US 20070254920A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0254920 A1 deLong et al. (43) Pub. Date: Nov. 1, 2007 (54) PRODRUG DERIVATIVES OF ACIDS USING (52) U.S. Cl. ......................... 514/319; 514/323: 514/573; ALCOHOLS WITH HOMOTOPIC HYDROXY 514/415: 514/443; 514/469; GROUPS AND METHODS FOR THEIR 546/196; 546/201: 546/206; PREPARATION AND USE 548/495; 549/49; 549/462 (75) Inventors: Mitchell A. deLong, Raleigh, NC (US); (57) ABSTRACT Jill M. McFadden, Chapel Hill, NC This invention relates to novel homotopic prodrugs and (US); Susan M. Royalty, Cary, NC medicaments and methods for their preparation, testing and (US); Eric J. Toone, Durham, NC use. In one embodiment, the homotopic prodrug has the (US); Jeffrey D. Yingling, Apex, NC general formula (US) Correspondence Address: O MICHAEL BEST & FRIEDRCH LLP 100 E WISCONSNAVENUE Rb, Suite 3300 --- MILWAUKEE, WI 53202 (US) wherein (73) Assignee: Aerie Pharmaceuticals, Inc., Research Triangle Park, NC (21) Appl. No.: 11/412,207 (22) Filed: Apr. 26, 2006 -- Publication Classification is a biologically-active moiety comprising a carboxylic acid functional group, and R is a homotopically-symmetrical (51) Int. Cl. alcohol bonded to the biologically-active moiety through the A6 IK 3/558 (2006.01) carboxylic acid functional group to form an ester linkage, as CO7D 409/02 (2006.01) well as optical isomers, enantiomers, pharmaceutically CO7D 405/02 (2006.01) acceptable salts, biohydrolyzable amides, esters, and imides CO7D 403/02 (2006.01) thereof and combinations thereof. US 2007/0254920 A1 Nov. 1, 2007 PRODRUG DERVATIVES OF ACDS USING WO 99/12896, and WO 99/12898.) However, such modifi ALCOHOLS WITH HOMOTOPIC HYDROXY cations have either resulted in only modest increases in GROUPS AND METHODS FOR THEIR half-life or resulted in compounds with diminished potency. PREPARATION AND USE An alternative approach has been to replace C with a heteroatom. For example, PGF analogs containing a Sulfonic FIELD OF THE INVENTION acid moiety at C (see Iguchi, Y.: Kori, S.; Hayashi, M. “The 0001. This invention relates to prodrug derivatives of chemistry of prostaglandins containing the Sulfo group'. J. carboxylic acids and methods for their preparation and use. Org. Chem., 1975, 40,521-523) and PGF analogs containing More specifically, this invention relates to polyhydroxy a phosphonic acid moiety at C (see Kluender, H. C. & alcohol esters possessing certain symmetry elements and Woessner, W., Prostaglandins and Medicine, 1979, 2, 441 methods for their preparation and use. 444) have been disclosed. However, such compounds suffer BACKGROUND OF THE INVENTION from significantly diminished potency. 0002 Many biologically-active materials have signifi 0006 Moreover, the Corey synthetic route to prostaglan cant limitations in their use as drugs and medications due to dins was specifically designed for a carboxylic acid moiety physico-chemical properties that are incompatible with in at C, and modifications are either incompatible with this vivo delivery via the desired dosing route. Other materials efficient route or require significant optimization of difficult can not be used due to local side-effects that occur at the high chemistry for each new C replacement. Syntheses of pros concentrations of the dosed materials before they are prop taglandin analogs via the Corey route are described in the erly dispersed in the body. Until recently, the solution to these problems was to go back to the laboratory and chemi following references: Corey, E. J.; Weinshenker, N. M.: cally-modify the core structure of the molecule to change its Schaaf, T. K. Huber, W.J. Am. Chem. Soc., 1969, 91,5675 properties. Unfortunately, this often causes a loss of the and Corey, E. J.; Schaaf, T. K. Huber, W.; Koelliker, U.: desirable characteristics as well. Weinshenker, N. M.; J. Am. Chem. Soc., 1970, 92, 397. 0003) A relatively recent concept has emerged which 0007 Thus, while a few prostaglandin analogs have been holds some promise to solve both of these problems. The disclosed wherein C has been replaced with a non acid idea that a drug or medicament need not be dosed in active moiety, there is a continuing need for Suitable esters that can form, but in a form that requires modification by the be used to modify the activity of the many potent, selective organism before becoming active is similar to the Solution prostaglandin derivatives for the treatment of a variety of that cells themselves use when making certain proteins. The cells create a preliminary protein, typically a hormone or diseases and other conditions. enzyme, in an inactive form, and at the appropriate time and place, the active molecule is released by cleavage into its SUMMARY OF THE INVENTION active form. The prefixes used by biologists to explain the relationship between an inactive precursor and an active 0008. In one embodiment, the invention provides a com hormone or enzyme are pro and pre-pro (e.g., pro-insulin) pound having the formula depending on if one release step is needed (pro) or two (pre-pro). Medicinal chemists have adopted this language to the idea that a pro-drug, or more commonly prodrug, is one that requires biological modification to effect the release of the active chemical. (See: Albert, A. "Chemical Aspects Ra lsO -Rb of Selective Toxicity', Nature, 1958, 182:421-423: Roche, E. B. “Design of Biopharmaceutical Properties through Prodrugs and Analogs, Washington, DC: American Phar maceutical Association, 1977.) wherein 0004 While there are many enzymes in the body that are potentially capable of releasing a prodrug in its active form, there are relatively few that have been exploited to date. Phosphatases, amidases, and esterases have all seen appli cation in the literature as activators of prodrugs. In addition, non-biological release mechanisms have been exploited, Such as a chemical linkage that is sensitive to water, or low --3. pH. 0005 Prostaglandins and prostaglandin analogs are car boxylic acid derivatives that have often been preferentially is a biologically-active moiety comprising a carboxylic acid dosed as prodrugs, particularly in ocular formulations. All naturally occurring prostaglandins have a carboxylic acid functional group, and R is a homotopically-symmetrical moiety at the C position. The C position is therefore the alcohol bonded to the biologically-active moiety through the site for the chemical modification to create the prodrug carboxylic acid functional group to form an ester linkage, as moiety. Attempts have been made to modify the carboxylic well as optical isomers, enantiomers, pharmaceutically acid moiety at the C position as a Sulfonamide moiety, and acceptable salts, biohydrolyzable amides, esters, and imides as a tetrazole (See: PCT Publication Nos. WO 99/12895, thereof and combinations thereof. US 2007/0254920 A1 Nov. 1, 2007 0009. In another embodiment, the invention provides a istering to a Subject in need of treatment, a homotopic composition comprising A) a compound having the formula prodrug of a prostaglandin DP agonist. 0017. In a further embodiment, the invention provides a method for treating allergies comprising administering to a O Subject in need of treatment, a homotopic prodrug of a prostaglandin DP antagonist. R us O1 Rb, 0018. In another embodiment, the invention provides a method of ranking the susceptibility of an ester derivative to hydrolysis, said method comprising producing an ester wherein derivative by reacting a biologically-active moiety having a carboxylic acid group with a homotopically-symmetrical alcohol that binds the biologically-active moiety through the carboxylic acid group to form an ester linkage, reacting the ester derivative with an enzyme that cleaves the ester -- linkage and releases the biologically-active moiety, measur ing the rate at which the enzyme cleaves the ester linkage, and ranking the ester derivative for therapeutic usefulness. is a biologically-active moiety comprising a carboxylic acid functional group, and R is a homotopically-symmetrical DETAILED DESCRIPTION OF THE alcohol bonded to the biologically-active moiety through the INVENTION carboxylic acid functional group to form an ester linkage, as 0019. This invention relates to novel hydroxy- or poly well as optical isomers, enantiomers, pharmaceutically hydroxy-prodrug forms of drugs and medicaments including acceptable salts, biohydrolyzable amides, esters, and imides prostaglandins, ethacrynic acid derivatives and cephalospor thereof and combinations thereof. ins and methods for their preparation, testing, and use. These derivatives represent a significant advance over simple 0010. In yet another embodiment, the invention provides monofunctional hydrophobic esters as they are water-solu method for treating a condition comprising administering to bilizing, in contrast to the insoluble nature of the lower alkyl a Subject in need of treatment, a homotopic prodrug of a esters, and are thus particularly Suitable for aqueous formu prostaglandin EP agonist, wherein the condition is selected lations. These derivatives also represent an advance over from the group consisting of glaucoma, ocular hypertension, other attempts to create water-solubilizing prodrugs, as they premenstrual tension, asthma and bone disorders. are of well-defined structure, as opposed to the PEG, or 0011. In a further embodiment, the invention provides a polyethylene-glycol-type ester prodrugs, and are structurally method for treating a condition comprising administering to a stable single isomer, as opposed to the Sugar alcohol and a Subject in need of treatment, a homotopic prodrug of a glyceryl-type prodrugs. prostaglandin EP agonist, wherein the condition is selected 0020. Before any embodiments of the invention are from the group consisting of arthritis, bone disorders, vas explained in detail, it is to be understood that the invention cular disease, hepatic diseases, renal diseases, pancreatitis, is not limited in its application to the details of construction mycardial infarct, and gastric disturbances. and the arrangement of components set forth in the follow 0012. In another embodiment, the invention provides a ing description or illustrated in the following drawings.