizing the Hemolytic Plaque Forming Cell Aεεay Thiε procedure iε a modification of "The agar plaque technique for recognizing antibody producing cellε, " a procedure initially deεcribed by Jerne et al., [Cellbound Antibodies, Amos and Kaprowski editors (Wistar Institute Presε, Philadelphia, 1963) , p. 109] . Groups of 5-6 adult C578B1/6 male mice were sensitized with 1X10 8 sheep red blood cells ("SRBC") and simultaneously treated with an oral dosage form.of the test material in an aqueouε vehicle. Animalε in a control group receive the same volume of vehicle. Four dayε after SRBC inoculation, spleens are dispersed in loose Ten Broeck homogenizerε. The number of nucleated cellε ("WBC") is determined and the spleen cell suspension is mixed with SRBC, guinea pig complement and agar solution at 0.5% concentration. Aliquots of the above mixture (0.1 ml) are dropped on four separate quadrants of a Petri dish and are covered with cover slipε. After two hourε incubation at 37°C, areas of hemolysis around plaque-forming cells ("PFC") are counted with a disεecting microscope. Total WBC/εpleen, PFC/spleen and PFC/10 6 WBC ("PPM") are calculated for each mouse εpleen. Geometric means of each treatment group are then compared with the vehicle-treated control group. The compounds of the present invention show immunosuppresεive activity when teεted by thiε method. While the preεent invention has been described with reference to the εpecific embodiments thereof, it should be understood by those skilled in the art that variouε changeε may be made and equivalentε may be εubstituted without departing from the true spirit and scope of the invention. In addition, many modificationε may be made to adapt a particular situation, material, composition of matter, proceεε, proceεε step or stepε, to the objective, εpirit and scope of the preεent invention. All εuch modificationε are intended to be within the scope of the claims appended hereto. All of the patents and publications referenced above are hereby incorporated by reference.

Claims: - 110 - hat is claimed is: 1. A compound of the formula: Formula A wherein: R 1 is H or C(0)R 10 , where R 10 is lower alkyl, aryl or NH-aryl; R 2 is lower alkyl, cycloalkyl, vinyl, fluorovinyl, difluorovinyl, trifluorovinyl, alkenyl, -C≡C-R 11 , allenyl, CHO or CH,OR 12 , where R" is H or lower alkyl, and R 12 is H or 4-methoxybenzyl; and Z iε a side chain εelected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH: Formula ZA wherein: Z 1 iε H, lower alkyl, halo or CF 3 - Z 2 iε H, lower alkyl, lower alkoxy, aryl, or CH 2 -Z π , where Z 11 iε halo, CN, aryl or heteroaryl; Z 3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, or S(0) m -lower alkyl, where m is 0, 1 or 2; Z 4 is H, lower alkyl, halo, or phenyl; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH 2 ) n -NG'G 2 , or 0- (CH 2 ) n -N=G 3 , where n is an integer from l to 6, G 1 is H or lower alkyl, G 2 is H or lower alkyl, and RECTIFIED SHEET (RULE 91) ISA/EP =G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atomε pluε one member that is -0-, -S-, or -N(G 4 ) - where G 4 is H or lower alkyl; or Formula ZB wherein: Z 5 is H or lower alkyl; Z 8 is H, lower alkyl or formε a double bond with D 2 ; D 1 and D 2 together with their adjacent carbon atomε form an optionally εubεtituted, εaturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and G iε as defined above; or Formula ZC wherein: Z 8 is H or lower alkyl; and Z 5 and G are as defined above; or Formula ZD wherein: D 3 is -CH,- or -CHj-CH j -; and G is aε defined above; or RECTIFIED SHEET (RULE 91) ISA/EP Formula ZE wherein: Z* is H, lower alkyl, COOH, NH 2 , azido or halo; Z 7 is H, lower alkyl or halo; and Z s and G are as defined above; or Formula ZF wherein: Z 1 and G are as defined above; or Formula ZG wherein: D 3 , Z 2 , Z 3 , Z 4 and G are aε defined above; or Formula ZH wherein: RECTIFIED SHEET (RULE 91) ISA/EP D 4 is -CH,-, -CHj-CH,-, -CH,-CH,-CH,-, -0-, or -O-CH,-; and Z 1 and G are as defined above; or a pharmaceutically acceptable salt thereof. 2. The compound or salt of Claim 1 wherein Z iε εelected from Formulae ZA, ZB, ZE and ZH. 3. The compound or εalt of Claim 1 wherein R 1 is H. 4. The compound or salt of Claim 3 wherein G is OH. 5. The compound or salt of Claim 4 where R 2 iε methyl, ethyl, vinyl or cyclopropyl. 6. The compound or εalt of Claim 3 wherein G iε morpholinoethoxy. 7. The compound or salt of Claim 1 comprising a single enantiomer, a diaεtereomer, a racemic mixture or a non-racemic mixture. 8. The compound or εalt of Claim 4 wherein Z is a side chain of Formula ZA. 9. The compound or salt of Claim 8 wherein R 2 iε methyl, namely (E) 6- (l,3-dihydro-4-hydroxy-6,7-dimethyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; R 2 iε ethyl, namely (E) 6- (l,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; R 2 iε cyclopropyl, namely (E) 6- (6-cyclopropyl-l,3-dihydro-4-hydroxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid; R 2 iε vinyl, namely (E) 6- (l,3-dihydro-4-hydroxy-7-methyl-3-oxo-6- vinylisobenzofuran-5-yl) -4-methyl-4-hexenoic acid; R 2 is ethyl and Z 2 iε methyl, namely (E) 6- (l,3-dihydro-6-ethyl-4- hydroxy-7-methyl-3-oxoiεobenzofuran-5-yl) -3, -dimethyl-4-hexenoic acid. 10. The compound or εalt of Claim 4 wherein Z iε a side chain of Formula ZB. 11. The compound or salt of Claim 10 wherein Z 5 and Z 8 are H, D'-D 2 is -(CH 2 ) 3 -, and R 2 iε ethyl, namely (E) -2- [2- [2- [1,3-dihydro-6-ethyl 4- hydroxy-7-methyl-3-oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1-yl]acetic acid. 12. The compound or εalt of Claim 4 wherein Z iε a εide chain of Formula ZE. 13. The compound or εalt of Claim 12 wherein Z 3 iε methyl, Z 7 iε H, and Z 6 iε H, namely (E) -2- [3- (1,3-dihydro-6,7-dimethyl-4-hydroxy-3- oxoiεobenzofurειn-5-yl) -1-methylprop-1-en-1-yl]benzoic acid. 14. The compound or εalt of Claim 4 wherein Z iε a εide chain of Formula ZH. 15. The compound or εalt of Claim 14 wherein D 4 iε -CH 2 -, namely (E) -2- [3- (1,3-dihydro-6,7-dimethyl-4-hydroxy-3- oxoiεobenzofuran-5-yl) -1-methylprop-1-en-1-yl] cyclopentane-1-carboxylic acid; D 4 iε -CH 2 -CH 2 -, namely Ethyl (E) -2- [3- (1,3-dihydro-6-ethyl-4-hydroxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -1-methylprop-1-en-1-yl] cyclohexeine-IR- carboxylate. 16. A pharmaceutical composition comprising a therpeutically effective amount of the compound or salt of Claim 1 admixed with at least one pharmaceutically acceptable excipient. 17. A method of treatment for immune, inflammatory, tumor, proliferative, viral or psoriatic diεorderε in a mammal, comprising administering a therapeutically effective amount of a compound or salt of Claim 1 to a mammal in need thereof. 18. A process for the preparation of compounds of the formula: Formula A wherein: R 1 is H or C(0)R 10 , where R 10 is lower alkyl, aryl or NH-aryl; R 2 iε lower alkyl, cycloalkyl, vinyl, fluorovinyl, difluorovinyl, trifluorovinyl, alkenyl, -C≡C-R", allenyl, CHO or CH,OR 12 , where R" iε H or lower alkyl, and R 12 iε H or 4-methoxybenzyl; euαd Z iε a εide chain εelected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH: Formula ZA wherein: Z' iε H, lower alkyl, halo or CF 3 ; Z 2 iε H, lower alkyl, lower alkoxy, aryl, or CH,-Z", where Z" iε halo, CN, aryl or heteroaryl; Z 3 iε H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, or S(0) m -lower alkyl, where m iε 0, 1 or 2; Z 4 is H, lower alkyl, halo, or phenyl; RECTIFIED SHEET (RULE 91) ISA/EP ■115- or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, NG ! G 2 , O- (CH,) B -NG'G 2 , or O- (CH 2 ) n -N=G 3 , where n is an integer from 1 to 6, G 1 is H or lower alkyl, G 2 is H or lower alkyl, and =G 3 iε lower alkylene of four to six carbon atomε, or lower alkylene of three to five carbon atoms plus one member that is -O- -S-, or -N(G 4 )- where G 4 H or lower alkyl; or Formula ZB wherein: Z 3 iε H or lower alkyl; Z 8 is H, lower alkyl or forms a double bond with D 2 ; D 1 and D 2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and G is as defined above; or Formula ZC wherein: Z 8 is H or lower alkyl; and Z 3 and G are aε defined above; or RECTIFIED SHEET (RULE 91) ISA/EP ■116 - Formula ZD wherein : D 3 iε -CH,- or -CH,-OI,- ; and G iε as defined above ; or Formula ZE wherein: Z 6 iε H, lower alkyl, COOH, NH,, azido or halo; Z 7 iε H, lower alkyl or halo; and Z 3 and G are aε defined above; or Formula ZF wherein: Z 1 and G are aε defined above; or Formula ZG wherein: RECTIFIED SHEET (RULE 91) ISA/EP ■ 117 - Z 4 and G are aε defined above; or Formula ZH wherein: D 4 iε -CH,-, -CH,-CH,-, -CH J -CH J -O , -O-, or -O-CHj-; and Z 1 and G are aε defined above; or a pharmaceutically acceptable salt thereof, which comprises: a) hydrolyzing a compound of Formula I wherein G iε lower alkyl to a compound of Formula I wherein G iε -OH; or b) deprotecting a compound of Formula I wherein R 2 iε a protecting group, to form a compound of Formula I wherein R 2 iε -CHOH; or c) oxidizing a compound of Formula I wherein R 2 iε -CH,OH to a compound of Formula I wherein R 2 iε -CHO; or d) reducing a compound of Formula I wherein R 2 iε vinyl or alkenyl to a compound of Formula I wherein R 2 iε alkyl other than methyl; or e) eε.terifying a compound of Formula I wherein G is OH to a compund of Formula I wherein G is lower alkoxy, lower thioalkyl, -NG'G 2 , O- (CH,),-NG'G 2 , or O- (CH,).-N=G 3 ; or f) converting a free compound of Formula I to a pharmaceutically acceptable salt of the compound of Formula I; or g) converting a pharmaceutically acceptable εalt of a compound of Formula I to the free compound of Formulal; or h) converting a pharmaceutically acceptable εalt of a compound of Formula I to another pharmaceutically acceptable εalt of the compound of Formula I. RECTIFIED SHEET (RULE 91) ISA/EP

Inventors: ANDRADE FIDENCIO F, ARTIS DEAN R, ELWORTHY TODD R, GARCIA ALICIA C, HAWLEY RONALD C, HERNANDEZ MARIA T L, LOUGHHEAD DAVID G, MARTIN TERESA A T, MORGANS DAVID J JR, MURRA FRANCISCO X T, NELSON PETER H, PATTERSON JOHN W JR, SJOGREN ERIC B, SMITH DAVID B, WALTOS ANN MARIE, WEIKERT ROBERT J, ZERTUCHE MARIO F, ANDRADE, FIDENCIO, F., ARTIS, DEAN, R., ELWORTHY, TODD, R., GARCIA, ALICIA, C., HAWLEY, RONALD, C., HERNANDEZ, MARIA, T., L., LOUGHHEAD, DAVID, G., MARTIN, TERESA, A., T., MORGANS, DAVID, J., JR., MURRA, FRANCISCO, X., T., NELSON, PETER, H., PATTERSON, JOHN, W., JR., SJOGREN, ERIC, B., SMITH, DAVID, B., WALTOS, ANN, MARIE, WEIKERT, ROBERT, J., ZERTUCHE, MARIO, F.
Applicants: SYNTEX INC, SYNTEX (U.S.A.) INC.
Application year: 1995
Main classification: C07D307
IPC codes: A61K31, A61P17, A61P29, A61P35, A61P37, C07D307, C07D405, C07D407, C07D409, C07D413, C07D417