4-AMINO DERIVATIVES OF 5-SUBSTITUTED MYCOPHENOLIC ACID

Abstract: The disclosed derivatives of mycophenolic acid of formula (IE) are therapeutic agens advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil and other immunosuppressant agents. In said formula, Z is a side chain selected from formulae (ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH).

Description: 4-AMINO DERIVATIVES OP 5-SUBSTITUTED MΪCθ_?HENO IC ACID Field of the Invention The present invention relates to mycophenolic acid derivatives in which the 4-hydroxy group has been replaced by amino εubstituents. The invention includes natural and derivative side chains at the 5-position. The invention is also directed to formulations and methods for treatment. Background Information and Related Disclosures Mycophenolic acid ("MPA") is a weakly active antibiotic found in the fermentation broth of Penicillium brevicompactum, having the following structure. Mycophenolic Acid 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 Noε. 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. Wed. Chem., 33(2), 833-8 (1990); Austr. J. Chem. , 31(2), 353-64, (1978) ; and J. AπtiJbiot., 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 Derivatives of mycophenolic acid and their esters and the pharmaceutically acceptable salts thereof, i.e. the compounds of Formula I: wherein: R 1 is hydrogen or lower alkyl; R 2 is hydrogen, lower alkyl, -C(0)R 3 , -C(0)NR 4 R 5 , -C0 2 R 6 , or -S0 2 R 3 where: R 3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl; R 4 is hydrogen, lower alkyl or optionally substituted phenyl; R 5 is hydrogen, lower alkyl or optionally substituted phenyl; R 6 is lower alkyl or optionally substituted phenyl; 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 -CI^Z 13 , where Z 13 is aryl or heteroaryl; Z 3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, - P(O) (OCH 3 ) 2 , -P(O) (OH) (0CH 3 ) , or -S(0)._.Z 12 , where Z 12 is lower alkyl, and m is 0, 1 or 2; Z 4 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 , -0(CH 2 ) n NG l G 2 , or - 0(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 -0-, -S-, or -N(G 4 )- where G 4 is H or lower alkyl; provided that when Z 1 is methyl, Z 2 , Z 3 and Z 4 are not all H; or Formula ZB wherein: Z~ is H or lower alkyl; Z 8 is H or lower alkyl; 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 5 , Z ~ , 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 , lower alkoxy, -COOH, -NH 2 or halo; Z 7 is H, lower alkyl , lower alkoxy or halo; and Z 5 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 as defined above; or Formula ZH wherein: D 4 is -CH 2 -, -CHjCHj-, -CHjCft-CH-,-, -0-, or -OCH 2 -; and Z 1 and G are as defined above; and the pharmaceutically acceptable salts thereof. In still another aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I 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 I 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. As used herein, the term "alkyl" refers to a fully saturated monovalent radical of one to twelve carbon atoms 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, cyclopentyl, cyclohexyl, heptyl, cycloheptyl and adamantyl. The term "lower alkyl" refers to a monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl) , isoamyl, pentyl, cyclopentyl, i-pentyl, hexyl and • cyclohexyl. 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 "halo" refers to fluoro and chloro, unless otherwise specified. The term "halo lower alkyl" refers to a lower alkyl radical substituted with one or more chlorine or fluorine atoms. This term is further exemplified by such radicals as trichloromethyl, trifluoromethyl, dichloromethyl, fluoromethyl, difluoro-chloro-methyl, 3-chloropropyl and 4-trifluoro-2-chloro-butyl. The term "halomethyl" refers to a methyl radical substituted with one or more chlorine and/or fluorine atoms. This term is further exemplified by such radicals as trichloromethyl, trifluoromethyl, dichloromethyl, fluoromethyl and difluoro-chloromethyl. The term "lower alkylene" refers to a 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 "alkoxy" means the group -OR wherein R is lower alkyl. The term "lower alkanol" means an alcohol of the formula ROH where R is a lower alkyl. This term is further exemplified by such alcohols as methanol, ethanol, n-propanol, i-propanol, n-butanol, t-butanol, i-butanol (or 2-methylpropanol) , pentanol, n-hexanol. The moiety "-N=G 3 " as defined represents a heterocycle radical such as pyrrolidino, piperidino, hexamethyleneimino, imidazolidino, thiazolidino, morpholino, thiomorpholino, piperazino, thiopentamethyleneimino, and the like. The term "optionally substituted phenyl" refers to phenyl and mono-, di-, or tri-substituted phenyl, wherein the optional substituents are lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, or halo. This term is further exemplified by such radicals as 2-chlorophenyl, 2- trifluoromethylphenyl, -methoxyphenyl, -chlorophenyl, 3,4- dimethoxyphenyl, 2-chloro-3,4-dimethoxyphenyl, 4-hydroxyphenyl, 4-methylphenyl, 3-t-butylphenyl, and 4-hexylphenyl. 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 "heteroaryl" refers to a monovalent aromatic carbocyclic radical having at least one heteroatom, such as N, O or S, 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)-, -C(N-NX d X e ) -, -0-, -S-, -S(O)-, -S(0) 2 - or -NX C -, where X 1 is H, lower alkyl or forms a double bond; X b is acyl, carbamoyl or ureido; X c is lower alkyl, C(0)X d , S(0)_-X d or C(0)NX d X e ; and X d and X° 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. Thus, a sidechain of Formula ZB in which D r and D 2 together represent -CH 2 CH 2 CH 2 CH 2 -, and Z 5 and Z 8 are both hydrogen, would be named as a 2- [(2-ethylidene) -2-cyclohex-l-yl]acetic acid derivative. Likewise, a sidechain of Formula ZB in which D 1 and D 2 together represent , and Z~ and Z 8 are both hydrogen, would be named as a 2- [ (2-ethylidene) -4-tetrahydropyran-3-yl]acetic acid derivative. The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which said event or circumstance occurs and instances in which it does not. For example, "optionally substituted phenyl" means that the phenyl may or may not be substituted and that the description includes both unsubstituted phenyl and phenyl wherein there is substitution: "optionally" followed by "converting the free base to the acid addition salt" means that such conversion may or may not be carried out in order for the process described to fall within the invention, and the invention includes those processes wherein the free base is converted to the acid addition salt and those processes in which it is not. A "pharmaceutically acceptable salt" may be any salt derived from an inorganic or organic acid or base. Salts may be derived from acids or bases. The acid addition salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the εulfate and bisulfate 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 are derived from inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, calcium hydroxide, magnesium hydroxide and the like. Cations derived from organic bases include those formed from primary, secondary and tertiary amines, such as isopropylamine, diethylamine, trimethylamine, triethylamine, pyridine, cyclohexylamine, ethylene diamine, monoethanolamine, diethanolamine, triethanolamine, and the like. As used herein, the term "inert organic solvent" or "inert solvent" means a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, diethyl ether, chloroform, methylene chloride, pyridine, xylene, dimethylformamide, 1,4-dioxane, dichloromethane, and the like) . As uβed herein, the term "treatment" or "treating" means any treatment of a disease in a mammal, and includes: (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. As used herein, the term "effective amount" means a dosage sufficient to provide treatment. This will vary depending on the patient 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. "Enantiomers" 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. "Diastereoisomers" 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. When a compound is a racemic mixture the stereochemistry at each chiral carbon may be specified by either RS or SR by reference to a single enantiomer of the racemate. In this manner relative stereochemistry is conveyed unambiguously. 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 I 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 I by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. Specific examples of the separation of isomers are set forth in the Examples. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about -20°C to about 100°C, more preferably from about 10°C to about 50°C, and most preferably at about room temperature. Isolation 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 found by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used. Nomenclature The compounds of Formula I will be named using the numbering system illustrated below. The iεobenzofuranyl nucleus of the compounds of Formula I iε numbered as follows: Following are examples of how some representative compoundε of Formula I are named. Sidechains of Formula ZA are numbered as shown below: Representative compoundε of Formula I where the sidechain iε ZA are aε followε: and are named: 1. (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (S) , -dimethyl-4-hexenoic acid; 2. (E) -6- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4- trifluoroacetylaminoiεobenzofuran-5-yl) -2 (S) -ethyl- -methyl-4- hexenoic acid; 3. methyl (E) -6- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-yl) -3-hydroxy-2-methyl-2-phenyl-4-trifluoromethyl• 4-hexenoate; 4. thiomethyl (E) -4-chloro-6- (l,3-dihydro-4- (3,3-dimethylureido) -6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -3-methyl-2-methylsulfonyl- 4-hexenoate. Sidechainε of Formula ZB in which D 1 and D 2 do not contain a hetero atom are numbered aε shown below: Representative compounds of Formula I where the sidechain iε ZB in which D 2 doeε not include a hetero atom are aε follows: and are named: 1. (E) -2-{2- [2- [4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] cyclopent-1- (S) -yl}acetic acid; 2. (E) -2-{2- [2- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-yl)ethylidene] cyclohex-l-yl}acetic acid; 3. (E) -2-{2- [2- (l,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3- oxoiεobenzofuran-5-yl)ethylidene] cyclohept-l-yl}propionic acid dimethylamide (where G 1 and G 2 are both methyl) ; 4. thiomethyl (E) -2-{2- [2- (l,3-dihydro-4- (3,3-dimethylureido) -6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl)ethylidene] -cyclobut-1- (R) - yl}octanoate. Sidechainε of Formula ZB that include a heteroatom are numbered differently, depending upon the poεition of the heteroatom(s) in the ring. For example, a sidechain of Formula ZB in which D 1 and D 2 together with their adjacent carbon atoms form a saturated heterocyclic ring of 6 atoms iε numbered aε εhown below: where D representε -0-, -S(0) p -, -N(R 9 )-, and the like. Repreεentative compoundε of Formula I where the sidechain iε ZB including a hetero atom are aε followε: and are named: 1. (E)-2-{4-[2- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene]tetrahydrofuran-3-yl}acetic acid; 2. hexyl (E) -2-{4- [2- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoroacetylamino-3-oxoiεobenzofuran-5-yl)ethylidene] -3- methylpiperidin-3 (S) -yl}propionate; 3. (E) -2-{4- [2- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-yl)ethylidene] thiepan-3-yl}heptanoic acid dimethylamide (where G 1 and G 2 are both methyl) . Sidechainε of Formula ZC are numbered aε εhown below: Representative compoundε of Formula I where the sidechain is ZC are as follows: and are named: 1. 3- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- ylmethyl) -2-methylcyclopent-2-enyl-l- (S) -acetic acid; 2. hexyl 3- (l,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetyl-amino-3- oxoiεobenzofuran-5-ylmethyl)cyclopent-2-enyl-1-acetate; 3. 2- (S) - [3- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-ylmethyl) -2-methylcyclopent-2-en-l (S) -yl] -1- (S) -3- methylbutyric acid; 4. (2-dimethylamino)ethyl 3- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-ylmethyl) -2-hexylcyclopent-2-enyl-1-acetate (where G 1 and G 2 are both methyl) . Sidechainε of Formula ZD are numbered aε εhown below: where D i s CH, where D is CH 2 CH 2 Repreεentative compoundε of Formula I where the sidechain iε ZD are aε follows: are named as follows: 1. (E) -3- [2- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl)ethylidene] cyclopentane-1- (R) -carboxylic acid; 2. hexyl (E) -4- [2- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoroacetylamino-3-oxoiεobenzofuran-5-yl)ethylidene]cyclohexane- 1-carboxylate; 3. methyl (E) -3- [2- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-yl)ethylidene]cyclopentane-1-thiocarboxylate. Sidechainε of Formula ZE are numbered aε shown below: Representative compoundε of Formula I where the εidechain iε ZE are aε follows: and are named: 1. (E) -2- [3- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl) -l-methylprop-l-en-l-yl]benzoic acid; 2. (E) -2- [3- (l,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3- oxoiεobenzofuran-5-yDprop-l-en-l-yl] -6-methylbenzoic acid dimethylamide (where G 1 and G 2 are both methyl) ; 3. hexyl (E) -6-chloro-2- [3- (l,3-dihydro-6-methoxy-7-methyl-4- methylamino-3-oxoiεobenzofuran-5-yl) -1-hexylprop-l-en-l-yl] -4- methoxybenzoate. Sidechains of Formula ZF are numbered as shown below: Representative compoundε of Formula I where the εidechain iε ZF are aε follows: and are named: 1. 4- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- ylmethyl) -3-methylcyclopent-3-ene-l- (S) -carboxylic acid; 2. ethyl 4- (l,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3- oxoiεobenzofuran-5-ylmethyl) -3-hexylcyclopent-3-ene-1-carboxylate; 3. thiomethyl 4- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-ylmethyl) cyclopent-3-ene-1-carboxylate. Sidechainε of Formula ZG are numbered aε εhown below: Representative compounds of Formula I where the sidechain is ZG are as follows: and are named: 1. 3- [3- (S) - (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl) cyclopent-1-en-l-yl] -propionic acid; 2. 3- [3- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3-oxo-furan-5- yl) cyclopent-1-en-l-yl] -3-methyl-2-phenyl propionic acid. Sidechainε of Formula ZH are numbered as shown below: Representative compounds of Formula I where the εidechain iε ZH are aε follows: are named aε follows: 1. (E) -2- [3- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl) -1-methylprop-l-en-l-yl] cyclopentane-1-carboxylic acid; 2. Ethyl (E) -2- [3- (1,3-dihydro-6-methoxy-7-methyl-4- trifluoroacetylamino-3-oxoiεobenzofuran-5-yl) -1-methylprop-1-en-1- yl] cyclohexane-1R-carboxylate; 3. Thiomethyl (E) -2- [3- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoisobenzofuran-5-yl)prop-1-en-1-yl] cycloheptane-1-carboxylate. Compoundε of Formula I where the εide chain iε ZH, in which D 4 iε a heteroatom, are numbered differently, in that the heteroatom iε deεignated aε poεition 1 of the ring. For example, the compound where D 4 iε oxygen, and R 1 and R 2 are both hydrogen, Z 1 is methyl, and G is hydroxy, iε named aε followε: (E) -2- [3- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl) -1-methylprop-1-en-1-yl] etrahydrofuran-3-carboxylic acid. PREPARATION OF COMPOUNDS OF FORMULA I The compoundε of Formula I are prepared from the lower alkyl 4- iεocyanato eεters of Formula 6, the structure of which iε εhown below: •16- Formula 6 where Z" iε a εidechain of Formula Z aε defined in the Summary of the Invention in which G iε lower alkoxy. The compoundε of Formula 6 are then converted to the compoundε of Formula I by εeveral different synthetic pathways, depending on the deεired εubstitutionε at the 4-poεition. Many of the esterification routes and/or final esterification εteps for the esters of the -substituted derivatives of mycophenolic acid are described in U.S. Patent Nos. 4,686,234; 4,725,622; 4,727,069; 4,748,173; 4,753,935; 4,861,776; and the pending application entitled "Direct Eεterification of Mycophenolic Acid", Serial No. 07/911635, filed July 10, 1992 (by inventors working in the same research organization as that of the present applicants, and subject to an obligation of aεsignment to the same aεεignee aε in the present application) all previously incorporated herein by reference. By subεtituting the acidε of Formula I for mycophenolic acid or itε acid derivativeε aε described in the above references, the esterification routes and/or final stepε described may likewiεe be uεed. Starting Materialε The intermediateε of Formula 6 are prepared starting from compoundε of Formula 1, the εtructure of which iε εhown below: For ula 1 where Z is aε defined in the Summary of the Invention. The compoundε of Formula 1 may be prepared aε deεcribed below in Reaction Schemes I to XXII. The preparation of such compounds iε also described in more detail in co-pending Application Serial No. 08/???,???, Attorney Docket No. 27960, entitled "5-Substituted Derivatives of Mycophenolic Acid", filed contemporaneously herewith, which is hereby incorporated by reference in its entirety. Preparation of Compounds of Formula 1 where Z is Sidechain ZA One method of preparing compoundε of Formula 1 where Z is the εidechain of Formula ZA, illuεtrated as compounds of Formula 1A, is εhown below in Reaction Schemeε I to X. REACTION SCHEME I lky l Formula 101 Formula 102 Formula 102 Formula 1D3 F Formula 104 Formula 103a Fo lkyl Formula 104a Formu la 105 Formula 1A as an ester Preparation of Formula 102 Aε illustrated in Reaction Scheme I, Step 1, the phenolic hydroxyl group of a mycophenolic acid lower alkyl ester is protected. A mycophenolic acid lower alkyl eεter of Formula 101, in a εolvent (εuch aε ether, ethyl acetate, dimethylamide, 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 εilyl chloride, e.g., trimethylsilyl chloride, diphenylmethylεilyl chloride, or preferably tert-butyldimethylsilyl chloride) in presence of an equimolar amount of an organic base (such as diiεopropylethylamine, triethylamine, or imidazole) . The reaction takeε place at -20 to 35°C (preferably at 25°C) for 1 to 24 hourε (preferably 16 hourε) to give the correεponding compound of Formula 102 (where R* iε the protecting group) . Preparation of Formula 103 Aε illuεtrated in Reaction Scheme I, Step 2, the εide chain double bond of a protected mycophenolic acid lower alkyl eεter iε ozonized to yield an aldehyde. A stream of ozonized oxygen iε passed through a solution of a protected compound of Formula 102 in a εolvent (such aε an alcohol, a halocarbon, or preferably a mixture of methanol and dichlorome hane) . The reaction takeε place at -100 to -40°C (preferably at -80°C) , and continues until the presence of excess ozone is detected by the development of a blue color. The intermediate hydroperoxide thus formed iε reduced without further purification, by the addition of a reducing agent (εuch as 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 illuεtrated in Reaction Scheme I, 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 iε halo) with an alkyllithium (preferably n-butyllithium) in an ethereal εolvent (εuch aε ether, or preferably tetrahydrofuran) . The reaction takeε place at -100 to 0°C (preferably -40°C) over a period of 0.5 to 5 hours (preferably 1 hour) . Alternatively the halovinyl compound of Formula 103a is reacted with magnesium metal in an ethereal solvent (such aε ether or preferably tetrahydrofuran) . The reaction takes place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hours (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 with a zinc or cadmium halide, preferably chloride. The compound of Formula 103a where M iε 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 iε trifluoromethanesulfonate may be prepared from a ketone of the formula: by reaction with a strong base (such as εodium hydride or potassium 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 l -C≡C-Z 2 . One molar equivalent of the reεultant organometallic reagent iε added to a εolution of an aldehyde of Formula 103 (in the same εolvent εystem 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 minuteε (preferably 10 minutes) to give the corresponding carbinol of Formula 104. Preparation of Formula 105 As illustrated in Reaction Scheme I, Step 4, an alkyl ester of Formula 105 iε formed by a Claiεen ortho eεter 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 is 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 (preferably 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 equivalents (preferably 0.10 molar equivalentε) of an organic acid catalyεt (such aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hourε (preferably 3 hourε) to give the corresponding alkyl ester of Formula 105. Preparation of Formula 1A Compounds of Formula 1A are prepared as eεterε by deprotection of compounds of Formula 105 aε described below with reference to Reaction Scheme X, Step 1; they are hydrolyzed to the correεponding carboxylic acid aε deεcribed below with reference to Reaction Scheme X, Step 2. Preparation of Enantiomers of Formula 1A where Z 2 is Lower Alkyl One method of preparing individual enantiomerε of compoundε of Formula 1A iε from chiral compoundε of Formula 104b, the preparation of which iε shown below in Reaction Scheme II. REACTION SCHEME II Formu la 103 Formula 103f Formu la 103f Formula 103g where Y is chloro or bromo. Formu l a 103g Formu l 103a For u la 103h Formu la 103h Formula 104b Preparation of Formula 103f Aε illustrated in Reaction Scheme II, Step 1, an aldehyde of Formula 103 is oxidized to the corresponding carboxylic acid of Formula 103f. An aldehyde of Formula 103 is 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 (such as toluene, or preferably ethyl acetate) , in the presence of water and a catalytic amount (for example, about 0.01 molar equivalentε) of a catalyεt (εuch as ruthenium oxide, or preferably ruthenium trichloride) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 30 minuteε to 8 hourε (preferably 2 hours) , to give the corresponding carboxylic acid of Formula 103f. Preparation of Formula 103g Aε illuεtrated in Reaction Scheme II, Step 2, a carboxylic acid of Formula 103f is converted to the corresponding acyl halide of Formula 103g. A carboxylic acid of Formula 103f is reacted with about one molar equivalent, preferably 1.1 molar equivalentε, of an halogenating agent (for example, thionyl chloride, thionyl bromide, or preferably oxalyl chloride) , in an inert solvent (εuch aε dichloromethane, or preferably ethyl acetate) , in the preεence of a catalytic amount (for example, about 0.05 molar equivalentε) 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 corresponding acyl halide of Formula 103g. Preparation of Formula 103h Aε illuεtrated in Reaction Scheme II, 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 as shown in the preparation of compounds of Formula 104) , in an inert solvent (such 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 tetrakiε (triphenylphosphine)palladium] . The reaction takeε place at -10 to 20°C (preferably 0°C) for 30 inuteε to 8 hourε (preferably 4 hourε) , to give the correεponding keto olefin of Formula 103h. Preparation of Formula 104b Aε illuεtrated in Reaction Scheme II, Step 4, a keto olefin of Formula 103h iε reduced εtereoεpecifically to the correεponding carbinol of Formula 104b by reduction with borane methyl εulfide in the presence of a catalytic amount of (R) -tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo- [1,2-c] [1,3,2]oxazaborole. A keto olefin of Formula 103h is εteroεpecifically 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 εolvent (preferably a mixture of toluene and dichloromethane) . The reaction takeε place at -30 to 40°C (preferably -20°C) for 1-24 hourε (preferably 12 hourε) , to give the correεponding carbinol of Formula 104b. Preparation of Enantiomers of Compounds of Formula 1A The chiral carbinol of Formula 104b iε then converted to an enantiomer of a compound of Formula 1A in the same manner as εhown above in Reaction Scheme I (converεion of compoundε of Formula 104 to 105 to 1A) . Preparation of Compounds of Formula 1A where Z 2 is Lower Alkoxy Compounds of Formula 1A where Z 2 iε lower alkoxyare prepared from the correεponding hydroxy compounds aε εhown below in Reaction Scheme III. REACTION SCHEME III Formula 10B Formula 103b Fo Formula 106a Preparation of Formula 106 Aε illuεtrated in Reaction Scheme III, Step 1, an aldehyde of Formula 103 iε tranεformed into an unsaturated 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 aε 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 unsaturated aldehyde of Formula 106. Preparation of Formula 107 As illustrated in Reaction Scheme III, 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 eεter of Formula 107. An eεter of Formula 106a iε converted to an alkali metal εalt by reacting a solution of the eεter in an ethereal εolvent (εuch as ether or preferably tetrahydrofuran) with an equimolar amount of an alkali metal hydride, hexamethyldisilazide or amide (preferably lithium diiεopropylamide) at a temperature of -100 to 0°C (preferably -80°C) , for 30 minuteε to 2 hourε (preferably 30 minuteε) to give a solution of the corresponding ester anion. The ester anion εolution (1.0 to 1.5 molar equivalentε, preferably 1.0 molar equivalentε) iε added to a εolution of an unεaturated aldehyde of Formula 106 in the εame ethereal solvent. The condensation reaction takeε place at a temperature of -100°C to 0°C (preferably -80°C) for 1 to 6 hours (preferably 2 hours) to give the corresponding beta-hydroxy ester of Formula 107. Preparation of Compounds of Formula 1A where Z 2 is Lower Alkoxy Compounds of Formula 1A where Z 2 iε lower alkoxy are prepared from compoundε of Formula 107 aε εhown below in Reaction Scheme IV. REACTION SCHEME IV Formula 107 Formu la 108 Preparation of Formula 108 As illustrated in Reaction Scheme IV, Step 1, the beta-hydroxy group of an ester of Formula 107 iε O-alkylated to give the corresponding beta- alkoxy ester (R b ) 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, such aε methyl iodide or n-butyl iodide, preferably methyl iodide) and 1 to 3 (preferably 1.25) molar equivalentε of silver oxide, in a polar organic solvent (such aε dioxane, dimethylformamide or preferably acetonitrile) . The reaction takeε place at 25 to 100°C (preferably 70°C) for 1 to 24 hourε (preferably 4 hourε) to give the correεponding beta-alkoxy eεter of Formula 108. Preparation of Compounds of Formula 1A where Z 4 is Hydroxy Compoundε of Formula 1A where Z 4 iε hydroxy are prepared aε εhown below in Reaction Scheme V. REACTION SCHEME V Formula 105 Formula 1A Preparation of Formula 1A where Z* is Hydroxy Aε illuεtrated in Reaction Scheme V, Step 1, an alpha-halo alkyl eεter of Formula 105 (where Z 1 iε H, lower alkyl or CF 3 , Z 2 iε H or lower alkyl, Z 3 iε H, lower alkyl, lower alkenyl, or phenyl, and Z 4 is halo) iε converted to an alpha-hydroxy acid of Formula 1A where Z 4 iε hydroxy. The reaction takeε place by hydrolyεis of an alpha-alkanoyloxy ester intermediate, formed by diεplacement of the alpha-halo group with an alkali metal alkanoate. An alpha-halo (preferably chloro) eεter of Formula 105 iε reacted with 1 to 5 (preferably 3) molar equivalents of an alkali metal alkanoate (the metal preferably potassium and the alkanoate preferably acetate) in a polar organic solvent (εuch aε acetonitrile or preferably dimethylformamide) The reaction takes place at 40 to 100°C (preferably 75°C) for 1 to 24 hours (preferably 12 hours) to give the correεponding alpha-alkanoyloxy eεter intermediate (not εhown) , which iε employed without iεolation or further purification. The alpha-alkanoyloxy ester is then subjected to basic hydrolyεiε by reaction with 1 to 5 (preferably 2) molar equivalentε of an alkali metal hydroxide (preferably εodium hydroxide) in a mixture of water and an organic εolvent (such as methanol, dimethoxyethane or preferably tetrahydrofuran) . The reaction takeε place at 0 to 60°C (preferably 40°C) for 1 to 12 hours (preferably 4 hourε) , to afford the correεponding alpha- hydroxy acid of Formula 1A. As illuεtrated in Reaction Scheme V, when R" of Formula 105 iε a εilyl protecting group, the hydrolysis conditions are also effective for deprotection to reεtore the phenolic hydroxyl group. Alternatively, for example when R* iε me hoxymethylethyl, the deprotection and hydrolysis procedures described with reference to Reaction Scheme X, can be employed. Preparation of Chiral Compounds of Formula 1A One method of preparing chiral compounds of Formula 1A iε εhown below in Reaction Scheme VI. REACTION SCHEME VI Formula 106 Formula 109 Formula 109 alkyl j Formula 110 Formula 109a Formula 110 Formula 1A Preparation of Formula 109 Aε illuεtrated in Reaction Scheme VI, Step 1, an unsaturated aldehyde of Formula 106 is reduced and then converted to the corresponding compound of Formula 109 in which R b iε a leaving group (a εulfonate 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 (εuch aε εodium cyanoborohydride or preferably sodium borohydride) in an alcoholic solvent (such aε ethanol, iεopropanol or preferably methanol) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 12 hourε (preferably 2 hourε) to give the correεponding allylic alcohol (not εhown) which is used without isolation or further purification. The allylic alcohol iε reacted with from 1 to 1.5 (preferably 1.25) molar equivalents of a εulfonating agent (εuch aε p-tolueneεulfonyl chloride) and an organic baεe, or preferably reacted with a halogenating reagent (εuch as carbon tetrachloride/triphenylphoεphine or preferably N-bromoεuccinimide/triphenylphosphine) in an inert organic solvent (εuch aε 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 compound of Formula 109. Preparation of Formula 110 As illuεtrated in Reaction Scheme VI, Step 2, an allylic halide or εulfonate of Formula 109 iε alkylated with a chiral -alkyl N-acyl oxazolidinone of Formula 109a to give the correεponding chiral εubεtituted 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- iεopropyl) by reaction of the N-acyl oxazolidinone with 1 to 1.25 (preferably 1.05) molar equivalents of an alkali metal hydride, hexamethyldisilazide or dialkylamide (preferably lithium diiεopropylamide) 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 minutes (preferably 30 minuteε) . The εolution of the salt (1 to 1.5, preferably 1.25 molar equivalentε) iε then added to a εolution of an allylic compound of Formula 109 in the same solvent. The alkylation reaction takes place at -100 to 0°C (preferably -80°C) for 30 minuteε to 6 hourε (preferably 1 hour) to afford the correεponding chiral substituted acyl oxazolidinone of Formula 110. Preparation of Chiral Formula 1A As illuεtrated in Reaction Scheme V , Step 3, a chiral εubstituted acyl oxazolidinone of Formula 110 is hydrolyzed to the correεponding chiral acid of Formula 1A. Uεe of an acyl oxazolidinone of Formula 109a having a 4-alkyl εubεtituent of the opposite configuration in Reaction Scheme VI, Step 2, followed by hydrolysiε aε deεcribed in Step 3 reεultε in the correεponding chiral acid where Z 3 haε the oppoεite configuration. An acyl oxazolidinone of Formula 110 is reacted with from 1.25 to 3.5 (preferably 3.0) molar equivalents of lithium hydroxide, in a mixture of water and a water-miscible organic εolvent (εuch aε dioxane or preferably tetrahydrofuran) containing from 6 to 10 (preferably 8) molar equivalentε of 30% aqueouε 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 1A. Alternative Preparation of Compounds of Formula 1A An alternative preparation of compoundε of Formula 1A is shown below in Reaction Scheme VTI. REACTION SCHEME VII For aIkyI Formula 112 Formula 109b Preparation of Formula 112 Aε illuεtrated in Reaction Scheme VII, Step 1, an allylic compound of Formula 109 in which R b is a leaving group (a εulfonate or halide, preferably a bromide) iε condensed with an ester of Formula 109b to give the mono- or di-alkyl ester of Formula 112 (where Z 3 iε H, lower alkyl, lower alkenyl, or phenyl and Z 4 iε H, lower alkyl, or phenyl) . An eεter of Formula 109b iε converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalentε of an alkali metal amide (such as sodium hexamethyldisilazide, potassium tetramethylpiperidide or preferably lithium diisopropylamide) in an organic solvent (such as ether, dioxane or preferably tetrahydrofuran) . The reaction takeε place at -40 to 30°C (preferably 0°C) for 15 minuteε to 3 hours (preferably 30 minuteε) . Without iεolation or further purification, the reεulting εolution of the alkali metal εalt of the eεter of Formula 109b (1.2 to 1.6, preferably about 1.3 molar equivalentε) iε 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 triamide. The reaction takeε place at -100 to -40°C (preferably -80°C) for 30 minuteε to 6 hourε (preferably 1 hour) to afford the correεponding alkyl eεter of Formula 112. Preparation of Formula 1A Compound of Formula 1A are then obtained aε eεterε by deprotection of compounds of Formula 105 as deεcribed below with reference to Reaction Scheme X, Step 1; they are hydrolyzed to the correεponding carboxylic acid aε deεcribed below with reference to Reaction Scheme X, Step 2. Preparation of Compounds of Formula 1A where Z 3 is S(0) m alkyl Compounds of Formula 1A where Z 3 is S(0) m alkyl are prepared as shown below in Reaction Scheme VTII. REACTION SCHEME VIII F w Formula 1A where Z " is SC03 m alkyl Preparation of Formula 1A where Z 3 is S(θ) m alkyl As illustrated in Reaction Scheme VIII, Step 1, a 2- (alkylthio) -4- hexenoic acid ester of Formula 1A (where Z 3 is S-lower alkyl, and Z 4 is H or lower alkyl) iε oxidized to give the correεponding 2- (alkylεulfinyl) - or 2- (alkylsulfonyl) -4-hexenoic acid eεter of Formula 1A where Z 3 iε S(O) lower alkyl or S(0) 2 lower alkyl. Alternatively, the reaction can be performed with an acid of Formula 1A where Z 3 iε S-lower alkyl, to give the correεponding acid where Z 3 iε 2- (alkylεulfinyl) or 2- (alkylεulfonyl) . An alkylthio-4-hexenoic acid ester of Formula 1A iε reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of an oxidizing agent (εuch aε oxone ® ) optionally in the preεence of an inert support (such as alumina) , in a εolvent (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 1A where Z 3 iε S(O)lower alkyl. By repeating the foregoing procedure under the εame conditions [εtarting with the 2- (alkylεulfinyl) -4-hexenoic acid eεter εo-produced], or by conducting the reaction with the 2- (alkylthio) -4-hexenoic acid eεter εtarting material [and using 2.0 to 2.5 (preferably 2.25) molar equivalentε of oxone] the correεponding 2-alkylεulfonyl-4-hexenoic acid eεters are produced. A 2- (alkylεulfinyl) - or 2- (alkylεulfonyl) - -hexenoic acid ester of Formula I-ZA-K is hydrolyzed to give the corresponding acid as described with reference to Reaction Scheme X, Step 2. Preparation of Compounds of Formula 1A where Z 1 is Halo Compounds of Formula 1A where Z 1 iε halo are prepared aε shown below in Reaction Scheme IX. REACTION SCHEME IX Formula 103c Formula 114 Formula 115 Formu la 106b Formu I a 1A where Z s ha lo Preparation of Formula 114 Aε illustrated in Reaction Scheme IX, Step 1, a protected aldehyde of Formula 103 and a triphenylphosphoranylideneacetate 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 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of an alkyl 2-halo-2-triphenylphosphoranylidene- acetate of Formula 103c (the halo group preferably being chloro) in an organic solvent (such as acetonitrile, or preferably toluene) . The reaction takes place at 50 to 120°C (preferably 110°C) for 4 to 48 hourε (preferably 24 hourε) to afford the correεponding alkyl 2-halo-4-aryl-2- butenoate eεter of Formula 114. Preparation of Formula 115 As illuεtrated in Reaction Scheme IX, Step 2, a protected alkyl 2- halo-4-aryl-2-butenoate eεter of Formula 114 iε converted to the correεponding bromide of Formula 115 after reduction to the correεponding alcohol (not εhown) . A 2-halo-4-aryl-2-butenoate eεter of Formula 114 (preferably a t- butyl eεter) iε converted to the correεponding acid (preferably by diεεolution in trifluoroacetic acid at room temperature for 1 to 2 hourε) . The acid iε iεolated and purified by conventional means, then reacted with 0.5 to 3 (preferably 1.6) molar equivalentε of a reducing agent (εuch aε εodium cyanoborohydride, εodium borohydride, or preferably borane dimethyl diεulfide complex) in an inert εolvent (εuch aε methanol, ethanol, iεopropanol or preferably THF) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 48 hourε (preferably 24 hourε) to give the corresponding alcohol (not shown) which is used after purification. The allylic alcohol εo-produced iε reacted with from 1 to 1.5 (preferably 1.25) molar equivalentε of a εulfonating agent (εuch aε p-tolueneεulfonyl chloride) and an organic baεe, or preferably reacted with a halogenating reagent (εuch aε carbon tetrachloride/triphenylphoεphine or preferably N-bromoεuccinimide/triphenylphoεphine) in an inert organic εolvent (εuch aε 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 correεponding 2-halo-4-aryl-2-butenyl bromide compound of Formula 115. Preparation of Formula 1A where Z 1 is Halo As illuεtrated in Reaction Scheme IX, Step 3, a protected 2-halo-4- aryl-2-butenyl bromide compound of Formula 115 iε condensed with a dialkyl malonate of Formula 106b (εubεtituted by Z 4 where Z 4 iε hydrogen, lower alkyl, or phenyl) , which iε hydrolyεed and decarboxylated to give the correεponding 4-halo-4-hexenoic acid derivative of Formula 1A where Z 1 iε halo. A malonic eεter of Formula 106b (where Z 4 is H, lower alkyl, or phenyl) is converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalents of an alkali metal hydride (preferably εodium hydride) in an organic εolvent (εuch 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 isolation or further purification, the resulting solution of the alkali metal salt of the eεter of Formula 106b (1.2 to 1.6, preferably about 1.3 molar equivalentε) iε then reacted with an allylic bromo compound of Formula 115 in the εame solvent. The reaction takeε place at -20 to 50°C (preferably 25°C) for 30 minutes to 6 hours (preferably 2 hourε) to afford the correεponding dialkyl ester derivative. The dialkyl eεter thus produced iε then hydrolysed conventionally, uεing a εtrong baεe, preferably aqueouε sodium hydroxide, in a protic εolvent, preferably ethanol, heating to reflux. The dicarboxylic acid thuε produced iε separated conventionally, and then decarboxylated by heating, preferably in a high-boiling inert εolvent, most preferably 1,2- dichlorobenzene, to give the correεponding 4-halo-4-hexenoic acid derivative of Formula 1A where Z 1 iε halo. Preparation of Compounds of Formula 1A Compounds of Formula 1A as esterε and carboxylic acidε are obtained by deprotection and hydrolyεiε as shown below in Reaction Scheme X. REACTION SCHEME X For ula 117 Formu la A as an ester Formula 1A as an ester Step 2 Formula 1A as an acid Preparation of Formula 1A as an Ester As illustrated in Reaction Scheme X, Step 1, a protected phenol of Formula 117 (which can be any of the corresponding protected compoundε of Reaction Schemeε I to IX, εuch aε Formulae 105, 107, 108, 112, and the like) iε deprotected to give the correεponding alkyl eεter of Formula 1A aε an eεter. An alkyl ester of Formula 117 (having either an acetal-type or a silyl-type protecting group) iε treated with from 0.05 to 0.2 molar equivalentε (preferably 0.1 molar equivalentε) of an aqueouε mineral acid (εuch aε εulfuric, perchloric, or preferably hydrochloric acid) , in a water-miεcible organic εolvent (εuch aε methanol, acetone, or preferably ethanol) . The reaction takeε place at 0 to 50°C (preferably 25°C) over a period of 1 to 6 hourε (preferably 2 hours) to give the corresponding free phenol of Formula 1A. Alternatively, to remove acetal-type protecting groups (such aε MEM) a compound of Formula 117 iε treated with 0.05 to 0.25 molar equivalentε (preferably 0.1 molar equivalentε) of a Lewiε acid (εuch aε zinc chloride or preferably zinc bromide) , in a εolvent (such as benzene, chloroform, or preferably dichloromethane) . The reaction takeε place at 0 to 50°C (preferably 25°C) over a period of 1 to 12 hourε (preferably 3 hourε) to give the correεponding free phenol of Formula 1A. Alternatively, to remove εilyl-type protecting groupε (εuch aε t- butyldimethylεilyl) a compound of Formula 117 is reacted with 1.0 to 1.5 (preferably 1.25) moleε of a tetraalkyl ammonium fluoride (preferably tetrabutylammonium fluoride) in an ethereal εolvent (εuch aε 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 correεponding free phenol of Formula 1A. Preparation of Formula 1A as a Carboxylic Acid As illuεtrated in Reaction Scheme X, Step 2, a compound of Formula 1A as an ester (prepared as described above) iε hydrolyzed to give the correεponding acid of Formula 1A aε a carboxylic acid. An alkyl eεter of Formula 1A is reacted with from 1.5 to 4 molar equivalentε (preferably 2 molar equivalentε) of an inorganic hydroxide (εuch as potaεεium, εodium, or preferably lithium hydroxide) in a mixture of water and an organic εolvent (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 resulting anion iε acidified with an aqueouε mineral acid (εuch aε hydrochloric acid) . The acidification takes place at 0 to 40°C (preferably 25°C) over a period of 1 to 10 minutes (preferably 2 minuteε) to give the correεponding carboxylic acid of Formula 1A. Preparation of Compounds of Formula IB One method of preparing compoundε of Formula 1 where Z iε a εidechain of Formula ZB, illustrated as compoundε of Formula IB, iε εhown below in Reaction Schemeε XI and XII. REACTION SCHEME XI Formula 103 + Formu la 202 where M iε Li or MgBr. Formula 202 Formu la 203 Formula 203 Formula 1B Preparation of Formula 202 As illustrated in Reaction Scheme XI, Step 1, the aldehyde of Formula 103 iε converted to a carbinol of Formula 202 by addition of an unsaturated cyclic organometallic compound of Formula 201 where M is Li or MgBr, prepared for example aε deεcribed above with reference to Reaction Scheme I, Step 3. One molar equivalent of the organometallic reagent 201 iε added to a εolution of an aldehyde of Formula 103 (in the εame εolvent εyεtem uεed to make the organometallic reagent) . The reaction takeε place at -80 to -20°C (preferably -40°C) over a period of 5 to 60 minuteε (preferably 15 minuteε) to give the correεponding carbinol of Formula 202. Resolution of Formula 202 The racemic compound of Formula 202 may be εeparated into itε two enantiomerε by conventional means, for example by conversion into two diastereoiεomerε that are then εeparated by crystallization, chromatography, or by any conventional separation technique. Preferably, the carbinol iε reacted with a chiral isocyanate to give a mixture of diaεtereoiεomeric carbamateε, which are εeparated 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 preεence of 1 to 1.5 molar equivalentε (preferably 1.2 molar equivalentε) of a strong organic base, for example 4-dimethylaminopyridine, in a hindered tertiary amine (for example diiεopropylethylamine) aε a εolvent. The reaction takeε place over a period of 1 to 24 hourε (preferably 7 hours) to give the corresponding carbamate as a mixture of diaεtereoiεomerε. The mixture of diaεtereoisomeric carbamateε iε εeparated by conventional meanε, preferably chromatography. The individual diastereoisomerε are then εeparately cleaved by treatment with l to 1.5 molar equivalentε (preferably 1.2 molar equivalentε) of a trihaloεilane, for example trichloroεilane, in the presence of an excess of a tertiary amine, for example triethylamine, in an inert solvent, for example toluene. The reaction takes place at a temperature of 90-120°C (preferably 110°C) over a period of 5 minuteε to 2 hourε (preferably 15 minuteε) to give the corresponding enantiomer of the carbinol of Formula 202. Preparation of Formula 203 Aε illuεtrated in Reaction Scheme XI, Step 2, an alkyl eεter of Formula 203 iε formed by a Claiεen ortho ester reaction of a carbinol of Formula 201 (or an enantiomer thereof) with an appropriately subεtituted orthoeεter. A carbinol of Formula 202 iε heated at 50 to 140°C (preferably 130°C) with a large exceεε of an orthoeεter of Formula 104a (εee Reaction Scheme I, εtep 4), in the preεence of from 0.05 to 0.25 molar equivalentε (preferably 0.10 molar equivalentε) of an organic acid catalyεt (such as 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 correεponding alkyl eεter of Formula 203. Preparation of Formula IB Compoundε of Formula IB are prepared aε described with reference to Reaction Scheme X, Step 1 (deprotection to afford the corresponding alkyl ester of Formula IB) , and Step 2 (hydrolysiε to afford the correεponding acid of Formula IB) . Alternative Preparation of Enantiomers of Compounds of Formula IB Another method of preparing individual enantiomers of compounds of Formula 1 where Z is sidechain ZB, illustrated aε compoundε of Formula IB, iε from chiral compoundε of Formula 202b, the preparation of which is shown below in Reaction Scheme XII. REACTION SCHEME XII Formula 103g + For u la 202a Formula 202a For u la 202b Preparation of Formula 202a Compounds of Formula 202a are prepared aε deεcribed above with reference to Reaction Scheme II, 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 II, Step 4 (converεion of 103h to 104b) . Preparation of Enantiomers of Compounds of Formula IB The chiral carbinol of Formula 202b is then converted to an enantiomer of a compound of Formula IB in the same manner aε εhown above in Reaction Scheme XI (converεion of compoundε of Formula 202 to 203 to IB) . Preparation of Compounds of Formula IC One method of preparing compounds of Formula 1 where Z is a sidechain of Formula ZC, illuεtrated aε compoundε of Formula IC, iε εhown below in Reaction Scheme XIII. REACTION SCHEME XIII Formula 302 Formu I a 301 Formu la 302 Formu la 303 Formu la 303 Formu la 304 Formula 304 Formu I a 305 Formu la 305 For ula 306 Formu la 306 Formu I a 307 Formu la 307 For u l 30Θ Formu la 30. Formu la 309 Formu la 309 Formula 1C Preparation of Formula 302 As illuεtrated in Reaction Scheme XIII, Step 1, an aldehyde of Formula 103 (prepared, for example as deεcribed above with reference to Reaction Scheme I, 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 ~ 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 (εuch 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 Aε illuεtrated in Reaction Scheme XIII, Step 2, an unεaturated aldehyde of Formula 302 iε converted to the correεponding vinyl carbinol of Formula 303. An aldehyde of Formula 302 iε reacted with from 1.0 to 1.25 (preferably 1.1) molar equivalentε of an organovinyl compound (preferably vinylmagneεium bromide) in a εolvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takeε place at -30 to 20°C (preferably at 0°C) for 0.1 to 4 hourε (preferably 0.5 hours) to give the corresponding vinyl carbinol of Formula 303. Preparation of Formula 304 As illustrated in Reaction Scheme XIII, Step 3, a vinyl carbinol of Formula 303 is oxidized to give the corresponding dienone of Formula 304. A vinyl carbinol of Formula 303 is 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 εolvent (εuch aε pyridine or preferably dichloromethane) . The reaction takeε place at 0 to 30°C (preferably 25°C) for 30 minuteε to 4 hourε (preferably 1 hour) to give the correεponding dienone of Formula 304. Preparation of Formula 305 As illuεtrated in Reaction Scheme XIII, Step 4, a dienone of Formula 304 iε cyclized to give the correεponding 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 aε boron trichloride, tin (IV) chloride or preferably boron trifluoride etherate) in a εolvent (εuch aε tetrachloroethane or preferably dichloromethane) . The reaction takes place at 0 to 30°C (preferably 25°C) for 1 to 6 hours (preferably 2 hourε) to give the correεponding cyclopentenone of Formula 305. Preparation of Formula 306 Aε illuεtrated in Reaction Scheme XIII, Step 5, a cyclopentenone of Formula 305 iε reduced to give the corresponding cyclopentenol of Formula 306. A cyclopentenone of Formula 305 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of a reducing agent (εuch aε lithium tri-tert-butoxyaluminium hydride or preferably εodium borohydride in the preεence of an equimolar amount of cerium trichloride) in a mixture of an ethereal εolvent (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 hourε) to give the cyclopentenol of Formula 306. Preparation of Formula 307 Aε illuεtrated in Reaction Scheme XIII, Step 6, a cyclopentenol of Formula 306 iε tranεformed to the correεponding vinyl ether of Formula 307. A cyclopentenol of Formula 306 iε reacted with from 10 to 100 (preferably 50) molar equivalentε of a 1-alkenyl ether, optionally in the preεence of a co-εolvent (εuch aε ether or tetrahydrofuran) , in the preεence of from 0.1 to 0.5 (preferably 0.3) molar equivalentε of a mercury (II) εalt (preferably mercury (II) acetate) . The reaction takeε 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 As illuεtrated in Reaction Scheme XIII, 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 equivalentε of a lithium εalt (such as the tetrafluoroborate or preferably the perchlorate) in a solvent (such aε 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 correεponding acetaldehyde of Formula 308. Preparation of Formula 309 Aε illuεtrated in Reaction Scheme XIII, Step 8, an acetaldehyde of Formula 308 iε oxidized to give the corresponding acid of Formula 309. An acetaldehyde of Formula 308 iε reacted with 1 to 3 (preferably 1.5) molar equivalentε of a suitable oxidizing agent (εuch aε εilver oxide, Jones reagent or preferably sodium chlorite) in the presence of an equimolar amount of a phenol (εuch aε quinol or preferably reεorcinol) . The reaction iε conducted in a mixture of water and a water-miεcible organic εolvent (εuch 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 minuteε to 2 hourε (preferably 30 minuteε) to give the correεponding acid of Formula 309. Preparation of Formula IC Aε illuεtrated in Reaction Scheme XIII, Step 9, an acid of Formula 309 iε deprotected to give the correεponding acid of Formula IC. An acid of Formula 309 where R* iε a εulphonyloxy protecting group hydrolyzed under baεic conditionε, uεing from 1 to 5 (preferably 3) molar equivalentε of an alkali metal hydroxide (preferably lithium hydroxide) in a mixture of water and a water-miεcible organic εolvent (εuch aε dioxane or preferably methanol) . The reaction takeε place at 40 to 100°C (preferably 60°C) for 1 to 48 hourε (preferably 12 hours) to afford the correεponding cyclopentene carboxylic acid of Formula IC. Alternatively, for other protecting groupε, the deprotection reaction takes place aε deεcribed above with reference to Reaction Scheme X, Step 1. Preparation of Compounds of Formula ID One method of preparing compounds of Formula 1 where Z is a sidechain of Formula ZD, illustrated as compounds of Formula ID, is εhown below in Reaction Scheme XIV. REACTION SCHEME XIV Formu la 103 Formu la 401 Formu la 103d 0-a I ky I Formu I a 104a Formu la 402 Formu la 402 For u la 403 Formu l a 403 Formu la 1 D Preparation of Formula 401 Aε illuεtrated in Reaction Scheme XIV, 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 (such as a substituted vinyl organolithium, or preferably a Grignard reagent where: M iε MgBr or Li; Z 2 iε H or lower alkyl; and TBS iε a tert-butyldimethylεilyl protecting group) . The aldehyde of Formula 103 iε reacted with from 1.1 to 1.5 (preferably 1.25) molar equivalentε of an organometallic, preferably organolithium, derivative of a protected 2-halo (preferably 2-bromo) but-1- en-4-ol. The reaction iε performed at from -100 to -40°C (preferably at -78°C) for from 30 minuteε to 6 hourε (preferably 1 hour) to afford the correεponding compound of Formula 401. Preparation of Formula 402 Aε illustrated in Reaction Scheme XIV, Step 2, an alkyl ester of Formula 402 is formed by a Claisen ortho eεter 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 orthoeεter of Formula 104a, in the preεence of from 0.05 to 0.25 (preferably 0.10) molar equivalentε of an organic acid catalyεt (εuch aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hourε (preferably 8 hourε) to give the corresponding alkyl ester of Formula 402. Preparation of Formula 403 Aε illuεtrated in Reaction Scheme XIV, Step 3, an alkyl eεter of Formula 402 iε 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 equivalentε of a tetraalkylammonium (preferably tetrabutylammonium) fluoride, in a εolvent (such aε dioxane, tetrahydrofuran, or preferably methylene chloride) at from 0 to 25°C (preferably 10°C) , for from 30 minuteε to 4 hourε (preferably 1 hour) . The product so obtained is 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-bromoεuccinimide) in a εolvent εuch as 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 corresponding halogenated ester of Formula 403. Preparation of Formula ID Aε illustrated in Reaction Scheme XIV, Step 4, a halogenated ester of Formula 403 is cyclized to give a cycloalkyl eεter of Formula IC. A compound of Formula 403 iε reacted with from 2.0 to 2.5 (preferably 2.25) molar equivalents of a strong base (such aε lithium diiεopropylamide, εodium hydride or preferably εodium hexamethyldiεilazide) in an ethereal εolvent (εuch as ether, dioxane or preferably tetrahydrofuran) The reaction takes place at from -100 to -60°C (preferably -78°C) for 1 to 12 hours (preferably 4 hourε) to give the cycloalkyl eεter of Formula ID, which may be hydrolyzed to the carboxylic acid of Formula ID aε deεcribed above with reference to Reaction Scheme X, Step 2. Preparation of Compounds of Formula IE Methodε of preparing compoundε of Formula 1 where Z iε εidechain of Formula ZE, illuεtrated aε compoundε of Formula IE, iε εhown below in Reaction Schemeε XV to XVII. REACTION SCHEME XV Formula 501 Formula 502 Formula 502 Formula 503 l Formula 503 Formula 504 Formula 504 Formula 103 Formula 505 Formula 505 Formula 506 Preparation of Formula 502 As illustrated in Reaction Scheme XV, Step 1, the 2-methyl group of an alkyl 2-methylbenzoate of Formula 501 (where Z ~ and Z 7 are εelected from H, lower alkyl, lower alkoxy, lower alkoxycarbonyl, halo and nitro) iε 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 equivalentε of a brominating agent (εuch aε N-bromoacetamide or preferably N-bromoεuccinimide) , optionally in the preεence of an initiator (εuch aε viεible light) or from 0.001 to 0.01 (preferably 0.005) molar equivalentε of a chemical initiator (εuch aε azobiεisobutyronitrile or preferably benzoyl peroxide) in a solvent (such 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 meanε or preferably used directly for the next step. Preparation of Formula 503 As illustrated in Reaction Scheme XV, Step 2, a 2-bromomethyl group of Formula 502 is converted to the correεponding phoεphonium εalt 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 phoεphine (preferably triphenyl phoεphine) in a εolvent (such aε dimethylformamide or preferably acetonitrile) . The reaction takes place at 25 to 90°C (preferably 50°C) for 1 to 24 hours (preferably 2 hourε) to afford the corresponding phoεphonium εalt of Formula 503. Preparation of Formula 504 As illuεtrated in Reaction Scheme XV, Step 3, a phoεphonium εalt of Formula 503 iε converted to the correεponding εubεtituted benzylidenetriphenylphoεphorane ylid of Formula 504. A phosphonium salt of Formula 503 iε dissolved or suspended in a solvent (such as dioxane, ether or preferably dimethylformamide) and reacted with 1.0 to 1.25 (preferably 1.05) molar equivalents of a base (εuch aε εodium hydride, triethylamine or preferably 1,5- diazabicyclo[4.3.0]non-5-ene) . The reaction takeε place at 0 to 60°C (preferably 25°C) for 1 to 6 hourε (preferably 2 hourε) to afford the corresponding ylid of Formula 504, which can be isolated by conventional means or itε εolution can be used directly for the next εtep. Preparation of Formulae 505 and 506 Aε illustrated in Reaction Scheme XV, Step 4, an ylid of Formula 504 and a protected aldehyde of Formula 103 (prepared, for example, as deεcribed in connection with Reaction Scheme ZA-A, Step 2) are employed in a Wittig reaction to give the corresponding protected substituted benzoic acid alkyl ester of Formula 505 aε a mixture of E and Z isomers, from which the deεired E isomer of Formula 506 is isolated, aε illuεtrated in Reaction Scheme XV, Step 5. A εolution of 0.8 to 1.0 (preferably 0.95) molar equivalents of a protected aldehyde of Formula 103 in a εolvent (εuch aε ether, dioxane or preferably dimethylformamide) iε added to a εolution of an ylid of Formula 504 in the εame εolvent. The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 12 hourε) to afford the correεponding protected εubεtituted benzoic acid alkyl eεter of Formula 505 aε a mixture of E and Z iεomerε, from which the deεired E-iεomer of Formula 506 can be iεolated by conventional means (such aε diεtillation, chromatography or preferably fractional cryεtallization) . REACTION SCHEME XVI Formula 507 Formula 508 Formula 508 Formula 509 Formula 509 Formula 103 Formula 510 Formula 510 Preparation of Formula 508 As illustrated in Reaction Scheme XVT, Step 1, the alpha carbon of an alkyl 2-alkylbenzoate of Formula 507 (where Z ~ iε H or lower alkyl,~ and Z 6 and Z 7 are selected from H, lower alkyl, lower alkoxy, lower alkoxycarbonyl, halo and nitro) is brominated to give the corresponding co pound of Formula 508. The reaction takeε place under the conditionε described with reference to Reaction Scheme XV, Step 1. Preparation of Formula 509 As illustrated in Reaction Scheme XVI, Step 2, an alkyl 2-bromo- alkylbenzoate of Formula 508 and a trialkyl phosphite are combined in an Arbuzov reaction to give the corresponding phoεphonate of Formula 509. A compound of Formula 508 iε reacted with from 5 to 20 (preferably 10) molar equivalentε of a trialkyl phoεphite (preferably triethyl phoεphite) . The reaction takeε place at 100 to 200°C (preferably 150°C) for 1 to 24 hourε (preferably 6 hourε) to afford the correεponding phoεphonate of Formula 509. Preparation of Formulae 510 and 511 Aε illuεtrated in Reaction Scheme XVI, Step 3, a phoεphonate of Formula 509 and a protected aldehyde of Formula 103 (prepared, for example, aε deεcribed in connection with Reaction Scheme I, Step 2) are reacted to give the correεponding protected εubεtituted benzoic acid alkyl eεter of Formula 510 aε a mixture of E and Z iεomerε, from which the deεired E iεomer of Formula 511 iε iεolated, aε illustrated in Reaction Scheme XV, Step 4. A phoεphonate of Formula 509 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of a baεe εuch (aε εodium amide, potaεεium 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 εolvent (εuch as dioxane, dimethylformamide or preferably dimethoxyethane) , to give a solution or suεpenεion of the correεponding alkali metal εalt of Formula 509, which is employed without isolation or further purification. The alkali metal εalt iε reacted with from 0.9 to 1.1 (preferably 1.0) molar equivalentε of a protected aldehyde of Formula 103, diεεolved in the εame εolvent. The reaction takeε place at 0 to 60°C (preferably 40°C) for 1 to 6 hours (preferably 2 hours) to afford the correεponding protected optionally εubεtituted benzoic acid alkyl eεter of Formula 510 aε a mixture of E and Z iεomerε, from which the deεired E-iεomer of Formula 511 can be isolated by conventional means (such aε diεtillation, chromatography or preferably fractional crystallization) . REACTION SCHEME XVII For Br Formula 513 F rmula 512 Formu l a 513 Formula 514 Formula 514 Formu la 5 5 where R° is TBDMS where R° is acy Formula 516 Preparation of Formula 513 Aε illuεtrated in Reaction Scheme XV I, Step 1, a protected aldehyde of Formula 103 iε 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 equivalentε of a trialkylεilylalkyl-magneεium bromide (εuch aε trimethylεilylpropylmagneεium bromide, or preferably trimethylεilylmethylmagneεium bromide) of Formula 512, in an ethereal εolvent (εuch aε 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 correεponding trialkylεilylcarbinol of Formula 513. Preparation of Formula 514 Aε illuεtrated in Reaction Scheme XVII, Step 2, a protected trialkylsilylcarbinol of Formula 513 iε dehydrated to give the correεponding protected alkene aε a mixture of E and Z iεomerε, from which the deεired Z iεomer of Formula 514 is isolated. A carbinol of Formula 513 iε reacted with from 1.0 to 1.5 (preferably 1.05) molar equivalents of a sulphonyl chloride (εuch aε p-tolueneεulphonyl chloride or preferably methanesulphonyl chloride) in the preεence of the εa e molar proportion of a tertiary organic baεe (εuch aε N-methyl- pyrrolidine or preferably triethylamine) . The reaction takeε place at 0 to 40°C (preferably 15°C) for 30 minuteε to 4 hourε (preferably 2 hourε) to afford the correεponding protected alkene of Formula 514 aε a mixture of E and Z iεomerε, from which the deεired Z-iεomer of Formula 514 can be iεolated by conventional meanε (εuch aε diεtillation, chromatography or preferably fractional cryεtallization) . Preparation of Formula 515 Aε illuεtrated in Reaction Scheme XV I, Step 3, an alkene of Formula 514 where R" iε a εilyl protecting group iε converted to an alkene of Formula 515 where R a iε an acyl group. An alkene of Formula 514 iε 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 deεired acyl group) , preferably a mixture of acetic acid and acetic anhydride. The reaction takeε place over a period of 6 to 48 hourε (preferably 18 hourε) to give the corresponding alkene of Formula 515 where R" is the acyl group. Preparation of Formula 511 Aε illustrated in Reaction Scheme XVII, 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 iε reacted with 1.0 to 2.0 (preferably 1.25) molar equivalentε of an alkyl 2-halobenzoate (εuch aε an alkyl 2-bromobenzoate or preferably 2-iodobenzoate) . The reaction iε conducted in the presence of from 0.001 to 0.1 (preferably 0.05) molar equivalentε of a palladium catalyεt [εuch aε tetrakiε (tri-o-tolylphoεphine) palladium, or tetrakiε(triphenylphoεphine)palladium or preferably palladium (II) acetate] optionally in the preεence of from 1.0 to 1.25 (preferably 1.05) molar equivalentε of a baεe (εuch εilver carbonate, εodium bicarbonate or preferably triethylamine) , in a εolvent (εuch aε acetonitrile or preferably dimethylformamide) . The reaction iε conducted at from 0 to 120°C (preferably 60°C) for 1 to 48 hours (preferably 6 hours) to yield the corresponding protected optionally εubεtituted benzoic acid alkyl ester of Formula 511. Preparation of Formula IE The protected optionally εubεtituted benzoic acid eεter of Formula 506 or Formula 511 are then deprotected to give the corresponding ester of Formula IE. The deprotection reaction takeε place aε deεcribed above with reference to Reaction Scheme X, Step 1. The optionally substituted benzoic acid eεter of Formula IE may then be hydrolyzed to give the correεponding acid of Formula IE as described above with reference to Reaction Scheme X, Step 2. Preparation of Formula IE where Z* is Amino The compoundε of Formula IE where Z ~ iε nitro are employed as precursorε to the correεponding compoundε of Formula IE where Z 6 is amino. The nitro compounds are also active aε IMPDH inhibitorε when teεted aε deεcribed below. A nitrobenzoic acid of Formula IE (where Z 6 iε nitro) iε reacted with 1.0 to 3.0 (preferably 2.0) molar proportionε of a reducing agent (εuch aε εodium hydroεulfite or preferably tin (II) chloride) in hydrochloric acid εolution, optionally in the preεence of a water-miεcible co-εolvent (εuch 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 hourε) to afford the correεponding amino-εubεtituted benzoic acid of Formula IE (where Z 6 iε amino) . REACTION SCHEME XVIII Formula 509 Formula 517 Formula 51B Fo mu la 520 Fo mu I a •ZE-D1 -* • Formula I-2E-D2 Step 5 Step 6 Preparation of Formula 517 Aε illustrated in Reaction Scheme XVIII, Step 1, a phosphonate of Formula 509 undergoeε a baεe catalyzed condenεation (e.g., uεing 1 molar equivalent of εodium hydride) with tetrahydropyranyloxyacetaldehyde, in a εolvent εuch aε 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 eanε, such aε chromatography. Preparation of Formula 518 Aε illuεtrated in Reaction Scheme XVTII, Step 2, the tetrahydropyranyloxy group of a compound of Formula 517 iε hydrolyzed in the preεence of a catalytic amount of a dilute acid (e.g., HC1) in aqueouε tetrahydrofuran. The reaction takeε place at 25°C over a period of 1 to 4 hourε, to give the correεponding carbinol of Formula 518. Preparation of Formula 519 Aε illuεtrated in Reaction Scheme XV II, Step 3, a carbinol of Formula 518 iε converted to the halo (e.g., chloro or bromo) derivative of Formula 519 uεing 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 hourε. Preparation of Formula 520 Aε illustrated in Reaction Scheme XVTII, Step 4, a halo derivative of Formula 519 undergoes a baεe-catalyzed ether formation with the indicated phenol, uεing 5 molar equivalentε of potaεεium carbonate, in dimethylformamide. The reaction takeε place at 25°C over a period of 4 hourε. Preparation of Formula IE Aε illuεtrated in Reaction Scheme XVTII, Step 5, an ether of Formula 520 is rearranged to give the correεponding eεter of Formula IE by a thermal rearrangement catalyεed by florisil. The rearrangement takes place in toluene at 110°C over a period of one to four days. Aε illuεtrated in Reaction Scheme XV II, Step 6, the ether so- produced is hydrolyzed to the corresponding acid of Formula IE aε described with reference to Reaction Scheme X, Step 2. Preparation of Compounds of Formula IF One method of preparing compounds of Formula 1 where Z iε a εidechain of Formula ZF, illuεtrated as compounds of Formula IF, iε εhown below in Reaction Scheme XIX. REACTION SCHEME XIX CH For u la BO 1 Formu la 602 Formula 604 Formula 605 Formula 606 Preparation of Formula 602 As illustrated in Reaction Scheme XIX, Step 1, an aldehyde of Formula 601, prepared for example aε εhown in J. Org. Chem.. 1977, p3408, iε reduced to a carbinol of Formula 602. An aldehyde of Formula 601 iε reacted with a reducing agent capable of selectively reducing an aldehyde in the presence of ester groups, preferably from 1 to 2 (preferably 1.5) molar equivalentε of εodium borohydride in the preεence of from 1 to 2 (preferably 1.5) molar equivalentε 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 minuteε) to give the correεponding carbinol of Formula 602. Preparation of Formula 604 Aε illuεtrated in Reaction Scheme XIX, Step 2, a phenol of Formula 603 iε alkylated with a carbinol of Formula 602 by means of the Mitεonobu 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 equivalentε of a triarylphoεphine, preferably triphenylphoεphine, pluε from 1 to 3 (preferably 1.5) molar equivalentε of diethyl azodicarboxylate in an ethereal solvent (preferably tetrahydrofuran) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 10 hourε (preferably 3 hourε) to give the corresponding ether of Formula 604. Preparation of Formula 605 As illustrated in Reaction Scheme XIX, 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 partε by weight of an activated magneεium silicate, preferably Floriεil ® . The reaction takeε place at reflux temperature for 1 to 10 dayε (preferably 4 dayε) to give the correεponding dieεter of Formula 605. Preparation of Formula 606 Aε illuεtrated in Reaction Scheme XIX, Step 4, a dieεter of Formula 605 iε hydrolyzed to give a dicarboxylic acid of Formula 606. A dieεter of Formula 605 iε reacted with an exceεε of an inorganic baεe, preferably about 50 molar equivalentε of lithium hydroxide, in an aqueouε εolvent (preferably 5:1 methanol:water) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 10 dayε (preferably 2 dayε) to give the correεponding dicarboxylic acid of Formula 606. Preparation of Formula IF Aε illuεtrated in Reaction Scheme XIX, Step 5, a dicarboxylic acid of Formula 606 iε decarboxylated to give a monocarboxylic acid of Formula IF. A dicarboxylic acid of Formula 606 iε heated (optionally in the preεence of a high boiling inert εolvent, for example tetramethylbenzene, but preferably in the abεence of any solvent) . The reaction takes place at 160 to 240°C (preferably 195°C) for about 5 minutes to give the corresponding monocarboxylic acid of Formula IF. Preparation of Compounds of Formula IG One method of preparing compoundε of Formula 1 where Z iε εidechain of Formula ZG, illuεtrated aε compoundε of Formula IG, iε shown below in Reaction Scheme XX. REACTION SCHEME XX Formu la 701 Formu la 702 For u la 703 Formula 703 For u I a 704 Formu la 704 Formu la 705 Formula 705 Formu la 706 Formu la 706 For mu I a 707 Formu la 707 Formu l a 70E Formu la 708 Formu la 709 Formu I a 709 Formu la 710 Formu l a 710 Formu l a 711 Formula 711 Formula 1G Preparation of Formula 703 As illustrated in Reaction Scheme XX, Step 1, the phenol of Formula 701 iε alkylated with 3-hydroxycyclohexene to give the correεponding ether of Formula 703, by meanε of the Mitεonobu reaction. The Mitεonobu reaction takeε place aε deεcribed with reference to Reaction Scheme XIX, Step 2. Similarly, by εubεtituting 3-cyclohexene with 3-cycloheptene, and carrying out the procedures of Reaction Scheme XX, the corresponding compounds where Z is a side chain of Formula ZG where D 3 iε -CH- J -CH J - are obtained. Preparation of Formula 704 Aε illuεtrated in Reaction Scheme XX, Step 2, a Claiεen rearrangement of the ether of Formula 703 giveε the alkylated phenol of Formula 704. The reaction takeε place, e.g., at 200°C for 12 to 16 hours in the presence of N,N-diethylaniline. Preparation of Formula 705 As illuεtrated in Reaction Scheme XX, Step 3, the alkylated phenol of Formula 704 iε protected to give a protected phenol of Formula 705 (where R a iε silyl or toεyl) . An alkylated phenol of Formula 704 iε reacted with an equimolar amount of t-butyl dimethylsilyl chloride or p-tolueneεulfonyl chloride, in the preεence of an equimolar amount, reεpectively, of imidazole or 4- dimethylaminopyridine. The reaction takeε place in dichloromethane at a temperature of 25°C for 1 to 4 hours to give the corresponding protected phenol of Formula 705. Preparation of Formula 706 Aε illuεtrated in Reaction Scheme XX, Step 4, a protected phenol of Formula 705 iε converted to the correεponding dialdehyde of Formula 706 by ozonolyεiε. The ozonolyεiε reaction takes place as described with reference to Reaction Scheme I, Step 2. Preparation of Formula 707 As illustrated in Reaction Scheme XX, Step 5, an intramolecular base- catalyzed aldol reaction with a dialdehyde of Formula 706 produces the corresponding formyl cyclopentene of Formula 707. The reaction iε 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 illuεtrated in Reaction Scheme XX, Step 6, a formyl cyclopentene of Formula 707 iε reduced to the correεponding carbinol. The reaction employε εodium borohydride/cerium chloride, aε deεcribed with reference to Reaction Scheme XIX, Step 1. Preparation of Formula 709 Aε illuεtrated in Reaction Scheme XX, Step 7, a carbinol of Formula 708 iε converted to the correεponding acetate of Formula 709. The reaction iε conducted with equimolar amounts of acetyl chloride and triethylamine, taking place in methylene chloride at 0°C for 1 hour. Preparation of Formula 710 As illustrated in Reaction Scheme XX, Step 8, an acetate of Formula 709 iε converted to the correεponding dieεter of Formula 710. The reaction iε conducted aε deεcribed in J. Am. Chem. Soc , 102:4730 (1980), with 4 moleε of εodium dimethylmalonate, 0.5 moleε triphenylphosphine and 0.25 moleε of tetrakiε triphenylphoεphine palladium at 50°C in tetrahydrofuran. ϋεe of sodium dimethylmalonate substituted by Z 3 or Z 4 leadε to a compound of Formula 711 where one of Z 3 and Z 4 iε as defined in the Summary of the Invention and the other iε hydrogen. Preparation of Formula 711 Aε illuεtrated in Reaction Scheme XX, Step 9, a dieεter of Formula 710 iε converted to the correεponding eεter of Formula 711, by reaction with ceεium acetate in hexamethylphosphoric triamide at 120°C for 1 to 3 hourε. Preparation of Formula IG Aε illuεtrated in Reaction Scheme XX, Step 10, an eεter of Formula 111 iε hydrolyzed to give the correεponding compound of Formula IG. The reaction takeε place aε deεcribed with reference to Reaction Scheme X, Step 2. Preparation of Compounds of Formula IH One method of preparing compoundε of Formula 1 where Z iε sidechain of Formula ZH, illustrated as compoundε of Formula IH, iε shown below in Reaction Scheme XXI. REACTION SCHEME XXI Formula 103e Formula 801 Formu la 802 Formu la 802 Formu la 803 Formu la 803 Formu l a B04 Formu 804 Fo mu la 805 Formu l a 805 Formu l a H Preparation of Formula 801 Aε illuεtrated in Reaction Scheme XXI, Step 1, an aldehyde of Formula 103 is converted to a carbinol by addition of an organometallic compound of Formula 103e (εuch aε a substituted vinyl organolithium, or preferably a Grignard reagent, where M iε MgBr; TBS is a tert-butyldimethylsilyl protecting group; and n is 3-5) . A halovinyl (preferably bromovinyl) compound of Formula 103e (where M is halo) iε reacted with magneεium metal in an ethereal εolvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takes place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hourε (preferably 2 hourε) . One molar equivalent of the reεultant organometallic reagent iε added to a εolution of an aldehyde of Formula 103 (in the εame εolvent εyεtem 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 correεponding εilyl-protected carbinol of Formula 801. Preparation of Formula 802 Aε illuεtrated in Reaction Scheme XXI, Step 2, an alkyl eεter of Formula 802 iε formed by a Claiεen ortho eεter rearrangement reaction of a carbinol of Formula 801 and an orthoeεter compound of Formula 104a (aε illuεtrated in Reaction Scheme I, where Z 3 and Z 4 are H) . A silyl-protected carbinol of Formula 801 iε heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalentε of an orthoeεter of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalents (preferably 0.10 molar equivalents) of an organic acid catalyst (εuch aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hours (preferably 8 hours) to give the correεponding alkyl ester of Formula 802. Preparation of Formula 803 Aε illustrated in Reaction Scheme XXI, Step 3, the silyl-protected carbinol of an alkyl eεter of Formula 802 iε deprotected. A compound of Formula 803 is reacted with from 5 to 30 (preferably 20) molar equivalents of hydrogen fluoride, in a mixture of water and a water-miscible organic εolvent (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 XXI, Step 4, a carbinol of Formula 803 iε converted to a halide (preferably a bromide) of Formula 804, by meanε of a one-step or a two-step procedure. In the one-step procedure, a carbinol of Formula 803 iε reacted with from 1.0 to 1.3 (preferably 1.1) molar equivalentε of a triaryl (preferably triphenyl) phosphine, and from 1.0 to 1.3 (preferably 1.1) molar equivalents of a halogen εource (εuch aε N-bromoεuccinimide or preferably carbon tetrabromide) . The reaction iε conducted in an inert εolvent (εuch as ether or preferably tetrahydrofuran) . The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 12 hourε (preferably 3 hours) to afford the corresponding halide of Formula 804. Alternatively, in the two-step procedure, which iε preferred, a carbinol of Formula 803 is converted firεt into a εulphonate eεter (εuch aε a p-toluenesulphonate or preferably a methanesulphonate) by reaction with from 1.0 to 1.5 (preferably 1.3) molar equivalentε a εulphonyl halide (preferably methaneεulphonyl chloride) in the presence of an equimolar amount of a tertiary organic base (preferably diisopropylethylamine) in a εolvent (εuch aε chloroform or preferably dichloromethane) . The reaction takeε place at -20 to 30°C (preferably 0°C) for 10 to 60 minuteε (preferably 30 minuteε) . The εo-obtained εulphonate eεter iε then reacted with from 5 to 20 (preferably 20) molar equivalentε of an alkali metal halide (preferably lithium bromide) in a εolvent (t-such aε 2-butanone or preferably acetone) . The reaction takeε place at 0 to 56°C (preferably at reflux) for 30 to 180 minuteε (preferably 90 minuteε) to afford the corresponding halide of Formula 804. Preparation of Formula 805 As illustrated in Reaction Scheme XXI, Step 5, a halogenated carbinol/alkyl ester of Formula 804 is deprotected at the phenolic group to give the corresponding halogenated carbinol/alkyl eεter of Formula 805. The deprotection reaction takeε place aε described above with reference to Reaction Scheme X, Step 1. Preparation of Formula IH Aε illuεtrated in Reaction Scheme XXI, Step 6, a halogenated carbinol/alkyl eεter of Formula 805 iε εubjected to a baεe-induced cyclization reaction to afford the product of Formula IH. A compound of Formula 805 iε reacted with from 2.0 to 2.5 (preferably 2.3) molar equivalentε of a εtrong baεe (εuch aε lithium diiεopropylamide, εodium hydride or preferably εodium hexamethyldiεilazide) in a εolvent (εuch aε dioxane or preferably tetrahydrofuran) . The reaction takeε place at -20 to 30°C (preferably at 0°C) for 5 to 60 minuteε (preferably 15 minuteε) to afford the correεponding cycloalkylester of Formula IH. The cycloalkyl ester of Formula I-ZH-A1 may then be hydrolyzed to give the corresponding acid of Formula IH. The hydrolysiε takeε place as deεcribed above with reference to Reaction Scheme X, Step 2. Compoundε of Formula 1 where Z iε a εidechain of Formula ZH in which D 4 iε O or 0-CΑ_, are preferably prepared aε deεcribed below in Reaction Scheme XXII. RΞACTION SCHEME XXII Formu la 806 Formula 807 Formu la 807 Formu la 808 q -Br Formu la BOB Formu la 809 q -Br Formu la B 10 Formu l a B10 Formula 1 H Preparation of Formula 807 As illustrated in Reaction Scheme XXII, Step 1, an aldehyde of Formula 302 (where Z~ 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. Amer. Chem. Soc , 103, 2121 , 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 diiεopropylamide or preferably di-n-butylboryl trifluoromethane εulphonate/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 correεponding acyloxazolidinone of Formula 807. Preparation of Formula 808 Aε illuεtrated in Reaction Scheme XXII, Step 2, an acyloxazolidinone of Formula 807 is 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 minuteε (preferably 30 minuteε) to give the correεponding carboxylic acid of Formula 808. Preparation of Formula 809 Aε illuεtrated in Reaction Scheme XXII, Step 3, a carboxylic acid of Formula 808 iε deprotected to give the corresponding phenol of Formula 809, using the method described with reεpect to Reaction Scheme X, Step 1. Preparation of Formula 810 A phenol of Formula 809 iε eεterified to give the correεponding eεter of Formula 810. A phenol of Formula 809 iε treated with methanol in the preεence of 0.05 to 0.2 (preferably 0.1) molar equivalentε of an acid catalyεt (preferably p-tolueneεulphonic acid) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 12 hours) to give the corresponding methyl eεter of Formula 810. Preparation of Formula IH A methyl eεter of Formula 810 undergoeε an intramolecular cyclization reaction to give the correεponding cyclized eεter of Formula IH. A methyl eεter of Formula 810 iε treated with 1.9 to 2.5 (preferably 2.0) molar equivalentε of a strong base (εuch aε lithium diiεopropylamide or preferably εodium hydride) in tetrahydrofuran (or preferably dimethylformamide) . The reaction takes place at -10 to 25°C (preferably 0°) for 1-12 hours (preferably 2 hours) to give the correεponding cyclized eεter of Formula IH, which may be hydrolyzed to give the correεponding acid of Formula IH, uεing the method deεcribed with reεpect to Reaction Scheme X, Step 2. Preparation of Esters of Formula 1 The eεterε of Formula 1 (compoundε where G iε not OH) can be prepared aε deεcribed in U.S. Patents Nos. 4,727,069 and 4,753,935, incorporated herein by reference, by deprotection of a precursor (e.g., as deεcribed with reference to Reaction Scheme X, Stepε 1) or aε deεcribed below by attachment of a leaving group and itε replacement by the deεired eεter. Preparation of Intermediates of Formula 6 The preparation of a compound of Formula 6 iε εhown in Reaction Scheme XXIII below. REACTION SCHEME XXIII Formula 1 Formula 2 Formula 2 Formula 3 Formula 3 Formula 4 Formu la 4 Formula 5 Formula 5 Formula 6 where Z" iε a εidechain of Formula Z aε defined in the Summary of the Invention in which G is lower alkoxy, and Z ~ is a sidechain of Formula Z as defined in the Summary of the Invention in which G is hydroxy. Preparation of Starting Materials The compound of Formula 1 (an eεter) may be prepared from the correεponding carboxylic acid by reaction with a large exceεε of an alcohol of the formula GH, where G iε lower alkoxy, preferably methanol, with a catalytic amount of an acid catalyεt, (εuch aε methaneεulfonic acid, εulfuric acid, hydrochloric acid and p-tolueneεulfonic acid) , preferably p-tolueneεulfonic acid) . The reaction iε carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 1 to 7 dayε, preferably about 24 hourε. The lower alkyl eεter of Formula 1 iε iεolated and purified by conventional meanε. Preparation of Compounds of Formula 2 As illustrated in Reaction Scheme XXIII, Step 1, an ester of Formula 1 is converted to the trifluoromethylεulfonyl compound of Formula 2. A compound of Formula l iε reacted in an organic εolvent, preferably dichloromethane, with about 1 to 3 molar equivalentε, preferably about 2 molar equivalentε, of a baεe, preferably pyridine, and with a εlight exceεε, preferably about 1.1 molar equivalentε, of a εulfonic anhydride, (εuch aε a halo lower alkyl εulfonic anhydride, halomethyl sulfonic anhydride, and haloεulfonic anhydride, or preferably trifluoromethane- εulfonic anhydride or fluoroεulfonic anhydride) or a sulfonyl halide, (such aε trifluoromethylεulfonyl bromide, preferably trifluoromethylεulfonyl chloride) . The reaction iε carried out in an inert εolvent, preferably dichloromethane, in the temperature range from about -20°C to 20°C, preferably at about 0°C, for about 15 to 45 minuteε, preferably about 30 minuteε. The trifluoromethylεulfonyl reaction product, a compound of Formula 2, iε iεolated and purified by conventional meanε. Preparation of Compounds of Formula 3 As illustrated in Reaction Scheme XXIII, Step 2, a trifluoromethylsulfonyl derivative of Formula 2 iε converted to the cyano compound of Formula 3. A compound of Formula 2 iε reacted with about 1 to 3 molar equivalentε, preferably about 1.85 molar equivalentε, of potaεεium cyanide with a catalytic amount of a triarylphoεphine palladium complex, preferably tetrakiε (triphenylphoεphine) palladium, in an organic εolvent, preferably 1,4-dioxane. The reaction iε carried out in the temperature range from about 70°C to 130°C, preferably at about the reflux temperature of 1,4- dioxane, for about 10 to 30 hourε, preferably about 18 hourε. The cyano reaction product, a compound of Formula 3, iε iεolated and purified by conventional means, preferably with extraction by an organic solvent and column chromatography. Preparation of Compounds of Formula 4 As illustrated in Reaction Scheme XXIII, Step 3, the cyano compound of Formula 3 is hydrolyzed to the carboxy compound of Formula 4. A compound of Formula 3 is hydrolyzed by reacting it with about 1 to 10 molar equivalents, preferably about 4 molar equivalents, of an inorganic base (e.g., εodium hydroxide, lithium hydroxide, or potaεεium hydroxide, preferably εodium hydroxide,) in a large exceεε of organic εolvent, preferably in about 3:2 water-.methanol solution. The reaction is carried out in the temperature range from about 40°C to 130°C, preferably at about the reflux temperature of the 3:2 water/methanol solvent, for about 1 to 3 hourε, preferably about 2 hourε. The reaction εolution iε diεtilled, and an additional of about 1 to 1.6 molar equivalentε, preferably about 1.3 molar equivalentε, of an inorganic base (e.g., sodium hydroxide, lithium hydroxide, or potasεium hydroxide, preferably εodium hydroxide,) iε added and the reaction iε continued in the temperature range from about 40°C to 130°C, preferably at about the reflux temperature of the remaining εolution, for about 1 to 3 dayε, preferably about 2 dayε. The reaction product, a compound of Formula 4, iε iεolated and purified by conventional meanε. Alternatively, the compound of Formula 4 may be prepared by reacting a correεponding compound of Formula 2 with a catalytic amount of 1,1' -biε (diphenylphoεphine)ferrocene palladium dichloride in a large exceεε of an alkanol (preferably methanol) in an organic εolvent (preferably dimethylformamide) with a εlight excess, preferably 1.01 molar equivalentε, of an organic baεe (preferably triethylamine) , under a carbon monoxide atmoεphere of increaεed pressure of about 400-1000 PSI, preferably at about 600 PSI. The reaction product, which iε a dieεter of a compound of Formula 4, iε then hydrolyzed by reacting it with about 1 to 10 molar equivalentε, preferably about 4 molar equivalentε, of an inorganic baεe, preferably aqueouε lithium hydroxide, in a large exceεε of an organic εolvent, preferably 4:1 methanol/water εolution. The εolution iε heated to a temperature range from about 30°C to 80°C, preferably from about 50°C to 60°C, for about 1 to 10 hourε, preferably for about 2 to 6 hourε. The reaction product, a compound of Formula 4, iε iεolated and purified by conventional means. Preparation of Compounds of Formula 5 As illustrated in Reaction Scheme XXIII, Step 4, a carboxy derivative of Formula 4 iε converted to the eεter of Formula 5. The compound of Formula 4 iε reacted in a large excess of a compound of the formula GH, where G iε lower alkoxy, preferably methanol, with catalytic amountε of an acid catalyεt, preferably p-tolueneεulfonic acid. The reaction iε carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 4 hourε to 3 dayε, preferably about 24 hourε. The reaction product, a 4-carboxy derivative of Formula 5, iε iεolated and purified by conventional means. Preparation of Compounds of Formula 6 As illustrated in Reaction Scheme XXIII, Step 5, a 4-carboxy derivative of Formula 5 is converted to the 4-iεocyanate derivative of Formula 6. A compound of Formula 5 iε reacted with about 1 to 3 molar equivalentε, preferably about 2 molar equivalentε, of an organic baεe, preferably triethylamine, in a large exceεε of an organic εolvent, preferably dimethylformamide, and about 1 to 2 molar equivalents, preferably about 1.3 molar equivalents, of an alkyl or phenyl haloformate or of a dialkyl or diphenyl halophoεphate, preferably diphenyl chlorophoεphate, in the temperature range from about -20°C to 20°C, preferably at about 0°C, allowing it to warm to the temperature range from about 0°C to 40°C, preferably at about 20°C, allowing the reaction to proceed for about 0.5 to 2 hourε, preferably about 1 hour. The reaction mixture iε recooled to the temperature range from about -20°C to 20°C, preferably at about 0°C, and a large exceεε of εodium azide iε added and the reaction proceedε for about 10 to 30 hourε, preferably about 18 hourε. The iεocyanato reaction product, a compound of Formula 6, iε iεolated and purified by conventional meanε. Alternatively, a compound of Formula 5 iε reacted with about 1 to 3 molar equivalentε, preferably about 2 molar equivalents, of an organic base, preferably triethylamine, in a large excesε of an organic εolvent, preferably dimethylformamide, and with a εlight exceεε, preferably 1.2 molar equivalentε, of a diphenyl or dialkyl phoεphoroazide, preferably diphenyl phoεphoroazide, in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 12 to 36 hourε, preferably for about 24 hourε. The iεocyanato reaction product, a compound of Formula 6, is iεolated and purified by conventional meanε. PREPARATION OF COMPOUNDS OF FORMULA I In the following Reaction Schemes, it should be noted that Z ~ representε a εidechain of Formula Z aε defined in the Summary of the Invention in which G iε lower alkoxy, and Z ~ repreεentε a εidechain of Formula Z aε defined in the Summary of the Invention in which G iε hydroxy. 1. Preparation of Compounds of Formula I where R 1 and R 2 are both Hydrogen Compoundε of Formula I where R 1 and R 2 are both hydrogen are depicted aε Formula IA: Formu I a iA The preparation of compoundε of Formula IA iε εhown in Reaction Scheme XXIV below. REACTION SCHEME XXIV Formu I a 6 Formu l a χ _\ Formu I a IA where Z ~ and Z ~ are aε defined above. Preparation of Formula IA where Z is Z b A compound of Formula 6 iε hydrolyzed with about 1 to 20 molar equivalentε, preferably 10 molar equivalentε, of an inorganic base, preferably lithium hydroxide monohydrate, in an inert organic solvent, preferably 3:10 water:1,4-dioxane. The reaction iε carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 1 to 3 hours, preferably about 2 hourε. The reaction product, a 4- amino compound of Formula IA where Z iε Z b , iε iεolated and purified by conventional meanε, preferably column chromatography. Preparation of Formula IA where Z is Z ~ A compound of Formula IA iε eεterified with a lower alkanol of formula GH, where G iε lower alkoxy, aε deεcribed in the preparation of a compound of Formula I as an eεter. Preparation of Compounds of Formula I where R 1 is Hydrogen and R 2 is -CtO ^ 5 Compoundε of Formula I where R 1 iε hydrogen and R 2 iε -C(0)NR 4 R 5 are depicted aε Formula IB: Formu l a IB The preparation of compoundε of Formula IB iε εhown in Reaction Scheme XXV below. REACTION SCHEME XXV For ula 6 Formula jβ Preparation of Formula IB where Z is Z" A compound of Formula 6 iε reacted with a large exceεε of an amine compound of the formula HNR 4 R 5 , where R 4 and R 5 are aε defined in the Summary of Invention, for example, methylamine, dimethylamine, methylphenylamine, ammonia, and the like, in an inert organic εolvent, preferably tetrahydrofuran. The reaction iε carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 30 minuteε to 2 hours, preferably about 1 hour. The reaction product, a 4- (optionally εubεtituted ureido) eεter of Formula IB iε iεolated and purified by conventional meanε. Preparation of Formula IB where Z is Z b An ester of Formula IB is hydrolyzed by reacting with about 1 to 10 molar equivalents, preferably about 4 molar equivalents of an inorganic baεe, preferably aqueouε lithium hydroxide, in a large exceεε of an organic εolvent, preferably 4:1 methanol/water. The εolution iε heated to a temperature range from about 30°C to 80°C, preferably from about 50°C to 60°C, for about 1 to 10 hourε, preferably for about 2 to 6 hourε. The reaction product, a 4- (optionally εubstituted ureido) acid compound of Formula IB, iε iεolated and purified by conventional means. Preparation of Compounds of Formula I where R 1 is Hydrogen and R 2 is -C(0)R 3 Compoundε of Formula I where R 1 iε hydrogen and R 2 iε -C(0)R 3 are depicted as Formula IC: For ula IC The preparation of compounds of Formula IC iε εhown in Reaction Scheme XXVI below. REACTION SCHEME XXVI Formula IA For ula IC Preparation of Compounds of Formula IC where Z is Z" A compound of Formula IA iε reacted in a large exceεε of an inert organic εolvent, preferably dichloromethane, with about 1 to 6 molar equivalentε, preferably about 2.5 molar equivalentε, of an anhydride compound of the formula (R 3 C(0)) 2 0 or of a acyl chloride of the formula R 3 C(0)C1, where R 3 iε aε defined in the Summary of the Invention. The reaction iε carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 30 minuteε to 2 hourε, preferably about 1 hour. The reaction product, a carbamate eεter of Formula IC, iε isolated and purified by conventional meanε, preferably by recryεtallization. Preparation of Formula IC where Z is Z b A compound of Formula IC aε an eεter iε hydrolyzed as deεcribed in the preparation of a compound of Formula IB to give the correεponding compound of Formula IC aε a carboxylic acid. Preparation of Compounds of Formula I where R 1 is Lower Alkyl and R 2 is -C(θ)R 3 Compounds of Formula I where R 1 is lower alkyl and R 2 is -C(0)R 3 are depicted aε Formula ID: Formu I a ID The preparation of compoundε of Formula ID is shown in Reaction Scheme XXVTI below. REACTION SCHEME XXVII Formula IC Formula ID Preparation of Formula ID wherein R 1 is Lower Alkyl and Z is Z" A compound of Formula IC is reacted with about 1 to 10 molar equivalents, preferably about 4.5 molar equivalents, of a weak baεe, preferably potaεεium carbonate, and with about 1 to 10 molar equivalentε, preferably about 4 molar equivalentε, of a lower alkyl bromide or iodide, preferably an iodide, in an inert organic εolvent, preferably dimethylformamide. The reaction iε carried out in the temperature range from about 0°C to 40°C, preferably at about 20°C, for about 12 to 48 hourε, preferably about 24 hourε. The organic layer iε purified to give a carbamate eεter of Formula ID where R 1 iε lower alkyl and G iε lower alkoxy. Preparation of Formula ID wherein R 1 is Lower Alkyl and Z is Z b A carbamate eεter of Formula ID where R 1 iε lower alkyl iε hydrolyzed aε deεcribed in the preparation of a compound of Formula IB to give the correεponding carboxylic acid of Formula ID where R l is lower alkyl. Preparation of Compounds of Formula I where R 1 is Lower Alkyl and R 2 is Hydrogen Compoundε of Formula I where R 1 iε lower alkyl and R 2 is hydrogen are depicted as Formula IE: Formu la IE The preparation of compounds of Formula IE iε εhown in Reaction Scheme XXVTII below. REACTION SCHEME XXVIII Formula ID - Formu I a IE Preparation of Formula IE where R 1 is Lower Alkyl and Z is Z An amido ester of Formula ID iε hydrolyzed by reacting with about 1 to 10 molar equivalentε, preferably about 4 molar equivalentε of an inorganic baεe (for example εodium hydroxide, preferably lithium hydroxide), in a large exceεε of an organic εolvent, preferably 4:1 methanol/water. The solution iε heated to a temperature range from about 50°C to 100°C, preferably from about 60°C to 80°C, for about 4 to 24 hourε, preferably for about 12 hourε. The reaction product, a 4-alkylamino acid compound of Formula IE, iε iεolated and purified by conventional meanε. Preparation of Compounds of Formula I where G is Lower Alkoxy, Lower Thioalkoxy, or -0- (CH_*) m -N-Y The compounds of Formula I where Z iε a εidechain aε defined in the Summary of the Invention in which G iε lower alkoxy, lower thioalkoxy, or - 0- (CH 2 ) m -N=G 3 (i.e., the eεter derivativeε) may be prepared from the correεponding compoundε of Formula I where G iε hydroxy (i.e. where Z is Z b ) , including compoundε of Formulae IA, IB, IC, ID, and IE, by conventional meanε, for example as deεcribed in the preparation of a compound of Formula 1 aε an eεter. Preferred Preparation of Esters of Formula I where G is -0- (CH 2 ) tn -N«Y In a preferred procedure, a compound of Formula I where G iε hydroxy iε eεterified with an heterocyclic aminoalkyl alcohol of the formula GH, where G iε -0- (CH 2 ) m -N=Y, in which m and Y are aε defined in the Summary of the Invention, by the direct eεterification procedure deεcribed in the pending application entitled "Direct Eεterification of Mycophenolic Acid", Serial No. 07/911635, filed July 10, 1992. In the direct eεterification route, an acid compound of Formula I where G iε hydroxy iε eεterified εlowly in a refluxing inert organic εolvent capable of azeotropic removal of water (εuch as toluene, xylene, or a mixture thereof) using only a slight excesε (between 1.01 to 1.20 molar equivalentε, and preferably, 1.05 to 1.06 molar equivalentε) of an heterocyclic aminoalkyl alcohol of the formula HO(CH 2 ) m -N=G 3 . Water generated by the reaction iε removed azeotropically. For example, with toluene aε the εolvent: 1) the reaction takeε place with (a) a reaction time of 20 to 120 hourε, preferably 50 to 100 hours and most preferably 100 hourε and (b) an initial pot temperature range of 114 to 120°C increaεing to a final pot temperature range of 118 to 130°C, preferably an initial pot temperature range of 115 to 118°C increaεing to a final pot temperature range of 118 to 125°C, each depending on εolute concentration and atmoεpheric pressure, and moεt preferably an initial pot temperature of 116°C increaεing to a final pot temperature of 121°C with a ratio of the acid compound of Formula I (where G iε hydroxy) to toluene of lgm:2ml at one atmoεphere of pressure. The reaction product, a compound of Formula I where Z is a εidechain aε defined in the Summary of the Invention in which G iε -O- (CH 2 ) m -N=G 3 , iε iεolated and purified by conventional meanε. Salts of Compounds of Formula I Some of the compounds of Formula I may be converted to corresponding base addition saltε by virtue of the presence of a carboxylic acid group. The conversion is accomplished by treatment with a εtoichiometric amount of an appropriate baεe, such as potasεium carbonate, εodium bicarbonate, ammonia, ethylenediamine, monoethanolamine, diethanolamine, triethanolamine and the like. Typically, the free acid iε diεεolved in a polar organic εolvent εuch aε ethanol, methanol or ethyl acetate, and the baεe added in water, ethanol, methanol or iεopropanol. The temperature iε maintained at about 0°C to 50°C. The reεulting εalt precipitateε εpontaneouεly or may be brought out of εolution with a leεε polar εolvent. The baεe addition εaltε of the compoundε of Formula I may be decompoεed to the correεponding free acids by treating with at least a stoichiometric amount of a suitable acid, such aε hydrochloric acid or sulfuric acid, typically in the presence of aqueous εolvent, and at a temperature of between about 0°C and 50°C. The free acid form iε iεolated by conventional meanε, εuch as extraction with an organic solvent. By virtue of the presence of an amine group in the 4-position or in the group G, some of the compoundε of Formula I may be converted to the acid addition εaltε by the subεtitution of an organic or inorganic acid for the baεe in the above procedure. The acid εaltε can be decompoεed to the correεponding free baεeε by εimilar treatment with an appropriate baεe. Preferred Processes In εummary, compoundε of Formula I are prepared according to the following laεt εtepε: A proceεε for preparing compoundε of Formula I: wherein: R 1 iε hydrogen or lower alkyl; R 2 iε hydrogen, lower alkyl, -C(0)R 3 , -C(0)NR*R 5 , -C0 2 R 6 , or -S0 2 R 3 where: R 3 iε hydrogen, lower alkyl, halo lower alkyl or optionally εubεtituted phenyl; R 4 iε hydrogen, lower alkyl or optionally εubεtituted phenyl; R 5 iε hydrogen, lower alkyl or optionally substituted phenyl; R 6 is lower alkyl or optionally subεtituted phenyl; and Z iε a εide 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 13 , where Z 13 iε aryl or heteroaryl; Z 3 iε H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, P(0) (OCH 3 ) 2 , -P(O) (OH) (0CH 3 ) , or -S(0) m Z' 2 , where Z 12 iε lower alkyl, and m is 0, 1 or 2; Z 4 iε 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 atomε; and G iε OH, lower alkoxy, lower thioalkyl, -NG'G 2 , -0(CH 2 ) n NG 1 G 2 , or - 0(CH 2 ) n N=G 3 , where n iε an integer from 1 to 6, G 1 iε H or lower alkyl, G 2 iε H or lower alkyl, and =G 3 iε lower alkylene of four to six carbon atomε, or lower alkylene of three to five carbon atomε pluε one member that iε -0-, -S-, or -N(G 4 )- where G 4 iε H or lower alkyl; provided that when Z 1 iε methyl, Z 2 , Z 3 and Z 4 are not all H; or Formula ZB wherein: Z ~ iε H or lower alkyl; Z ~ iε H or lower alkyl; D 1 and D 2 together with their adjacent carbon atomε form an optionally εubεtituted, εaturated or unεaturated carbocyclic or heterocyclic ring of 3 to 7 atomε; and G iε aε defined above; or Formula ZC wherein: Z 5 , Z ~ , and G are as defined above; or Formula ZD wherein: D 3 iε -CH 2 - or -CHjCHz-; and G iε aε defined above; or Formula ZE wherein: Z ~ iε H, lower alkyl, lower alkoxy, -COOH, -NH 2 or halo; Z 7 iε H, lower alkyl, lower alkoxy or halo; and Z ~ and G are aε defined above; or Formula ZF wherein: Z 1 and G are aε defined above; or Formula ZG wherein: D 3 , Z 2 , Z 3 , Z 4 and G are aε defined above; or Formula ZH wherein: D 4 iε -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -0-, or -OCH 2 -; and Z 1 and G are aε defined above; and the pharmaceutically acceptable εaltε thereof; which comprises: a) reacting a compound of Formula I, wherein G iε lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH 2 ) n -NG'G 2 , or -0- (CH 2 ) n -N=G 3 , in which n, G 1 , G 2 , and G 3 are as defined above; with an inorganic base, to form a compound of Formula I wherein G is hydroxy; or b) reacting a compound of Formula I wherein G is hydroxy, with a compound of the formula GH, where G is lower alkoxy, lower thioalkyl, NG'G 2 , 0- (CH 2 ) n -NG'G 2 , or 0- (CH 2 ) n -N=G 3 , in which n, G 1 , G 2 , and G 3 are as defined above, to form a compound of Formula I wherein G is lower alkoxy, lower thioalkyl, NG'G 2 , 0- (CH 2 ) n -NG 1 G 2 , or 0- (CH 2 ) n -N=G 3 , in which n, G 1 , G 2 , and G 3 are aε defined above; or c) reacting a compound of Formula I wherein R 1 iε hydrogen, R 2 iε - C(0)R 3 wherein R 3 iε hydrogen, and G iε lower alkoxy, with a compound of the formula HNG'G 2 , where G 1 and G 2 are aε defined above, to form a compound of Formula I wherein G 1 and G 2 are aε defined above; or d) reacting a compound of Formula I wherein R 1 and R 2 are hydrogen, with a compound of the formula (R 3 C(0)) 2 0 or R 3 C(0)C1, to form a compound of Formula I wherein R 2 iε -C(0)R 3 wherein R 3 iε lower alkyl, halo lower alkyl or optionally substituted phenyl; or e) reacting a compound of Formula I wherein R 1 iε hydrogen, R 2 is -C(0)R 3 , where R 3 is lower alkyl, halo lower alkyl or optionally εubεtituted phenyl, and G iε lower alkoxy, with a compound of the formula R'X, where R 1 iε lower alkyl and X iε iodine or bromine, to form a compound of Formula I wherein R 1 iε lower alkyl; or f) reacting a compound of Formula I to form a pharmaceutically acceptable εalt of that compound; or g) reacting a εalt of Formula I to form the corresponding free compound of Formula I; or h) converting a pharmaceutically acceptable salt of a compound of Formula I to another pharmaceutically acceptable εalt of a compound of Formula I. Preferred Compounds Among the family of compoundε of the preεent invention, one preferred category includeε the compoundε where Z iε a εidechain of Formula ZA. Within thiε category a preferred group includeε the compounds where Z 1 iε hydrogen, eεpecially where R 1 is hydrogen and R 2 iε hydrogen or -C(0)R 3 . Within thiε group a preferred εubgroup includeε the compoundε where R 2 , Z 2 and Z 3 are all hydrogen, eεpecially where Z 4 iε methyl. Another preferred εubgroup includeε the compoundε where R 2 , Z 3 and Z 3 are all hydrogen, eεpecially where Z 2 iε methyl. Another preferred category includeε the compoundε where Z iε a εidechain of Formula ZB, eεpecially where R 1 iε hydrogen and R 2 iε hydrogen or -C(0)R 3 . Within this category a preferred group includes the compoundε where D 1 and D 2 together with the their adjacent carbon atomε form a εaturated carbocyclic ring of 5 or 6 carbon atomε. Within thiε group a preferred εubgroup includes the compounds where D 1 and D 2 together represent -CH 2 CH 2 CH 2 -, especially where Z ~ and Z ~ are both hydrogen. A preferred clasε within thiε εubgroup includeε the compoundε in which R' and R 2 are both hydrogen. Another preferred εubgroup includeε the compounds where D' and D 2 together represent -CB-CH j CH-CI^-, especially where Z~ and Z ~ are both hydrogen. A preferred claεs within thiε εubgroup includeε the compoundε in which R' and R 2 are both hydrogen. Yet another preferred εubgroup includes the compoundε where D 1 and D 2 together repreεent -CH 2 CH 2 OCH 2 -, especially where Z 5 and Z ~ are both hydrogen. A preferred claεε within thiε subgroup includeε the compoundε in which R 1 and R 2 are both hydrogen. At preεent, the moεt preferred compoundε are: (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (S) ,4-dimethyl-4-hexenoic acid; (E) -6- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -3 (S) ,4-dimethyl-4-hexenoic acid; (E) -2- [2- [2- [4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]cyclopent-1(S) -yl]acetic acid; and (E)-2-{4-[2- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (S) -yl}acetic acid. Utility, Testing and Administration General Utility The compoundε of the preεent invention, the pharmaceutically acceptable εaltε thereof and pharmaceutical co poεitionε therewith (collectively the "compoundε" for purpoεes of the following deεcription) are uεeful aε immunoεuppreεεive agentε, anti-inflammatory agentε, anti- tu or agentε, anti-proliferative agentε, anti-viral agentε and anti- pεoriatic agentε in mammals, whether domestic (cattle, pigs, εheep, goatε, horεeε) , petε (catε, dogε) , or preferably humans. The compoundε are inhibitors of inosine monophosphate dehydrogenase (IMPDH) and thus inhibit de novo purine εyntheεiε; they have anti-proliferative effectε (e.g., againεt εmooth muscle cells and both B and T lymphocytes) and inhibit antibody formation and the glycosylation of cell adheεion moleculeε in lymphocytes and endothelial cells. Aε immunoεuppreεεive agentε, the compoundε are uεeful in treating auto-immune related diεorderε, for example: Type I Diabeteε Mellituε; Inflammatory Bowel Diεeaεe (e.g., Crohn'ε Diεeaεe and ϋlcerative Colitiε) ; Syεtemic Lupuε Erythematoεuε; Chronic Active Hepatitiε; Multiple Scleroεiε; Grave'ε Disease; Hashimoto'ε Thyroiditiε; Behcet'ε Syndrome; Myaεthenia Gravis; Sjogren's Syndrome; Perniciouε Anemia; Idiopathic Adrenal Insufficiency; and Polyglandular Autoimmune Syndromes Type I and II. The compoundε are alεo uεeful aε therapeutic immunoεuppreεsive agents in the treatment of Asthma, Immunohemolytic Anemia, Glomerulonephritis, and Hepatitis. Preventative uεeε of the compounds as immunosuppreεεive agentε include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, εkin and corneal allografts, and prevention of Graft vε. Hoεt Diεeaεe. The compounds are useful for inhibiting proliferative reεponεeε to vaεcular injury, for example, εtenoεiε following an insult to a blood veεεel wall in poεt-angioplaεty reεtenoεiε, and poεt-cardiac by-paεε εurgery reεtenoεiε. The compoundε are uεeful aε anti-inflammatory agentε, for example, in treating Rheumatoid Arthritiε, Juvenile Rheumatoid Arthritiε and Uveitiε. Aε anti-tumor agentε, the compoundε are uεeful in treating εolid tumorε and malignancieε of lymphoreticular origin. For example, the compound ' 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 syεtem, 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; cancerε of the genitourinary εystem, 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 syεtem cancer; εoft tiεεue sarcomas; malignant mesotheliomaε; εkin cancer, including εquamous cell carcinoma, basal cell carcinoma and melanoma; cancer of the central nervous εyεtem; malignant bone tumorε; and plaεma cell neoplaεms. Aε anti-tumor agentε for the treatment of malignancieε of lymphoreticular origin, the compoundε are uεeful in treating, for example: Lymphomaε and Leukemiaε, including B, T and promonocyte cell line malignancieε, Mycoses Fungoideε, Non-Hodgkins Lymphoma, Malignancies of Burkitt Lymphoma Cells and other EBV-transformed B-lymphocyteε, Lymphomaε reεulting from Epεtein-Barr viral infectionε in allograft recipientε, Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and Hairy Cell Leukemia. Aε anti-viral agentε, the compoundε are useful in treating, for example: retroviruεeε, including Human T-leukemia Viruεeε, Types I and II (HTLV-1 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-lymphocyteε, CMV infection, Herpeε Viruε Type 6, Herpeε Simplex, Typeε 1 and 2, (HSV-1, HSV-2) and Herpeε Zoεter. As anti-psoriatic agentε, the compoundε are uεeful in treating, for example, pεoriaεiε and pεoriatic arthritiε. Testing Activity teεting iε conducted aε deεcribed in the following referenceε, and by modificationε thereof. General anti-inflammatory, anti-viral, anti-tumor, anti-pεoriatic and/or immunoεuppressive activity iε aεεociated with the inhibition of Inoεine 5' -Monophoεphate Dehydrogenaεe ("IMPDH"). In vitro assayε 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 εcreening teεts to determine anti-inflammatory activity potential include the adjuvant arthritis asεay, e.g., according to the method of Pearεon, Proc Soc Exp. Biol . Med. , 91:95-101 (1956). Alεo, in vitro teεtε, for example thoεe uεing εynovial explantε from patients with rheumatoid arthritis, Dayer, et al., J. Exp. Med. , 145:1399-1404 (1977) , are uεeful 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 deεcribed by Grieg, et. al., J. Pharmacol . Exp. Ther. , 173:85 (1970) . Human clinical trialε for efficacy in the treatment of aεthma are conducted, e.g., aε deεcribed by Erzurum, Leff, Cochran, et al. "Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double- blind, placebo controlled εtudy." Ann. Int . Med. , 114:353-360 (1991). Activity to prevent the rejection of organ or tiεεue allograftε in experimental animals iε determined, for example, aε deεcribed 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 levels. Human clinical trialε to establish efficacy in preventing rejection of εolid organ transplants (such aε renal) are conducted, e.g., aε deεcribed by Lindholm, Albrechtεen, Tufveson, et al., "A randomized trial of cycloεporin and predniεolone versus cyclosporin, azathioprine and predniεolone in primary cadaveric renal tranεplantation, " Transplantation, 54:624-631 (1992). Human clinical trials for graft vs. host diseaεe are conducted, e.g., aε deεcribed by Storb, Deeg, Whitehead, et al. , "Methotrexate and cycloεporin compared with cycloεporin alone for prophylaxiε of acute graft verεuε host diεease after marrow tranεplantation for leukemia." New England J. Med. , 314:729-735 (1986). Immunoεuppreεεive 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 aεεay, [Jerne, et al. , "The agar plaque technique for recognizing antibody producing cellε," Cell -bound Antibodies, Amoε, B. and Kaprowεki, H. editors (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 mitogenε," Nature, 248:698-701 (1974). Anti-viral activity iε determined, for example, by the procedure deεcribed by Smee, et al. ["Anti-Herpeεviruε Activity of the Acyclic Nucleoεide 9- (l,3-Dihydroxy-2-Propoxymethyl)Guanine, " Antimicrobial Agentε and Chemotherapy, 23 (5) :676-682 (1983)], or aε deεcribed 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 transcriptase activity, for example, according to the method described by Chen et al., Biochem. Pharm. , 36:4361 (1987). Human clinical trials for anti-HIV efficacy (together with clinical treatment εcenarioε) 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., as deεcribed by Volberding, P.A., et al. "Zidovudine in aεymptomatic human immunodeficiency viruε infection: a controlled trial in perεonε with fewer than 500 CD4 poεitive cellε per cubic millimeter, " New England J. Med., 322 (14) :941-949 (1990). A smaller εcale (Phaεe I) clinical trial can be conducted, e.g., aε deεcribed by Browne, et al., "2 ' ,3' -Didehydro-3' - deoxythymidine (d4T) in Patientε with AIDS or AIDS-Related Complex: A Phaεe I Trial," J. Infectious Diseases, 167:21-29 (1993). Teεtε for εyεtemic activity in pεoriaεiε can be carried out, for example, aε deεcribed by Spatz, et al., "Mycophenolic acid in pεoriaεiε," Bri tish Journal of Dermatology, 98:429 (1978) . Teεtε for anti-tumor activity can be performed, for example, aε deεcribed by Carter, et al. ["Mycophenolic acid: an anticancer compound with unuεual propertieε," Nature, 223:848 (1969)]. In vitro activity for treating εtenoεiε iε demonεtrated, for example, by inhibiting the proliferation of εmooth muεcle cellε, aε eεtabliεhed by the following human arterial εmooth muεcle cell proliferation aεεay. Human εmooth muεcle cellε are grown in culture. A teεt group iε treated with the teεt compound added at εelected concentrationε in freεh media. Both groupε receive 2μCi tritiated thymidine ( 3 HTdR) , a radioiεotope label. After 24 hourε, the cellε are harveεted and the amount of label incorporated into DNA iε counted by εcintillation; thiε iε compared for the teεt and control groupε, the amount being proportional to cell proliferation. Inhibition of εmooth muεcle proliferation is establiεhed when the teεt group haε a lower radioiεotope count than the control group. The concentrationε of teεt compound required to inhibit proliferation by 50% (the ICy,) , and to inhibit proliferation by more than 95% are determined. In vivo activity for treating εtenoεiε is demonstrated, for example, in rat and pig models for arterial εtenoεiε. In the rat model, a teεt group iε treated with the teεt compound, εtarting 6 days before and continuing for 14 dayε after injury to the left carotid artery; the teεt group iε 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 εection of the left artery. The right artery iε left intact. Arterial croεε-εectionε (10 μm) are taken from both the left and right arterieε of each εubject, and the area of the veεεel wall (endothelium, intima, media) iε meaεured, The amount of vaεcular 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 established when the test group shows less proliferation than the control group. Human clinical trialε for reεtenoεis after coronary angioplasty are conducted, e.g., aε deεcribed by Serruyε, Rutεch, Heyndrickx, et al., "Prevention of reεtenoεiε after percutaneouε transluminal coronary antioplaεty with thromboxane A 2 -receptor blockade: a randomozed, double- blind, placebo-controlled trial." Circulation, 84:1568-80 (1991). Administration The compoundε of Formula I are administered at a therapeutically effective dosage, e.g., a doεage εufficient to provide treatment for the diεeaεe εtateε previouεly deεcribed. Administration of the compounds of the invention or the pharmaceutically acceptable εaltε thereof can be via any of the accepted modeε of adminiεtration for agentε that εerve similar utilitieε. The compoundε can be uεed both prophylactically (e.g., to prevent allograft rejection) and therapeutically. While human doεage levels have yet to be optimized for the compoundε of the invention, generally, a daily doεe 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 most preferably about 0.3 to 43.0 mg/kg of body weight. Thus, for administration to a 70 kg person, the doεage range would be about 0.7 mg to 7 g per day, preferably about 7.0 mg to 4.5 g per day, and most preferably about 21 mg to 3.0 g per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of adminiεtration (e.g., oral adminiεtration one day prior to cancer chemotherapy and intravenouε adminiεtration during cancer chemotherapy) and the judgment of the preεcribing phyεician. In employing the compoundε of thiε invention for treatment of the above conditionε, any pharmaceutically acceptable mode of adminiεtration can be uεed. The compoundε of Formula I can be adminiεtered either alone or in combination with other pharmaceutically acceptable excipientε, including εolid, εemi-εolid, liquid or aeroεol doεage formε, such aε, for example, tablets, capεuleε, powderε, liquids, injectables, suspenεionε, εuppoεitorieε, aerosols or the like. The compounds of Formula I can also be administered in suεtained or controlled release dosage forms, including depot injections, osmotic pumps, pills, tranεdermal (including electrotranεport) patcheε, and the like, for the prolonged adminiεtration of the compound at a predetermined rate, preferably in unit doεage formε εuitable for εingle adminiεtration of preciεe doεageε. The compoεitionε will typically include a conventional pharmaceutical carrier or excipient and a compound of Formula I or a pharmaceutically acceptable εalt thereof. In addition, theεe compositionε may include other medicinal agentε, pharmaceutical agentε, carriers, adjuvants, etc., εuch aε multidrug reεiεtance modifying agentε, εteroidε, immunoεuppressantε εuch aε cycloεporine A, azathioprene, rapamycin, FK-506, brequinar, leflunomide and vincryεtine. 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 salt of Formula I, the remainder being εuitable pharmaceutical excipientε, carrierε, etc. One preferred manner of adminiεtration 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 compoεition iε formed by the incorporation of any of the normally employed excipientε, εuch aε, for example, mannitol, lactoεe, εtarch, povidone, magneεium εtearate, εodium εaccharine, talcum, celluloεe, croεcarmelloεe εodium, glucoεe, gelatin, εucroεe, magneεium carbonate, and the like. Such compoεitionε take the form of εolutions, suεpenεionε, tablets, diεperεible tablets, pills, capεuleε, powderε, εuεtained releaεe formulationε and the like. Preferably the compoεitionε will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent εuch aε lactoεe, εucroεe, dicalcium phoεphate, or the like; a lubricant εuch aε magneεium εtearate or the like; a diεintegrant εuch aε croscarmellose sodium or the like; and a binder such as εtarch, gum acacia, polyvinylpyrrolidine, gelatin, celluloεe and derivativeε thereof, and the like. Liquid pharmaceutically adminiεtrable compoεitionε can, for example, be prepared by diεεolving, diεperεing, etc. an active compound aε defined above and optional pharmaceutical adjuvantε in a carrier, εuch aε, for example, water, εaline, aqueouε dextroεe, glycerol, glycolε, ethanol, and the like, to thereby form a εolution or εuεpenεion. If deεired, the pharmaceutical compoεition to be adminiεtered may alεo contain minor amountε of nontoxic auxiliary substances εuch aε wetting agentε, suspending agentε, emulεifying agentε, or εolubilizing agentε, pH buffering agentε and the like, for example, εodium acetate, εodium citrate, cyclodextrine derivatives, polyoxyethylene, εorbitan monolaurate or εtearate, etc. Actual methodε of preparing εuch doεage formε are known, or will be apparent, to thoεe skilled in this art; for example, εee Remington 's Pharmaceutical Sciences, Mack Publiεhing Company, Eaεton, Pennεylvania, 15th Edition, 1975. The compoεition or formulation to be adminiεtered will, in any event, contain a quantity of the active compound in an amount effective to alleviate the symptomε of the εubject being treated. Doεage forms or compositionε 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 adminiεtration, a pharmaceutically acceptable compoεition iε formed by the incorporation of any of the normally employed excipientε, εuch aε, for example pharmaceutical gradeε of mannitol, lactoεe, εtarch, magneεium εtearate, talcum, povidone, celluloεe derivativeε, croεcarmelloεe εodium, glucoεe, sucrose, magnesium carbonate, sodium εaccharin, talcum and the like. Such compoεitionε take the form of εolutionε, εuεpenεionε, tablets, capsuleε, powderε, εuεtained releaεe formulationε and the like. Such compoεitionε may contain 0.01%-95% active ingredient, preferably 0.1-50%. For a εolid doεage form containing liquid, the εolution or εuεpenεion, in for example propylene carbonate, vegetable oilε or triglycerideε, iε preferably encapεulated in a gelatin capεule. Such eεter εolutionε, and the preparation and encapεulation thereof, are diεcloεed 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 εemi-εolid oral formulationε may be prepared by diεεolving or diεperεing the active compound or εalt in vegetable oilε, glycolε, triglycerideε, propylene glycol eεterε (e.g. propylene carbonate) and the like, and encapεulating theεe εolutionε or εuεpenεionε in hard or εoft gelatin capεule shells. Other useful formulations include those εet forth in U.S. Patentε Noε. Re. 28,819 and 4,358,603. Parenteral adminiεtration iε generally characterized by injection, either εubcutaneouεly, intramuεcularly or intravenouεly. Injectableε can be prepared in conventional forms, either as liquid solutions or suεpenεionε, εolid formε εuitable for εolution or εuεpenεion in liquid prior to injection, or aε emulεionε. Suitable excipientε are, for example, water, εaline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compoεitionε to be adminiεtered may alεo contain minor amountε of non-toxic auxiliary εubεtanceε εuch aε wetting or emulsifying agentε, pH buffering agentε, εolubility enhancerε, and the like, εuch aε for example, εodium acetate, polyoxyethylene, εorbitan monolaurate, triethanolamine oleate, cyclodextrinε, etc. A more recently devised approach for parenteral administration employε the implantation of a εlow-releaεe or εuεtained-releaεe εyεtem, εuch that a conεtant level of doεage iε maintained. See, e.g., U.S. Patent No. 3,710,795. The percentage of active compound contained in εuch parenteral compoεitionε iε highly dependent on the εpecific nature thereof, aε well aε the activity of the compound and the needε of the εubject. However, percentageε of active ingredient of 0.01% to 10% in εolution are employable, and will be higher if the compoεition iε a εolid which will be εubεequently diluted to the above percentageε. Preferably the compoεition will compriεe 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 aeroεol or εolution for a nebulizer, or aε a microfine powder for insufflation, alone or in combination with an inert carrier εuch aε lactoεe. In εuch a case, the particles of the formulation have diameters of leεε than 50 micronε, preferably leεε than 10 micronε. EXAMPLES The following exampleε are given to enable thoεe εkilled in the art to more clearly underεtand and to practice the preεent invention. They εhould not be conεidered aε limiting the εcope of the invention, but merely aε being illuεtrative and repreεentative thereof. PREPARATION 1 Preparation of Compoundε of Formula 1 IA. Preparation of 1 where Z iε ZA, in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hvdroσen. and G iε Methoxy A εolution of 15.1 g (47.1 mmol) of (E) -6- (1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid (mycophenolic acid) and 0.7 g (3.7 mmol) of p-tolueneεulfonic acid in 400 ml of methanol waε allowed to εtand at room temperature for 3 dayε. The mixture waε concentrated under reduced pressure to approximately 75 ml and then partitioned between aqueous εodium bicarbonate and ethyl acetate. The organic phaεe waε further washed with brine and then dried over sodium εulfate. Concentration of the organic phaεe under reduced preεεure gave 15.4 g (46.0 mmol, 98%) of methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate as a white εolid, mp 104-105°C. IB. Preparation of 1. varying Z Similarly, following the procedureε of Preparation IA above, but replacing (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoιsobenzofuran-5-yl) - -methyl-4-hexenoic acid with: (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (RS) ,4-dimethyl-4-hexenoic acid; (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (R) ,4-dimethyl-4-hexenoic acid; (E) -6- (1,3-dihydro- -hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (S) ,4-dimethyl-4-hexenoic acid; (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -3 (RS) ,4-dimethyl-4-hexenoic acid; (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yl]acetic acid; (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1(RS) -yl]acetic acid; (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1 (S) -yl]acetic acid; and (E)-2-{4-[2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (RS) -yljacetic acid; and optionally replacing methanol by ethanol, the following intermediates of Formula 1 were prepared: ethyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) - (RS) ,4-dimethyl-4-hexenoate, mp 59-63°C; methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (R) ,4-dimethyl-4-hexenoate; methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (S) ,4-dimethyl-4-hexenoate; methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3 (RS) ,4-dimethyl-4-hexenoate; methyl (E) -2- [2- [2- [1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yl]acetate; methyl (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]cyclohex-1(RS) -yl]acetate, mp 92-99°C; ethyl (E) -2- [2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1(S) -yl]acetate, mp 72-74°C; and methyl (E) -2-{4- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (RS) -yl}acetate. IC. Preparation of 1. varying Z Similarly, following the procedureε of Preparation IA above, but optionally replacing (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid with other compoundε of Formula (1) where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε hydroxy, and optionally replacing methanol with other alkanolε of formula GH, where G iε lower alkoxy, other intermediates of Formula 1 in which Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, are prepared. PREPARATION 2 Preparation of Compounds of Formula 2 2A. Preparation of 2 where Z is ZA. in which Z' is Methyl. Z 2 . Z 3 , and Z 4 are Hydrogen, and G is Methoxy To a 0°C solution of 4.59 g (13.7 mmol) of methyl (E) -6- (1,3-dihydro- 4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate and 2.22 ml (27.4 mmol) of pyridine in 100 ml of methylene chloride waε added 2.55 ml (15.1 mmol) of trifluoromethaneεulfonic anhydride dropwiεe. After 30 minuteε, the reaction mixture waε poured into IN aqueouε sodium hydrogen εulf te. Thiε mixture waε extracted with dichloromethane, and the organic phase was further washed with water and brine. The organic phase waε dried over magneεium εulfate and concentrated under reduced preεεure. Trituration of the reεidue with hexane gave 5.7 g of methyl (E)-6-(l,3- dihydro-6-methoxy-7-methyl-4-trifluoromethylεulfonyloxy-3-oxoiεobenzofuran- 5-yl) -4-methyl-4-hexenoate as a white εolid, mp 53-55°C. 2B. Preparation of 2, varying Z Similarly, following the procedureε of Preparation 2A above, but replacing methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 1, the following intermediateε of Formula 2 were prepared: ethyl (E) -6- (1,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoiεobenzofuran-5-yl) -2 (RS) ,4-dimethyl-4- hexenoate, oi1; methyl (E) -6- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoiεobenzofuran-5-yl) -2 (R) , -dimethyl-4- hexenoate; methyl (E) -6- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoisobenzofuran-5-yl) -2(S) , -dimethyl-4- hexenoate; methyl (E) -6- (1,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoisobenzofuran-5-yl) -3 (RS) ,4-dimethyl-4- hexenoate; ethyl (E) -2- [2- [2- [l,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoiεobenzofuran-5-yl]ethylidene]cyclopent- 1 (S) -yl]acetate, oil; methyl (E) -2- [2- [2- [1,3-dihydro-6-methoxy-7-methyl-4- trifluoro ethylsulfonyloxy-3-oxoiεobenzofuran-5-yl]ethylidene] cyclohex- 1 (RS) -yl]acetate, oil; ethyl (E) -2- [2- [2- [1,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylsulfonyloxy-3-oxoisobenzofuran-5-yl]ethylidene]cyclohex- 1(S) -yl]acetate, oil; and methyl (E) -2-{4- [2- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoiεobenzofuran-5- yl)ethylidene]tetrahydropyran-3 (RS) -yl}acetate. 2C. Preparation of 2. varying Z Similarly, following the procedureε of Preparation 2A above, but replacing methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate with other compounds of Formula 1 where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy, other intermediateε of Formula 2 are prepared. PREPARATION 3 Preparation of Compoundε of Formula 3 3A. Preparation of 3 where Z iε ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Methoxy A nitrogen-flushed mixture of 5.8 g (12.4 mmol) of methyl (E)-6-(l,3- dihydro-6-methoxy-7-methyl-4-trifluoromethyl-sulfonyloxy-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate, 1.5 g (23.0 mmol) of potaεεium cyanide, and 1.11 g (0.96 mmol) of tetrakiε(triphenylphoεphine) palladium in 100 ml of 1,4-dioxane waε heated at reflux for 18 hourε. Upon cooling, the mixture waε partitioned between water and ethyl acetate. The organic phaεe waε waεhed with water εix timeε, with brine once, and then dried over magneεium εulfate. The εolvent waε evaporated under reduced preεεure and the reεulting solid was stirred with hexane for 18 hourε and then filtered off. Thiε εolid waε further purified by εilica gel chromatography uεing 5:4 hexane:ethyl acetate to give 4.0 g (11.7 mmol) of methyl (E)-6-(4- cyano-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4- hexenoate, mp 87-88°C. 3B. Preparation of 3. varying Z Similarly, following the procedureε of Preparation 3A above, but replacing methyl (E) -6- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 2, the following intermediateε of Formula 3 were prepared: ethyl (E) -6- (4-cyano-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (RS) ,4-dimethyl-4-hexenoate, mp 63-66°C; methyl (E) -6- (4-cycmo-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (R) ,4-dimethyl-4-hexenoate; methyl (E) -6- (4-cyano-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (S) ,4-dimethyl-4-hexenoate; methyl (E) -6- (4-cyano-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3 (RS) ,4-dimethyl-4-hexenoate; ethyl (E) -2- [2- [2- [4-cyano-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]cyclopent-1(S) -yl]acetate, oil; methyl (E) -2- [2- [2- [4-cyano-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]cyclohex-1(RS) -yl]acetate, mp 150-151°C; ethyl (E) -2- [2- [2- [4-cyano-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1(S) -yl]acetate, mp 126-128°C; and methyl (E) -2-{4- [2- (4-cyano-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (RS) -yl}acetate. 3C. Preparation of 3. varying Z Similarly, following the procedures of Preparation 3A above, but replacing methyl (E) -6- (l,3-dihydro-6-methoxy-7-methyl-4- trifluoromethylεulfonyloxy-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 2, where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy, other intermediateε of Formula 3 are prepared: PREPARATION 4 Preparation of Compoundε of Formula 4 4A. Preparation of 4 where Z iε ZA. in which Z 1 iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Hvdroxy A mixture of 4.0 g (11.7 mmol) of methyl (E) -6- (4-cyano-1,3-dihydro- 6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate and 1.86 g (46.5 mmol) of εodium hydroxide in 100 ml of 3:2 water:methanol waε heated at reflux for 2 hourε. The reεulting homogenouε εolution waε diεtilled until 30 ml of diεtillate waε recovered. An additional 0.6 g (15 mmol) of εodium hydroxide waε added to the reaction solution and it was refluxed for 2 dayε. Upon cooling the εolution waε partitioned between IN aqueous HC1 and ethyl acetate. The organic phase was washed twice with water, once with brine, and then dried over magnesium sulfate. The εolvent waε evaporated under reduced preεεure to give a solid. Thiε εolid waε εtirred with hexane and then filtered off to give 3.88 g (11.1 mmol) of (E)-6-(4- carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4- hexenoic acid as a white solid, mp 172-174°C. 4B. Preparation of 4. varying Z Similarly, following the procedureε of Preparation 4A above, but replacing methyl (E) -6- (l,3-dihydro-4-cyano-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 3, the following intermediateε of Formula 4 were prepared: (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2(RS) ,4-dimethyl-4-hexenoic acid, mp 149-150 β C; (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2 (R) ,4-dimethyl-4-hexenoic acid; (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- y1) -2 (S) ,4-dimethyl-4-hexenoic acid; (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -3 (RS) ,4-dimethyl-4-hexenoic acid; (E) -2- [2- [2- [4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yl]acetic acid, mp 142- 148°C; (E) -2- [2- [2- [4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]cyclohex-1(RS) -yl]acetic acid, mp 194- 195°C; (E) -2- [2- [2- [4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1(S) -yl]acetic acid, mp 193- 197°C; and (E) -2-{4- [2- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (RS) -yl}acetic acid. 4C. Preparation of 4. varying Z Similarly, following the procedureε of Preparation 4A above, but replacing methyl (E) -6- (4-cyano-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate with other compounds of Formula 3 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy, other intermediates of Formula 4 where G iε hydroxy are prepared. PREPARATION 5 Preparation of Compounds of Formula 5 5A. Preparation of 5 where Z is ZA. in which Z 1 iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Methoxy A εolution of 3.88 g (ll.l mmol) of (E) -6- (4-carboxy-1,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl- -hexenoic acid and 0.2 g (1.0 mmol) of p-tolueneεulfonic acid in methanol (60 ml) waε εtirred at room temperature for 8 hourε. The εolvent waε evaporated under reduced preεεure. The reεidue waε diεεolved in ethyl acetate, and thiε εolution waε waεhed twice with water, once with brine, and dried over magneεium εulfate. The εolvent waε evaporated under reduced preεεure to give a solid which was recryεtallized from ethyl acetate to give 3.37 g (9.3 mmol) of methyl (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl) -4-methyl-4-hexenoate as a white εolid, mp 169-170°C. 5B. Preparation of 5. varying Z Similarly, following the procedureε of Preparation 5A above, but replacing (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid with other compoundε of Formula 4, the following intermediateε of Formula 5 were prepared: methyl (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2(RS) ,4-dimethyl-4-hexenoate, mp 157-159°C; methyl (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (R) ,4-dimethyl-4-hexenoate; methyl (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (S) ,4-dimethyl-4-hexenoate; methyl (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3 (RS) , -dimethyl-4-hexenoate; methyl (E) -2- [2- [2- [4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene]cyclopent-1 (S) -yl]acetate, mp 145-146°C; methyl (E) -2- [2- [2- [4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]cyclohex-1(RS) -yl]acetate, mp 155-157°C; methyl (E) -2- [2- [2- [4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1 (S) -yl]acetate, mp 156-157°C; and methyl (E) -2-{4- [2- <4-carboxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (RS) -yljacetate. 5C. Preparation of 5. varying Z Similarly, following the procedureε of Preparation 5A above, but replacing (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid with other compounds of Formula 4 where Z is a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε hydroxy, and optionally replacing methanol with other alkanolε of formula GH, where G iε lower alkoxy, other intermediates of Formula 5 where G is lower alkoxy are prepared. PREPARATION 6 Preparation of Compoundε of Formula 6 6A. Preparation of 6 where Z iε ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Methoxy To a εtirred, 0°C εolution of 6.0 g (16.6 mmol) of methyl (E)-6-(4- carboxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4- hexenoate in 150 ml of dimethylformamide waε added 4.62 ml (33.1 mmol) of triethylamine followed by dropwiεe addition of 4.5 ml (21.8 mmol) of diphenylchlorophoεphate. The mixture waε allowed to εtir at room temperature for 1 hour and then recooled to 0°C, and treated with 10.8 g (166 mmol) of εodium azide. Thiε mixture was εtirred for 24 hourε at 0°C and then partitioned between aqueouε εodium hydrogen εulfate and ethyl acetate. The organic phaεe waε waεhed four times with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane to give 5.8 g of methyl (E) -6- (l,3-dihydro-4- isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4- hexenoate. A small sample was further purified by rapid εilica gel chromatography with an eluant of 1:1 hexane:ethyl acetate followed by recryεtallization from hexane-ethyl acetate to give purified methyl (E) -6- (1,3-dihydro-4-iεocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4- methyl-4-hexenoate, mp 95-101°C. 6B. Preparation of 6. varying Z Similarly, following the procedures of Preparation 6A above, but replacing methyl (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl- -hexenoate with other compoundε of Formula 5, the following intermediateε of Formula 6 were prepared: methyl (E) -6- (l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (RS) ,4-dimethyl-4-hexenoate; methyl (E) -6- (l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (R) ,4-dimethyl-4-hexenoate; methyl (E) -6- (l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (S) ,4-dimethyl-4-hexenoate; methyl (E) -6- (l,3-dihydro-4-iεocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -3 (RS) ,4-dimethyl-4-hexenoate; methyl (E) -2- [2- [2- [l,3-dihydro-4-iεocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yl]acetate; methyl (E) -2- [2- [2- [l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene] cyclohex-1 (RS) -yl]acetate; methyl (E) -2- [2- [2- [l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene] cyclohex-1 (S) -yl]acetate; and methyl (E) -2-{4- [2- (l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]tetrahydropyran-3 (RS) -yl}acetate. 6C. Preparation of 6. varying Z Similarly, following the procedureε of Preparation 6A above, but replacing methyl (E) -6- (4-carboxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 5 where Z iε a sidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, other intermediates of Formula 6 where G iε lower alkoxy are prepared. EXAMPLE 1 Preparation of Compoundε of Formula I IA. Formula IA where Z iε ZA, in which Z' is Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Hvdroxy 2.0 g (5.5 mmol) of methyl (E) -6- (4-carboxy-l,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate, a compound of Formula 5, waε converted to crude methyl E-6- (1,3-dihydro-4-iεocyanato-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate, a compound of Formula 6, aε deεcribed in Preparation 6 above without purification. The reεulting 4-iεocyanate waε redissolved in 50 ml of 1,4-dioxane and treated with 16 ml of water and 2.0 g (47.7 mmol) of lithium hydroxide monohydrate. The mixture waε εtirred at room temperature for 2 hourε and then partitioned between aqueouε IN εodium hydrogen εulfate and ethyl acetate. The organic phaεe waε waεhed twice with water, once with brine, and was dried over magnesium εulfate. The εolvent waε evaporated under reduced preεεure and the reεidue waε purified by chromatography on εilica gel, using 50:40:1 hexane-.ethyl acetate:acetic acid as eluant to give 1.28 g (4.0 mmol) of (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) - -methyl-4-hexenoic acid as a white solid, mp 130-131°C. IB. Preparation of IA. varying Z b Similarly, following the procedures of Example IA above, but replacing methyl E-6- (l,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 6, in which Z* iε aε defined above, the following compoundε of Formula IA in which Z b iε aε defined above were prepared: (E) -6- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2 (RS) ,4-dimethyl-4-hexenoic acid, mp 173-174°C (tert butylmethyl ether) ,- (E) -6- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2 (R) ,4-dimethyl-4-hexenoic acid, mp 133-136°C (tert butylmethyl ether/hexane) ; (E) -6- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2 (S) ,4-dimethy1-4-hexenoic acid, mp 133-136°C (tert butylmethyl ether); (E) -6- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -3 (RS) ,4-dimethyl-4-hexenoic acid; (E) -2- [2- [2- [4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1 (S) -yl]acetic acid, mp 152-153°C (ethyl acetate/hexane) ; (E) -2- [2- [2- [4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclohex-1 (RS) -yl] acetic acid, mp 163-177°C (tert butylmethyl ether/hexane) ; (E) -2- [2- [2- [4-amino-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] cyclohex-1 (S) -yl]acetic acid, mp 175-177°C (tert butylmethyl ether) ; and (E)-2-{4-[2- (4-amino-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] tetrahydropyran-3 (RS) -yljacetic acid. IC. Preparation of IA. varying Z in which G iε Hydroxy Similarly, following the procedureε of Example IA above, but replacing methyl E-6- (l,3-dihydro-4-iεocyanato-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 6, in which Z" is a sidechain of Formula Z aε defined in the Summary of the Invention in which G iε lower alkoxy, the corresponding compounds of Formula IA in which G is hydroxy are prepared: For ula IA where Z is Sidechain ZA n ZB Formula IA where Z iε Sidechain ZE O 95/22537 -92 - Formula IA where Z iε Sidechain ZH EXAMPLE 2 Preparation of Compoundε of Formula I 2A. Formula IA where Z is ZA. in which Z' is Methyl. Z 2 . 2 Hydrogen, and G iε Methoxy To a εolution of 2.5 g (7.8 mmol) of (E) -6- (4-amino-l,3-dihydro-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoic acid in 50 ml (1.234 mol) of metheinol was added 0.125 g (0.66 mmol) of p-toluenesulfonic acid monohydrate. The solution was εtirred at room temperature for 2 dayε and then concentrated to a εmall volume. The reεidue waε partitioned between water and ethyl acetate. The organic layer waε dried over magneεium εulfate and concentrated to a εolid. Recryεtallization of thiε εolid from hexane-ethyl acetate gave 2.48 g of methyl (E) -6- (4-amino-l,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate, mp 91-93°C. 2B. Preparation of IA. varying Z in which G iε Lower Alkoxy Similarly, following the procedureε of Example 2A above, but optionally replacing (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -4-methyl- -hexenoic acid with other compoundε of Formula IA where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε hydroxy, and optionally replacing methanol with other alkanolε of formula GH, where G iε lower alkoxy, the correεponding compoundε of Formula IA where G iε lower alkoxy are prepared. EXAMPLE 3 Preparation of Compoundε of Formula I 3A. Formula IA where Z iε ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Morpholinoethoxy 7g (0.02 moleε) of (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl- -hexenoic acid and toluene (25ml) are warmed gently to form a εolution. A slight excesε (1.05 molar equivalents) of 2-morpholinoethanol (3g, 0.021 moles) and toluene (25ml) are added. The reaction mixture iε εtirred for half an hour and then heated to reflux at an initial pot temperature of 117°C (which increaεes a few degrees during reflux) under a Dean-Stark trap for 80 hourε. The reaction mixture iε cooled, waεhed with water (2 X 15ml) , 10% aqueouε εodium bicarbonate (2 x 15ml) and finally with water (15ml) . The toluene layer iε εtripped to a volume of about 20ml in vacuo. n-hexane (30ml) iε added and the reεulting εlurry iε aged at room temperature for 2 hourε. The product iε filtered, waεhed with n-hexane (ca. 10 ml) and dried in vacuo at 60°C to yield 2- (morpholin-4-yl)ethyl (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate. 3B. Preparation of IA. varying Z in which G iε Morpholinoethoxy Similarly, following the procedureε of Example 3A above, but replacing (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -4-methyl-4-hexenoic acid with other compoundε of Formula IA where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε hydroxy, the correεponding compoundε of Formula IA where G iε morpholinoethoxy are prepared. EXAMPLE 4 Preparation of Compoundε of Formula I 4A. Formula IB where R 4 and R 5 are Methyl, and Z is ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Methoxy A εolution of 0.65 g (1.8 mmol) of methyl (E) -6- (l,3-dihydro-4- isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate in 10 ml of tetrahydrofuran was treated with 5 ml of a solution of 40% dimethylamine in water. After 1 hour the reaction waε partitioned between water and ethyl acetate. The organic phaεe waε waεhed with water three timeε, dried over magneεium εulfate, and concentrated under reduced preεεure to give 0.4 g of methyl (E) -6- [l,3-dihydro-4- (3,3-dimethylureido) - 6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl] -4-methyl- -hexenoate, mp 116-118°C. 4B. Preparation of IB. varying Z Similarly, following the procedureε of Example 4A above, but replacing methyl (E) -6- (l,3-dihydro-4-iεocyanato-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula 6 where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy, the correεponding compoundε of Formula IB where G iε lower alkoxy are prepared. EXAMPLE 5 Preparation of Compoundε of Formula I 5A. Formula IB where R 4 and R 5 are Methyl, and Z iε ZA. in which Z 1 iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Hvdroxy To a εolution of 0.3 g (0.74 mmol) of methyl (E) -6- [l,3-dihydro-4- (3,3-dimethylureido) -6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl] -4-methyl- 4-hexenoate in 7.4 ml of 4:1 methanol:water waε added 0.13 g (2.96 mmol) of lithium hydroxide monohydrate. The εolution waε heated at 50-60°C for 4 hourε. Upon cooling, the reaction waε partitioned between aqueouε sodium hydrogen εulfate and ethyl acetate. The organic layer waε waεhed with brine, dried over magnesium sulfate, and concentrated to (E)-6-[l,3- dihydro-4- (3,3-dimethylureido) -6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl] - -methyl-4-hexenoic acid. Recryεtallization from hexane-ethyl acetate gave 0.27 g (0.7 mmol) of (E) -6- [l,3-dihydro-4- (3,3-dimethylureido) -6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoic acid, mp 170-190°C. 5B. Preparation of IB. varying R 4 . R 5 . and Z in which G is Hvdroxy Similarly, following the procedureε of Example 5A above, but replacing methyl (E) -6- [l,3-dihydro-4- (3,3-dimethylureido) -6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoate with other compoundε of Formula IB where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy, the following compoundε of Formula IB where G iε hydroxy are prepared: EXAMPLE 6 Preparation of Compounds of Formula I 6A. Formula IC where R 3 is -CH- or -CF*.. and Z is ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G is Methoxy To a εolution of 0.5 g (1.5 mmol) of methyl (E) -6- (4-amino-1,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate in 5 ml of dichloromethane was added 0.5 ml (3.5 mmol) of trifluoroacetic anhydride. After 1 hour the reaction was partitioned between water and dichloromethane. The organic layer waε waεhed twice with water, dried over magneεium εulfate, and όoncentrated to a εolid. Recryεtallization of thiε εolid from hexane-ethyl acetate gave 0.520 g of methyl (E) -6- [1,3-dihydro- 6-methoxy-7-methyl-4-trifluoroacetylamino-3-oxoiεobenzofuran-5-yl] -4- methyl-4-hexenoate aε a white εolid, mp 107-109°C. 6B. Formula IC where R 3 iε -CF,. and Z iε ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Morpholinoethoxy By following the procedure of Example 3A above, but replacing E-6- (4- amino-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4- hexenoic acid by (E) -6- [1,3-dihydro-6-methoxy-7-methyl-4- trifluoroacetylamino-3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoic acid, the following compound iε obtained: 2- (morpholin-4-yl)ethyl (E) -6- [1,3-dihydro-6-methoxy-7-methyl-4- trifluoroacetylamino-3-oxoisobenzofuran-5-yl] - -methyl-4-hexenoate. 6C. Formula IC where R 3 is -CF-,. and Z iε ZA. in which Z' iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Hvdroxy By following the procedure of Example 6A above, but replacing methyl (E) -6- (4-amino-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4- methyl-4-hexenoate by methyl (E) -6- [1,3-dihydro-amino-6-methoxy-7-methyl-4- trifluoroacetylamino-3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoate and methyl (E) -6- [4-acetamido-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoate, the following compoundε were obtained: (E) -6- [l,3-dihydro-6-methoxy-7-methyl-4-trifluoroacetylamino-3- oxoiεobenzofuran-5-yl] -4-methyl- -hexenoic acid, mp 140-141°C; and (E) -6- [4-acetamido-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl] -4-methyl-4-hexenoic acid, mp 206-210°C. 6D. Preparation of IC. varying R 3 and Z Similarly, following the procedureε of Example 6A, 6B, and/or 6C above, but optionally replacing methyl (E) -6- (4-amino-1,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with other compoundε of Formula IA where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G is lower alkoxy, and replacing trifluoroacetic anhydride with other compoundε of the formula (R 3 C(O) ),0 or of the formula R 3 C(0)C1, where R 3 iε aε defined in the Summary of the Invention, the following compounds of Formula IC where G iε hydroxy are prepared: 2537 -99- Formula IC where Z is Sidechain ZA RECTIFIED SHEET (RULE 91) ISA/EP /22537 -100 - ZE RECTIFIED SHEET (RULE 91) ISA/EP Formula IC where Z iε Sidechain ZH EXAMPLE 7 Preparation of Compounds of Formula I 7A. Formula ID where R' is Methyl. R 3 iε -CF,. and Z iε ZA. in which Z 1 iε Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G iε Methoxy To a εolution of 0.35 g (0.82 mmol) of methyl (E) -6- [1,3-dihydro-6- methoxy-7-methyl-4- (trifluoroacetylamino) -3-oxoisobenzofuran-5-yl] -4- methyl-4-hexenoate in 4 ml of dimethylformamide was added 0.47 g (3.40 mmol) of potassium carbonate and 0.23 ml (3.69 mmol) of iodomethane. The mixture waε εtirred for 24 hourε and then partitioned between ethyl acetate and water. The organic layer waε waεhed with water, dried over magneεium εulfate, and concentrated under reduced pressure to give methyl (E) -6- [1,3-dihydro-6-methoxy-7-methyl-4- (N-trifluoroacetyl-N-methylamino) - 3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoate, an oil. NMR: δ 5.22-5.17 (multiplet ("m") , 2H) ; 5.10-5.04 (broad triplet, IH) ; 3.81 (εinglet ("ε"), 3H) ; 3.62 (ε, 3H) ; 3.42-3.27 (m, 5H) ; 2.45-2.25 (m, 5H) ; 1.75 (ε, 3H) . 7B. Preparation of ID. varying R'. R 3 . and Z Similarly, following the procedureε of Example 7A above, but optionally replacing methyl (E) -6- [1,3-dihydro-6-methoxy-7-methyl-4- (trifluoroacetylamino) -3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoate with other compounds of Formula IC where Z is a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy, and optionally replacing iodomethane by other lower alkyl halideε of the formula R'Br or R'l, the following compoundε of Formula ID are prepared: 537 -103 - Formula ID where Z iε Sidechain ZB RECTIFIED SHEET (RULE 91) ISA/EP 37 -104* Formula ID where Z is" 1- Sidechain ZE RECTIFIED SHEET (RULE 91) ISA/EP 2537 -105- Formula ID where Z is Sidechain ZH RECTIFIED SHEET (RULE 91) ISA/EP 7C. Preparation of ID. varying R'. R 3 . and Z Hydrolysiε of the compoundε of Formula ID where G iε lower alkoxy to compoundε of Formula ID where G iε hydroxy iε accompliεhed aε shown in Example 5A above. Converεion of the compoundε of Formula ID where G iε hydroxy to compoundε of Formula ID where G iε lower alkoxy or morpholinoethoxy is accomplished as εhown in Example 2A or 6B above. EXAMPLE 8 Preparation of Compoundε of Formula I 8A. Formula IE where R 1 iε Methyl and Z is ZA. in which Z 1 is Methyl. Z 2 . Z 3 . and Z 4 are Hydrogen, and G is Hvdroxy Hydrolyεiε of (E) -6- [1,3-dihydro-6-methoxy-7-methyl-4- (N-trifluoroacetyl-N-methylamino) -3-oxoiεobenzofuran-5-yl] -4-methyl-4- hexenoic acid was carried on the same manner as shown in Example 5A, to give (E) -6- (l,3-dihydro-6-methoxy-7-methyl-4-methylamino-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid, mp 121-124°C. 8B. Preparation of IE, varying R' and Z Similarly, following the procedureε of Example 8A above, but replacing (E) -6- [l,3-dihydro-6-methoxy-7-methyl-4- (N-trifluoroacetyl-N- methylamino) -3-oxoiεobenzofuran-5-yl] -4-methyl-4-hexenoic acid with other compoundε of Formula ID where Z iε a εidechain of Formula ZA, ZB, ZC, ZD, ZE, ZF. ZG, or ZH, in which G iε lower alkoxy or hydroxy, the following compoundε of Formula IE are prepared: 5/22537 •107- Formula IE where Z iε Sidechain ZB RECTIFIED SHEET (RULE 91) ISA/EP 2537 -108- Formula IE where Z iε Sidechain ZE RECTIFIED SHEET (RULE 91) ISA/EP 537 -109* Formula IE where Z is Sidechain ZH RECTIFIED SHEET (RULE 91) Converεion of the compoundε of Formula IE where G iε hydroxy to compoundε of Formula IE where G iε lower alkoxy or morpholinoethoxy iε accomplished aε εhown in Examples 2A or 6B above. EXAMPLE 9 Thiε example illustrates the preparation of a repreεentative pharmaceutical formulation for oral adminiεtration containing an active compound of Formula I, e.g., (E) -6- (l,3-dihydro-4-amino-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid. Ingredientε Quantity per tablet, mgε. Active Compound 200 Lactoεe, spray-dried 148 Magnesium stearate 2 The above ingredientε are mixed and introduced into a hard-εhell gelatin capεule. Other compoundε of Formula I, such as those prepared in accordance with Examples 1-8, can be uεed aε the active compound in the preparation of the orally adminiεtrable formulationε of thiε example. EXAMPLE 10 Thiε example illuεtrateε the preparation of another repreεentative pharmaceutical formulation for oral adminiεtration containing an active compound of Formula I, e.g., (E) -6- (l,3-dihydro-4-amino-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid. Ingredientε Quantity per tablet, gs. Active Compound 400 Cornεtarch 50 Croεcarmelloεe εodium 25 Lactoεe 120 Magneεium εtearate 5 The above ingredients are mixed intimately and pressed into single εcored tablets. Other compoundε of Formula I, such as those prepared in accordance with Examples 1-8, can be used aε the active compound in the preparation of the orally adminiεtrable formulations of thiε example. EXAMPLE 11 Thiε example illuεtrateε the preparation of a representative pharmaceutical formulation containing an active compound of Formula I, e.g., (E) -6- (1,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2,4-dimethyl-4-hexenoic acid. An oral εuεpenεion iε prepared having the following compoεition. Ingredientε Active Compound Fumaric acid Sodium chloride Methyl paraben Propyl paraben Granulated sugar Sorbitol (70% solution) Veegum K (Vanderbilt Co.) Flavoring Colorings Distilled water q.ε. Other compoundε of Formula I, εuch aε thoεe prepared in accordance with Exampleε 1-8, can be uεed aε the active compound in the preparation of the orally administrable formulationε of thiε example. EXAMPLE 12 Thiε example illuεtrateε the preparation of a repreεentative pharmaceutical formulation for oral administration containing an active compound of Formula I, e.g., (E) -6- (l,3-dihydro-4-amino-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid. An injectable preparation buffered to a suitable pH is prepared having the following composition: Ingredientε Active Compound 0.2 g Sodium Acetate Buffer Solution (0.4 M) 2.0 ml HCL (IN) or NaOH (IN) q.ε. to pH 4 Water (diεtilled, εterile) q.ε. to 20 ml Other compoundε of Formula I, εuch aε thoεe prepared in accordance with Exampleε 1-8, can be uεed aε the active compound in the preparation of the injectable formulationε of this example. EXAMPLE 13 This example illustrateε the preparation of a repreεentative pharmaceutical formulation for topical application containing an active compound of Formula I, e.g., (E) -6- (l,3-dihydro-4-amino-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid. Ingredientε 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 with εtirring. A εufficient quantity of water at 60°C iε then added with vigorouε εtirring to emulsify the ingredientε, and water then added q.ε. 100 g. Other compounds of Formula I, such aε thoεe prepared in accordance with Exampleε 1-8, can be uεed aε the active compound in the preparation of the topical formulationε of thiε example. EXAMPLE 14 This example illustrateε the preparation of a repreεentative pharmaceutical formulation containing an active compound of Formula I, e.g., (E) -6- (l,3-dihydro-4-amino-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2,4-dimethyl-4-hexenoic acid. A εuppoεitory totalling 2.5 gramε iε prepared having the following compoεition: Ingredients Active Compound 500 mg Witepsol H-15 * balance Ctriglycerides of saturated vegetable fatty acid; a product of Riches-Nelson, Inc., New York, N.Y.) Other compoundε of Formula I, such as those prepared in accordance with Examples 8-22, can be used as the active compound in the preparation of the suppository formulationε of thiε example. EXAMPLE 15 In Vitro Determination of Therapeutic Activity (Aε an Anti-Inflammatory, Anti-Viral, Anti-Tumor, Anti-Pεoriatic and/or Immunoεuppreεεive Agent) Utilizing the Inhibition of IMP Dehydrogenaεe Assay Thiε aεεay iε a modification of the method of Anderson, J.H. and Sartorelli, A.C., Jour. Biol . Chem, 243:4762-4768 (1968). It measureε the formation of NADH (λ^ = 340 nm, e340 = 6,220 M "1 cm" 1 ) aε Inosine 5' -monophosphate ("IMP") is converted to Xanthosine 5' -monophosphate ("XMP") by the human Type II IMP dehydrogenaεe ("IMPDH") . Compounds are diεεolved and diluted in DMSO, and reaction solutions containing compoundε at 0, 0.01, 0.10, 1.0, 10, and lOOμM are prepared in disposable methacrylic plastic microcuvets ('UV-tranεparent' plastic, 1 cm pathlength, 1.5 ml capacity). The εolutionε (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 unitε/ml; one unit of enzyme catalyzeε the formation of one μmol NADH per minute at 40°C at saturating substrate concentrationε - 200 μM IMP and 400 μM NAD) . Reactionε are performed at 40°C and initiated by the addition of enzyme. Mycophenolic acid (IC Λ "• 0.02μM) εerveε aε the poεitive control. The reactionε are monitored at 340 nm for 10 minuteε in a UV/VIS εpectrophotometer, and rate data are collected. The 50% inhibitory value ("IC 50 ") iε determined by fitting the fractional activitieε relative to control to the following equation on a Macintoεh computer by the program Syεtat: Fractional activity = MAX/( (X/ICjo) n +l) . X iε the concentration of the compound, and the term n accounts for deviations of the data from a simple competitive inhibition model. The compounds of the present invention inhibit IMPDH when tested by thiε method, indicating their activity aε anti-inflammatory, anti-viral, anti-tumor, anti-pεoriatic and/or immunoεuppreεεive agentε, aε εhown in the below table. In Vitro Determination of Immunosuppresεive Activity Utilizing Resoonεeε of Human Peripheral Blood Lvπtphocvteε to T- and B-cell Mitogenε This procedure iε a modification of a procedure initially deεcribed by Greaveε, et al. ["Activation of human T and B lymphocytes by polyclonal mitogens," Mature, 248:698-701 (1974)]. Human mononuclear cellε ("PBL") are separated from heparinized whole blood by density gradient centrifugation in Ficoll-Plaque (Pharmacia) . After washing, 2 x 10 3 cells/well are cultured in microtiter plates with RPMI 1640 supplemented with 5% fetal calf serum, penicillin and streptomycin. PHA (Sigma) at 10 μg/ml is then added. Test materials are teεted at concentrationε between 10 4 and 10^, 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 glaεε fiber filterε with an automatic harveεter and radioactivity iε meaεured by εtandard εcintillation procedureε. The 50% inhibitory concentration ("IC j o") for mitogenic εtimulation iε determined graphically. To evaluate differential effects on T- and B-lymphocytes, different mitogenε are used: PWM (Sigma) at 20 μg/ml and Staphylococcus Protein A bound to Sepharoεe (SPA) (Sigma) 2 mg/ml or 14 μg/ml of Protein A. The compoundε of the preεent invention show immunosuppressive activity when tested by this method. EXAMPLE 17 Determination of Immunosuppresεive Activity Utilizing the Hemolvtic Plague Forming Cell Aεεav Thiε procedure iε a modification of "The agar plaque technique for recognizing antibody producing cellε," a procedure initially deεcribed by Jerne et al., [Cell-bound Antibodies, Amoε and Kaprowεki editorε (Wiεtar Inεtitute Preεε, Philadelphia, 1963), p. 109] . Groupε of 5-6 adult C578B1/6 male mice were εenεitized with 1X10 8 εheep red blood cellε ("SRBC") and εimultaneously treated with an oral dosage form of the test material in an aqueous vehicle. Animalε in a control group receive the same volume of vehicle. Four days after SRBC inoculation, spleenε are dispersed in loose Ten Broeck homogenizerε. The number of nucleated cellε ("WBC") iε determined and the spleen cell suspenεion iε mixed with SRBC, guinea pig complement and agar solution at 0.5% concentration. Aliquotε of the above mixture (0.1 ml) are dropped on four εeparate quadrantε of a Petri diεh and are covered with cover εlipε. After two hourε incubation at 37°C, areaε of hemolysis around plaque-forming cellε ("PFC") are counted with a diεεecting microεcope. Total WBC/εpleen, PFC/spleen and PFC/10 6 WBC ("PPM") are calculated for each mouse spleen. Geometric means of each treatment group are then compared with the vehicle-treated control group. The compoundε of the present invention show immunosuppresεive activity when teεted by thiε method, aε εhown in the below table. While the preεent invention haε been described with reference to the εpecific embodimentε thereof, it should be underεtood by thoεe εkilled in the art that variouε changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, procesε, proceεε step or steps, to the objective, spirit and εcope of the preεent invention. All such modificationε are intended to be within the εcope of the claimε appended hereto.

Claims: WHAT IS CLAIMED IS: 1. A compound represented by the formula: wherein: R 1 is hydrogen or lower alkyl; R 2 is hydrogen, lower alkyl, -C(0)R 3 , -CfOlNR^R 3 , -CO,R«, or -SO,R 3 where.- R 3 is hydrogen, lower alkyl, halo lower alkyl or optionally substituted phenyl; R" is hydrogen, lower alkyl or optionally substituted phenyl; R 3 is hydrogen, lower alkyl or optionally substituted phenyl; R* is lower alkyl or optionally substituted phenyl; 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,; Z 2 is H, lower alkyl, lower alkoxy, aryl, or -CΑ__Z'~ , where *- Z 13 is aryl or heteroaryl; ~Λ Z 3 is H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, - P(0) (OCHjJj, -P(O) (OH) (OCH,) , or -S(0) m Z 12 , where Z 12 is lower alkyl, and m is 0, 1 or 2; Z 4 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 , -OfCHjJ n NG'G 2 , or - 0(CH,) B N=G 3 , where n iε an integer from 1 to 6, G' 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 atoms plus one member that is -0-, -S-, or -N(G 4 ) - where G 4 is H or lower alkyl; provided that when Z 1 is methyl, Z 2 , Z 3 and Z 4 are not all H; or Formula ZB wherein: Z 3 is H or lower alkyl; Z* is H or lower alkyl; 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 ~ , Z ~ , and G are as defined above; or Formula ZD wherein: D 3 is -CH-- or -CHjCH,- ; and G is as defined above; or RECTIFIED SHEET (RULE 91) ISA/EP Formula ZE wherein: Z ~ iε H, lower alkyl, lower alkoxy, -COOH, -NH, or halo; Z 7 iε H, lower alkyl, lower alkoxy or halo; and Z 3 and G are as defined above; or Formula ZF wherein: Z 1 and G are as defined above; or Formula ZG wherein: j*~- Z* and G are as defined above; or Formula ZH wherein: D 4 is -CH,-, -CH- . CK--, -CHjCHjCH,-, -O-, or -OCH,-; 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 is sidechain ZA. 3. The compound or salt of Claim 2, wherein Z 1 iε methyl. 4. The compound or salt of Claim 3, wherein R 1 is hydrogen and R 2 RECTIFIED SHEET (RULE 91) ISA/EP is hydrogen or -C(0)R 3 . 5. The compound or salt of Claim 4, wherein R 2 , Z 2 and Z 3 are all hydrogen, and Z 4 is methyl. 6. The compound or εalt of Claim 4, wherein R 2 , Z 2 and Z 4 are all hydrogen, and Z 3 iε methyl. 7. The compound or εalt of Claim 1, wherein Z iε εidechain ZB. 8. The compound or εalt of Claim 7, wherein R 1 iε hydrogen and R 2 iε hydrogen or -C(0)R 3 . 9. The compound or εalt of Claim 8, wherein D 1 and D 2 together with their adjacent carbon atomε form a saturated carbocyclic ring of 5 or 6 carbon atoms. 10. The compound or salt of Claim 9, wherein D 1 and D 2 together represent -CH,CH,CH,-, and Z 3 and Z ~ are both hydrogen. 11. The compound or salt of Claim 10, wherein R 1 and R 2 are both hydrogen. 12. The compound or salt of Claim 9, wherein D 1 and D 2 together represent ■ ~~ - ~ 2 C ~~ 2 ~~ Α__Cl- 2 - , and Z 3 and Z ~ are both hydrogen. 13. The compound or salt of Claim 12, wherein R 1 and R 2 are both hydrogen. 14. The compound or salt of Claim 8, wherein D 1 and D 2 together with their adjacent carbon atoms form a saturated heterocyclic ring of 5 or 6 atoms. 15. The compound or salt of Claim 14, wherein D 1 and D 2 together repreεent CI^CH CH^-, and Z 3 and Z 8 are both hydrogen. 16. The compound or salt of Claim 15, wherein R 1 and R 2 are both hydrogen. 17. A pharmaceutical compoεition comprising a pharmaceutically acceptable non-toxic excipient and a therapeutically effective amount of a compound of Claim 1, or a pharmaceutically acceptable salt thereof. 18 A method of treatment for immune, inflammatory, tumor, proliferative, viral or psoriatic disorders in a mammal, comprising administering a therapeutically effective amount of a compound or salt of Claim 1 to a mammal in need thereof. 19. A procesε for preparing compoundε of Formula I: wherein: R' iε hydrogen or lower alkyl; R 2 iε hydrogen, lower alkyl, -C(0)R 3 , -C(0)NRR 3 , -CO,R 6 , or -S0,R 3 where: R 3 iε hydrogen, lower alkyl, halo lower alkyl or optionally εubεtituted phenyl; R 4 iε hydrogen, lower alkyl or optionally εubεtituted phenyl; R 3 iε hydrogen, lower alkyl or optionally εubstituted phenyl; R 6 iε lower alkyl or optionally εubεtituted phenyl; and Z iε a εide chain εelected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG, and ZH: _., or -CH-.Z 13 , where Z 13 is aryl or heteroaryl; Z 3 iε H, lower alkyl, lower alkenyl, lower alkoxy, phenyl, - P(O) (OCH 3 ) 2 , -P(0) (OH) (OCHs) , or -S(0) m Z 12 , where Z 12 is lower alkyl, and m is 0, 1 or 2; Z 4 iε 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 , -0(CH 2 ) II NG 1 G 2 , or - where n is an integer from 1 to 6, G' is H or lower alkyl, G 2 is H or lower alkyl, and =G 3 iε lower alkylene of four to εix carbon atomε, 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; provided that when Z 1 iε methyl, Z 2 , Z 3 and Z 4 are not all H; or Formula ZB wherein: Z 3 is H or lower alkyl; Z 8 is H or lower alkyl; 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 atomε; and G is as defined above; or Formula ZC wherein: Z 3 , Z s , and G are as defined above; or Formula ZD wherein: D 3 iε -CH 2 - or -CH,CH_*-; and G iε aε defined above; or Formula ZE wherein: Z~ is H, lower alkyl, lower alkoxy, -COOH, -NH 2 or halo; Z 7 is H, lower alkyl, lower alkoxy or halo; and Z 3 and G are as defined above; or Formula ZF wherein: Z 1 and G are aε defined above; or Formula ZG wherein: D 3 , Z 2 , Z 3 , Z 4 and G are aε defined above; or Formula ZH wherein: D 4 iε -CH 2 -, -CH 2 CH,-, -0-, or -OCH 2 -; and z' and G are aε defined above; and the pharmaceutically acceptable salts thereof; which comprises: a) reacting a compound of Formula I, wherein G is lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH,) n -NG'G 2 , or -O- (CH 2 )_.-N=G 3 , in which n, G 1 , G 2 , and G 3 are as defined above; with an inorganic baεe, to form a compound of Formula I wherein G iε hydroxy; or b) reacting a compound of Formula I wherein G iε hydroxy, with a compound of the formula GH, where G iε lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH 2 ) n -NG'G 2 , or 0- (CH 2 ) n - =G 3 , in which n, G 1 , G 2 , and G 3 are as defined above, to form a compound of Formula I wherein G iε lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH 2 ) r .-NG'G 2 , or O- (CH 2 ) n -N=G 3 , in which n, G 1 , G 2 , and G 3 are aε defined above; or c) reacting a compound of Formula I wherein R 1 iε hydrogen, R 2 is -C(0)R 3 wherein R 3 is hydrogen, and G iε lower alkoxy, with a compound of the formula HNG'G 2 , where G' and G 2 are aε defined above, to form a compound of Formula I wherein G' and G 2 are aε defined above; or d) reacting a compound of Formula I wherein R' and R 2 are hydrogen, with a compound of the formula (R 3 C(0)) 2 0 or R 3 C(0)C1, to form a compound of Formula I wherein R 2 iε -C(0)R 3 wherein R 3 iε lower alkyl, halo lower alkyl or optionally εubεtituted phenyl; or e) reacting a compound of Formula I wherein R 1 iε hydrogen, R 2 iε -C(0)R 3 , where R 3 iε lower alkyl, halo lower alkyl or optionally substituted phenyl, and G is lower alkoxy, with a compound of the formula R'X, where R 1 is lower alkyl and X is iodine or bromine, to form a compound of Formula I wherein R 1 iε lower alkyl; or f) reacting a compound of Formula I to form a pharmaceutically acceptable salt of that compound; or g) reacting a salt of Formula I to form the corresponding free compound of Formula I; or h) converting a pharmaceutically acceptable salt of a compound of Formula I to another pharmaceutically acceptable salt of a compound of Formula I.

Inventors: ARTIS DEAN R, CERVANTES ALICIA, ELWORTHY TODD R, FERNANDEZ MARIO, FRANCO FIDENCIO, HAWLEY RONALD C, LARA TERESA, LOUGHHEAD DAVID G, MORGANS JR DAVID, NELSON PETER H, PATTERSON JOHN W, SJOGREN ERIC B, SMITH DAVID B, TALAMAS FRANCISCO X, TREJO ALEJANDRA, WALTOS ANN M, WEIKERT ROBERT J, 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, FRANSISCO, 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, A61P37, C07D307, C07D405, C07D407, C07D409