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(12) Patent Application Publication (10) Pub. No.: US 2004/0152769 A1 Ekwuribe Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0152769 A1 Ekwuribe Et Al US 2004O152769A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0152769 A1 Ekwuribe et al. (43) Pub. Date: Aug. 5, 2004 (54) MODIFIED CARBAMATE-CONTAINING (52) U.S. Cl. ........................... 514,478; 514/615; 514/114 PRODRUGS AND METHODS OF SYNTHESIZING SAME (57) ABSTRACT (76) Inventors: Nnochiri Nkem Ekwuribe, Cary, NC (US); Jennifer Riggs-Sauthier, Prodrugs having a hydrolyzable carbamate moiety, compo Raleigh, NC (US); Tatyana A. Sitions including the prodrugs, methods of preparing the Dyakonov, Durham, NC (US) prodrugs and methods of treatment using the prodrugs are Correspondence Address: disclosed. The prodrug has the formula DC(X)XR, where D is a biologically active agent, X is O, S or NR', and R is a SS SIBLEY & SAJOVEC moiety that modifies various properties of the biologically RALEIGH, NC 27627 (US active agent. The biologically active agent either includes a 9 (US) functional group Such as an amide, thioamide, imide, thio imide, urea, thiourea, carbamate, thiocarbamate, Sulfona (21) Appl. No.: 10/703,647 mide, or Sulfonimide group, or includes a hydroxy, amine, 22) Filled: 7, 2003 carboxylic acid or thiol group that is modified to include (22) File Nov. 7, Such a group. An NH group from the biologically active Related U.S. Application Data agent can be coupled to an activated form the C(X)XR moiety to form the prodrugs described herein. Relative to a (60) Provisional application No. 60/424,796, filed on Nov. conventional carbamate group, the presence of the addi 9, 2002. Provisional application No. 60/483,676, filed tional carbonyl or Sulfonyl group makes the carbamate on Jun. 30, 2003. group more Susceptible to hydrolysis. The prodrugs are more Stable in certain environments than the biologically active Publication Classification agent, and can permit the drugs to be administered orally, in those embodiments where the biologically active agent must (51) Int. Cl." ....................... A61K 31/66; A61K 31/325; otherwise be administered by injection or intraveneous A61K 31/16 administration. Patent Application Publication Aug. 5, 2004 Sheet 1 of 5 US 2004/0152769 A1 Figure 1 CHEMICAL HYDROLYSS OF NOBEX008 TO PARENT COMPOUND s 2 Patent Application Publication Aug. 5, 2004 Sheet 2 of 5 US 2004/0152769 A1 Figure 2 THE LEVEL OF DRUG IN RATS DOSED ORALLY WITH CARBAMATE (25.6 mg/kg) a O s Ns e n a) s s s s 60 a s .9 e c 40 s t C9 2 Patent Application Publication Aug. 5, 2004 Sheet 3 of 5 US 2004/0152769 A1 Figure 3 THE LEVE OF PRODRUG 13 AND DRUGN RAT PASMA AFTER ORAL DOSING C e 800 600 G, 400 gs 200 O O Time (hours) Patent Application Publication Aug. 5, 2004 Sheet 4 of 5 US 2004/0152769 A1 Figure 4 PEG CHAN LENGTH WS AUC ACng. Patent Application Publication Aug. 5, 2004 Sheet 5 of 5 US 2004/0152769 A1 Figure 5 Eample 1 H H OR/nR a'?M N R ys Of Urea Drug O CmpoundX US 2004/0152769 A1 Aug. 5, 2004 MODIFIED CARBAMATE-CONTAINING 0007. The prodrugs can be formed from any drug includ PRODRUGS AND METHODS OF SYNTHESIZING ing these moieties, with the proviso that where a functional SAME group exists, and it is not desired to form a carbamate-like moiety at that functional group, it may be desirable to RELATED APPLICATION DATA protect the functional group, and possibly deprotect that 0001) This application claims the benefit of U.S. Provi functional group after the prodrug Synthesis is complete. sional Application Serial No. 60/424,796, filed Nov. 9, 2002, 0008. The technology allows one to attach hydrophilic, and U.S. Provisional Application Serial No. 60/483,676, lipophilic and/or amphiphilic polymers to the prodrug, filed Jun. 30, 2003, the disclosures of which are incorporated which can aid in allowing the compounds to pass through the herein by reference in their entireties. Stomach without degradation, and/or protect labile peptides and proteins from enzymatic degradation. Particularly where 1 FIELD OF THE INVENTION a polyethylene glycol moiety is attached, the presence of two 0002 The present invention relates to carbamate pro or more PEG units can provide increased protection from drugs, methods of Synthesizing Such carbamate prodrugs, enzymes Such as proteases that would otherwise adversely and methods of treatment employing the use of Such car affect the protein or peptide. bamate prodrugs. 0009. The prodrugs can be used to treat any condition for which the parent compound possesses utility, and often 2 BACKGROUND OF THE INVENTION permit oral administration of drugs that are otherwise only 0.003 Prodrug design represents an approach to drug able to be administered by injection or by intravenous delivery often employed to mask undesirable drug properties administration. In certain embodiments, the prodrugs can including, but not limited to, low bioavailability, lack of Site possess improved pharmaceutical characteristics, Such as Specificity, chemical instability, toxicity, immunogenecity, greater Solubility, greater chemical Stability, and/or higher and factors contributing to poor patient compliance Such as bioavailability than the native drug. Further, in certain bad taste, odor, or undesirable modes of administration. embodiments, the prodrugs can be prepared more easily Generally, prodrugs are chemical derivatives that can be and/or more cost effectively than other known prodrugs. metabolized in Vivo to provide active drug molecules 0010. In one embodiment, the prodrugs have the follow capable of exerting a therapeutic effect. ing formula: 0004 Current prodrugs, however, generally have short comings that limit their practical applications Such as the requirement for Specific enzyme digestion, which may make Formula I the prodrug unsuitable or at least leSS useful for in Vivo use; X the generation of toxic intermediates, and complex and/or costly Synthesis routes. It is desirable to provide new pro ls drugs with improved characteristics relative to prodrugs in the prior art, as well as methods for making and using Such prodrugs. The present invention provides Such prodrugs and 0011 wherein: methods. 0012 X is O, S, or NR', 3 SUMMARY OF THE INVENTION 0013 R' is, individually, hydrogen, alkyl, Substi 0005 Prodrug compounds comprising a modified car tuted alkyl, aryl, Substituted aryl, arylalkyl, Substi bamate linkage are disclosed. The carbamate linkage has tuted arylalkyl, alkylaryl, or Substituted alkylaryl, been modified from a normal carbamate linkage (-O- C(O)NH-) such that the H in an N-H bond is replaced 0014 “substituted,” as applied to alkyl, aryl, alky with a link to another functional group, Such as an amide, laryl, and arylalkyl, refers to Substituents Selected thioamide, imide, thioimide, urea, thiourea, carbamate, thio from alkyl, alkenyl, heterocyclyl, cycloalkyl, aryl carbamate and the like (i.e., the nitrogen in the NH bond (including heteroaryl), alkylaryl, arylalkyl, halo from the carbamate is also a nitrogen in the amide, thioa (e.g., F, Cl, Br, or I), alkoxy, amine, trifluoroalkyl, mide, imide, thioimide, urea, thiourea, carbarnate, thiocar such as trifluoromethyl, -CN, -NO, -SR', -Ns, bamate and the like). The O in the carbonyl in the carbamate moiety can be replaced with an NH, N-alkyl, N-aryl, or S. The resulting moieties can have improved biodegradability, and accordingly, provide improved drug release character istics, e.g., relative to prodrugs including a Standard car 0015 D is a biologically active agent ("drug”) that bamate moiety. includes a functional group, Such as a urea, thiourea, 0006. In contrast to extant carbamate groups, which only amide, thioamide, imide, thioimide, carbamate, thio allow one to form prodrugs of hydroxyl and/or amine carbamate, Sulfonamide, Sulfonimide, phosphora containing compounds, the present technology permits one mide, and the like, or which originally included a to functionalize compounds including carboxylic acid, hydroxyl, amine, thiol, and/or carboxylic acid group, amine, hydroxyl and/or thio groups, as well as amides, where Such group has been modified to be in the thioamides, imides, thioimides, ureas, thioureas, carbam form of a urea, thiourea, amide, thioamide, imide, ates, thiocarbamates, Sulfonamides, Sulfonimides, phos thioimide, carbamate, thiocarbamate, Sulfonamide, phoramides and the like. Sulfonimide, phosphoramide, and the like, US 2004/0152769 A1 Aug. 5, 2004 0016 the linkage between D and the C=X moiety than the drugs themselves, and in Such environments, one (Such as a carbonyl) is through an -N-linkage, can achieve greater drug bioavailability. In other environ formed from an NH group present in the urea, ments, the prodrugs are leSS Stable than the native drugs, or thiourea, amide, thioamide, imide, thioimide, car may have the same Stability as the native drugs, but the bamate, thiocarbamate, Sulfonamide, Sulfonimide, prodrug is inactive and/or exhibits reduced Side effects phosphoramide, and the like before being coupled to relative to the drug itself. This can provide for Sustained the C=X moiety in Formula I, resulting in func release of active drug without concomitant Side effects tional groups that are more readily hydrolyzable than asSociated with larger doses. traditional carbamate functional groups, 0026 Pharmaceutical compositions including the pro 0017) and R is a “modifying moiety.” drugs, methods of synthesizing the prodrugs, and methods of treatment using the prodrugs are also described. 0018. In a preferred embodiment, the -COX)XR portion of Formula I is -C(O)OR, and the carbonyl moiety of the 4 BRIEF DESCRIPTION OF THE DRAWINGS -C(O)OR group is coupled to an -NH-functionality of the urea, thiourea, amide, thioamide, imide, thioimide, car 0027 FIG. 1 illustrates a bar graph denoting the chemi bamate, thiocarbamate, Sulfonamide, Sulfonimide, phoS cal hydrolysis of a prodrug according to embodiments of the phoramide, moiety of DSuch that the amine functionality of present invention compared to the chemical hydrolysis of D and the carbonyl moiety and the oxygen of the -COO)OR the parent compound after 0, 1.5, 3.0, 4.5, and 6.0 hours group form a hydrolyzable carbamate moiety.
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