US 2003O130205A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0130205 A1 Christian (43) Pub. Date: Jul. 10, 2003

(54) NOVEL PHARMACEUTICAL Related U.S. Application Data ANTI-INFECTIVE AGENTS CONTAINING MOIETIES AND (63) Continuation-in-part of application No. 09/547,506, METHODS OF THEIR PREPARATION AND filed on Apr. 12, 2000. USE Continuation-in-part of application No. 09/547,501, filed on Apr. 12, 2000, now abandoned. (76) Inventor: Samuel T. Christian, Alabaster, AL Publication Classification (US) (51) Int. Cl." ...... A61K 31/70 (52) U.S. Cl...... 514/23: 514/36 Correspondence Address: (57) ABSTRACT JOHN S. SUNDSMO Hydrophilic N-linked pharmaceutical compositions, meth BIOMEDPATENT COM ods of their preparation and use in neuraxial drug delivery P.O. BOX 535 comprising a glycosyl CNS acting anti-infective prodrug Vista, CA 92085 (US) compound covalently N-linked with a Saccharide through an amide or an amine bond and a formulary consisting of an additive, a Stabilizer, a carrier, a binder, a buffer, an excipi (21) Appl. No.: 10/274,798 ent, an emollient, a disintegrant, a lubricating agent, with the proviso that the Saccharide moiety is not a cyclodextrin or a (22) Filed: Oct. 21, 2002 glucuronide. US 2003/0130205 A1 Jul. 10, 2003

NOVEL PHARMACEUTICAL ANTI-INFECTIVE The latter protein-binding features may contribute to devel AGENTS CONTAINING CARBOHYDRATE opment of adverse allergic and hyperSensitivity reactions in MOIETIES AND METHODS OF THEIR patients. Indicator of a possible underlying adverse reaction PREPARATION AND USE include rash, Sore throat, fever, arthralgia, cough, SortneSS of breath, pallor, purpura or jaundice. Adverse reactions FIELD OF THE INVENTION include gastrointestinal disturbances (nausea, vomiting, anorexia), allergic skin reactions (rash, urticaria) and Severe 0001. The invention relates generally to compositions thrombocytopenia, toxic epidermal necrolysis, fulminant and methods for treating infectious disease. This application hepatic necrosis, agranulocytosis, aplastic anemia, renal is a continuation-in-part of U.S. patent application Ser. NoS. failure and generalized bone marrow Supression. As a poten 09/547,506 and 09/547,501, both filed on Apr. 12, 2000, and tial inhibitor of mammalian folic acid metabolism, terato both incorporated herein by reference in their entirety. genicity has been recorded in animal Studies with congenital abnormalities Suggested in certain retrospective patient Stud BACKGROUND OF THE INVENTION ies. Where few good choices for intervention may exist, trimethoprim-Sulfamethoxazole has proved useful in treat 0002 Delivery of drugs from the blood into neural tissues ments of recalcitrant urinary tract, vaginal and middle ear (neuraxial delivery), joints and dense connective tissue is a infections, as well as, in treatments of Pneumocystis infec key aspect complicating clinical rehabilitation and interven tions in HIV-infected patients. However, the overt hepatic tion techniques. The blood brain barrier and connective and liver toxicity limit use of the drug in the elderly and in tissue barriers effectively limit access of many classes of patients with liver or renal insufficiency. Uses of these drugs known and potentially useful pharmaceutical agents. are undoubtedly limited by protein-binding, poor aqueous 0003) Development of novel anti-infective agents has solubility and toxicity. recently been rekindled due to emergence of multiple anti 0005. The ability of both sulfamethoxazole and trimetho biotic resistant bacteria and increased infection-related mor prim to evoke allergic and hyperSensitivity immune bidity and mortality. In 1994 it was reported that of about 40 responses has been attributed to formation of complexes million patients hospitalized in the United States 2 million with host proteins (e.g., Mauri-Hellweg et al., 1995). How patients acquired nosocomial infections and 50 to 60% ever, Significantly, it has recently been reported that Sul involved antibiotic resistant bacteria. Infection related mor fonilamide drugs may bind directly to antigen receptors of bidity was estimated (at that time) to be about 60-70,000 the major histocompatibility complex (von Greyerz et al., patients/year (e.g., see Tomasz, A. 1994. New Engl. J. Med. 1999), as well as, perhaps to cell Surface integrin receptors 330 (1): 1248). The death rate from infectious diseases has and fibronectin receptors, Such as the platelet gp1a/IIIb and increased by more than 50% since 1980 (e.g., see New and gpIIb/IIIb receptors involved in thrombosis (Curtis et al., Reemerging Infectious Diseases. A Global Crisis and Imme 1994). Sulfonamide anti-infective agents also have poor diate Threat to the Nation's Health. American Society for resistance to ultraViolet light forming free radicals even in Microbiology. 1996.) The Director General of the World crystaline pharmaceutical forms. Health Organization is quoted in the 1996 World Health Report as saying: “We stand on the brink of a global crisis 0006 Delivery of pharmaceutical agents is often compli in infectious diseases. No country is safe from them. No cated by endogenous mechanisms for recycling, Scavenging country can any longer afford to ignore their threat.” and transporting mediators and metabolites. For example, tissue enzyme Systems exist for altering and inactivating 0004 Anti-infective sulfonyl-amide drugs, of a general aromatic amines and amides, i.e., including oxioreductases, class of Sulfonilamide drugs, inhibit bacterial, fungal and methylases, acetylases, hdyroxylases and glucuronic acid parasitic growth by inhibiting Synthesis of microbial dihy conjugating enzyme Systems. Monoamine oxidases, (e.g. in drofolic acid (DHA), i.e., competing para-aminobenzoic Stomach and intestine), are oxioreductases that deaminate acid (PABA). Examples of these agents include, Sul benzylic ring Structures with preferential activity for phe famethoxazole, Sulfathiazole, Sulfamerazine, Sulfadiazine, nylethylamines and benzylamines. O-methyltransferases are Sulfademethoxine, Sulfamethizole, Sulfamoxole, Sulfapyri enzymes that catalyze addition of a methyl group, usually at dine, Sulfamethazine, Sulfamethoxidiazine, Sulfamethoxipy the 3 position of a hydroxyl-Substituted benzene ring. ridazine, Sulfisomidine and Sulfadoxine. Of the latter agents, O-methoxylated derivatives may be further modified by sulfamethoxazole i.e., N'-(5-methyl-3-isoxazolyl)sulfanil conjugation with glucuronic acid. Glucuronidation of drug amide is often used as a faithful backup medication in treatment of penicillinfamoxicillin-resistant infections. To metabolites, i.e., involving glucuronosyltransferase and increase potency and decrease toxicity, Sulfamethoxazole is enzyme Systems in kidney and intestine may be mechanisms often used in combination therapy, for example, in combi targeting urinary and biliary excretion of phenolic drugs nation with the microbial dihydrofolate reductase inhibitor (e.g., see Green et al., 1996). Sulfamethoxazole apparently trimethoprim, i.e., 2,4-diamino-5-(3,4,5-trimethoxyben undergoes N'-acetylation and glucuronidation in humans Zyl)pyrimidine (trimethoprim-Sulfamethoxazole) or with with formation of predominant inactive 1- and 3-Oxides and erythromycin. Combination therapy also reportedly helps 3'- and 4'-hydroxy derivatives. counter emergence of bacterial antibiotic resistance. Trime 0007 Certain cellular mechanisms for transporting glu thoprim-Sulfamethoxazole formlations are commonly avail cose are known. For instance, intestinal intracellular trans able, e.g. BactrimTM and Septa T.M. Unfortunately, both tri port vesicles containing Na+/ co-transporters methoprim and Sulfamethoxazole binding to endogenous (SGLTs) are reported to drive active transport of glucose and plasma proteins, e.g., up to 70% of Sulfamethoxazole and acroSS the intestinal brush border by harnessing 44% of trimethoprim may become protein-associated after Na+ gradients acroSS the membrane. Net rates of vesicle oral dosing (PDR, 47" Edition, 1993, p. 833 and p. 1973). transport and exocytosis have been estimated to be in the US 2003/0130205 A1 Jul. 10, 2003

range of 10 thousand to 1 million per Second (Wright et al., DETAILED DESCRIPTION OF THE 1997). Pointing out the essential nature of this transport, PREFERRED EMBODIMENT missense mutations in SGLT1 result in a potentially lethal inability to transport glucose and galactose (Martin et al., 0011 While it may be relatively common in the pharma 1996). Specificity's and capabilities of transport are subjects ceutical Sciences to develop chemical models in an attempt of active current investigation (Mizuma et al., 1994). Anti to refine Specificity and Selectivity of compounds, it is leSS oxidant flavonol compounds, (present in certain foods as common to develop models that Simultaneously Support the glycosides and quercetin glucosides), may be transported needs of two or more receptor-ligand interactions, or, of acroSS the rat Small intestine via a glucose co-transporter intracellular transport mechanisms; or, receptor-ligand bind pathway (Gee et al., 1998). Intestinal mechanisms for fruc ing interactions, and/or, increased Selective microbicidal tose and possible absorption are currently less well activity with decreased patient toxicity. Anti-infective agents understood. Unlike intestinal transport mechanisms, neural for treating infections are known to depend for their phar glucose transport at the blood brain barrier is reportedly maceutical activity upon a complex interplay between anti mediated by endothelial cells and the Sodium-independent microbial Specificity, lipophilicity, gastrointestinal bioavail facilitative transporter GLUT1 (Kumagai et al., 1999). At ability, and, for central nervous system (CNS) infections, neuronal cells, glucose transport is reportedly mediated blood-brain barrier penetrability. For use in anti-infective predominantly by GLUT3 (Vannucci, S. J. et al., 1998). CNS therapies, the active prodrug compound must theoreti Neural tissue and dense connective tissues are almost cally be delivered into the CNS or cerebrospinal fluid (CSF) in a relatively intact and active form. Gastrointestinal drug entirely dependent on glucose transport for normal meta delivery involves problems of transport, metabolism, methy bolic activity because tissue Stores of glucose are low lation, acetylation, deamidation, glucuronidation, metabo (relative to demand). lism and potential for toxicity. Most Surprisingly, composi 0008 Endothelial barriers effectively limit delivery of tions and methods have been discovered which many pharmaceutically active compounds, including Sul Simultaneously Solve the multiple aspects of these most fonamide anti-infective agents. Approaches disclosed for complex delivery problems. delivering drugs to the brain include the following: namely, (i) lipophilic addition and modification of hydrophilic drugs, 0012) Objects of the invention provide cyclic and hetero (e.g., N-methylpyridinium-2-carbaldoxime chloride; 2-PA; cyclic Sulfonyl-aminyl and -amidyl carbohydrate-linked U.S. Pat. Nos. 3,929,813 and 3,962,447; Bodor et al., 1976, prodrug anti-infective compounds, as disclosed further in 1978 and 1981); (ii) linkage of prodrugs to biologically regard to FORMULA I, below. In other objects, the inven active compounds, (e.g., phenylethylamine coupled to nico tion provides Sulphonyl-amidyl and -aminyl drug composi tinic acid as modified to form N-methylnicotinic acid esters tions having increased therapeutic efficacy at lower admin and amides, Bodor et al., 1981 and 1983; PCT/US83/00725; istered dosages. In other objects, the invention provides U.S. Pat. No. 4,540,564); (iii) derivatization of compounds anti-infective Sulphonyl-aminyl and -amidyl pharmaceutical to centrally acting amines (e.g., dihydropyridinium quater compositions comprising lowered effective unit dosage, at nary amine derivatives; PCT/US85/00236); (iv) caging which dosage risks of Systemic toxicity, allergy and/or compounds within glycosyl-, maltosyl-, diglucosyl- and hyperSensitivity are reduced. In other objects, the invention dimaltosyl-derivatives of cyclodextrin (Bodor U.S. Pat. No. provides novel therapeutically efficacious pharmaceutical 5,017,566, issued May 21, 1991; Loftsson U.S. Pat. No. compositions, e.g., tablets, capsules, Solutions and the like, 5,324,718, issued Jun. 28, 1994 disclosing cyclodextrin employing lower levels of the instant compounds than complexes); and (v) enclosing compounds in cyclodextrin possible with prior Sulfonamide compounds allowing use at lower concentrations with greater efficacy. In other objects, caged complexes (e.g., Yaksh et al., U.S. Pat. No. 5,180, the invention provides modified Sulfonyl-amide and -amine 716). However, these approaches suffer from various differ drug compositions which lack undesirable binding to MHC ent disadvantages including poor pharmacokinetic half-life, proteins, cellular receptors and host proteins thereby pro poor neuraxial bioavailability, variable dosing and Side Viding both increased therapeutic potency and decreased effects. patient risks of developing allergic, hyperSensitivity and 0009 Objects of the invention provide methods for thrombocytopenic adverse reactions. In other objects, the improved delivery of anti-infective Sulfonyl-aminyl and invention provides compositions, methods of production and -amidylglycoconjugateS pharmaceutical agents which also uses for timed-release, Subcutaneous and intradermal, intra have improved physical properties and decreased toxicity. nasal, buccal, trouch and Suppository forms comprising the instant compounds. SUMMARY OF THE INVENTION 0013 In yet other objects, the invention provides meth 0.010 Anti-infective sulfonamide compositions are dis ods for producing hydrophilic Sulfonyl-amine and -amide closed as well as methods for their preparation and use in prodrug pharmaceutical agents N-linked to a carbohydrate treating infectious diseases. The disclosed agents are hydro moiety. In other objects, the invention provides methods for philic prodrug N-linked glycoconjugate Sulfonyl-aminyl and improving the aqueous Solubility of poorly Soluble Sulfonyl -amidyl compounds, having aqueous Solubility. The com aminyl and -amidyl pharmaceutical agents. In other objects, pounds include cyclic and heterocyclic Sulfonyl-amidyl and the invention provides non-toxic multi-dose form composi -aminyl anti-infective compounds. Advantageously, the tions and methods for producing them and for using them to compounds are transportable by Saccharide transporters in treat infectious disease. The instant compounds advanta the gastrointestinal tract and in endothelial cells at tissue and geously have relatively high aqueous Solubility, e.g., up to blood brain barriers. Compounds produced according to the about 4 to about 5 mg/ml, i.e., compared with about 0.04 to methods of the invention find a variety of uses in therapeutic about 0.06 mg/ml for sulfamethoxazole. In certain other methods for treating infectious diseases. objects, the invention provides compositions, methods and US 2003/0130205 A1 Jul. 10, 2003

uses for relatively high therapeutically effective unit doses their constituent Structures the Subject compounds are gen of N-linked Sulfonyl-amidyl and -aminyl prodrug com erally described by the structure of FORMULAI: as set forth pounds in relatively Small volumes. In Still other objects, the below, invention provides therapeutic compositions and methods “A-B-D-E for delivery of Sulfonyl-amine and -amide prodrug com pounds lacking a chemically or enzymatically active reac Formula I tive benzylic amine or amide group. In yet other objects, the 0018 wherein: each of “-” constitutes a single bond; the invention provides therapeutic compositions and methods “A”-moiety constitutes a prodrug; the “B”-moiety consti for delivery of Sulfonanilamide prodrug compounds lacking tutes an optional “bridging” alkyl moiety; the “D'-moiety an Namine nitrogen capable of participating in hydrogen constitutes a nitrogen (N) “linker'; and, the “E”-moiety bonding interactions with Serum and tissue proteins. In other constitutes a saccharide, as disclosed further below. While objects, the invention provides Sulfanilamide for using com certain preferred instant compounds according to FOR MULA I are set forth below as representative examples pounds that are not deamidated by amidases operative in the (below), before addressing the specifics, the meanings of intestine and Stomach. general terms relating to FORMULA I are provided as 0.014 Objects of the invention also provide methods follows: namely, using the instant compounds in treatments of infectious 0019 “Prodrug”, is used interchangeably in reference to diseases, and particularly in infectious diseases localized in the “A-moiety”, FORMULAI (Supra), and is disclosed more dense tissues with poor blood Supply and/or within the particularly in regard to FORMULA IV, below, and is nervous System. In other objects, the invention provides intended to mean a pharmaceutical chemical entity active in methods for using the instant compounds to treat infections ameliorating one or more Symptoms of a disease in a Subject in neurological tissues and in dense tissues with relatively in need thereof. Representative examples are disclosed poor blood Supply, e.g., connective tissues, tendons and joints. (below) and illustrated in the EXAMPLES section. 0020) “Bridge', is used in reference to the B-moiety, of 0.015. In yet other objects, the invention provides meth FORMULA I (supra), and intended to mean an optional ods for treating Subjects in need thereof, in a manner group according to FORMULA II, below, (as depicted effective to achieve therapeutic levels of the instant com linked through Single bonds to each of the A-moiety and the pounds in neuraxial Spaces, connective tissues, tendons, D-moiety, Supra): ligaments and joints. The latter therapeutic method involves active transport of the instant compounds by endogenous Saccharide transporters acroSS the intestinal lumen; then Formula II passively transport in blood; followed by active and/or R5 V R6 facilitative transport at endothelial barriers, e.g., the blood A-Z brain barrier. In other objects, the invention provides treat M D ment methods for achieving Steady-state plasma concentra Rs' tions in Subjects in need thereof using Sulfonyl-amide or -amine prodrug compounds of high aqueous Solubility. In other objects, the invention provides novel therapeutic meth ods, not previously possible, occassioned by enhanced deliv 0021 wherein, ery and the hydrophilic properties imparted to poorly Soluble 0022 Z is optional and when present comprises an pharmaceutical agents according to the methods of the optionally Rs- and Rs-Substituted lower alkyl, preferably, Z invention. In other objects, the invention provides therapeu is absent or a lower alkyl comprising 1 or 2 carbon atoms, tic methods employing the instant compounds to treat infec most preferably, Z is absent or a one carbon atom; and, Rs tious diseases without need to desensitize a hyperSensitive or and Rs (when present) and R and R(when present) are allergic Subject. In yet other objects, the invention provides groupS Selected from among hydrogen, hydroxyl, alkoxyl, methods for transcutaneous delivery of stable sulfonyl carboxyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-car amide and -amine glycosyl prodrug pharmaceutical compo bonyl or dialkylamino-carbonyl. Sitions, i.e., not possible previously with many prior com pounds because of their chemical and UV-light instability. 0023 “Linker”, is used in reference to the D-moiety, FORMULA I (supra), is intended to mean an optionally 0016. Abbreviations used herein are as follows: namely, R7-Substituted amidyl or aminyl nitrogen linking the B-moi MHC, major histocompatibility complex; CNS, central ner ety with the E-moiety, i.e., through each of two Single bonds, vous system; CSF, cerebrospinal fluid; DHA, dihydrofolic according to FORMULA III, below (depicted linking the B acid; PABA, para-aminobenzoic acid; SMX, Sulfamethox and E-moieties of FORMULAI): azole; STH, Sulfathiazole; SMR, Sulfamerazine, SDZ, Sul fadiazine; SDM, Sulfadimethoxine; SID, Sulfisomidine; 0024 namely, SDX, Sulfadoxine; SMT, Sulfamethizole; SMO, Sulfamox ole; SPD, sulfapyridine; SMZ, sulfamethazine; SMD, Sul famethoxidiazine; and, SMP, sulfamethoxipyridazine. Formula III 0017 For purposes of organizing the following disclo Sure, as well as, improved understanding of the Scope and breadth of the Subject prodrug compounds which may be used according to the instant therapeutic methods, as well as US 2003/0130205 A1 Jul. 10, 2003

0.025 wherein, N comprises a nitrogen atom of a primary include the D- and L- and derivatives or Secondary amine or an amide, preferably R-7 is a hydrogen thereof e.g., glyceraldehyde and glyceric acid phosphates, or methyl, most preferably, R-7 is hydrogen. the keto- D- and L- and derivatives 0.026 “Saccharide', is used in reference to the “E-moi thereof. Representative tetraosyl residues include the ety” of FORMULAI (Supra), and is intended to mean a aldoses D- and L-, , Streptose and apiose, Substituted or unsubstituted mono-, di-, tri- or oligosaccha the keto-SugarS D- and L-, and derivatives ride residue having e.g., constituent Sugars comprising 3 thereof. Representative pentosyl residues include the D- and carbon atoms (), 4 carbons (tetraose), 5 carbons (pen L-aldoses , , and ; the D- and tose), 6 carbons (), 7 carbons (), 8 carbons L- and ; and, derivatives thereof. (Octose) or 9 carbon atoms () Such as may be present Representative hexosyl residues include aldosyl, furanosyl in interrelated Straight chain, branched chain and cyclic and pyranosyl Sugars, e.g., cyclic and acyclic D- and L-al forms, e.g., in a hexosyl Straight chain, furanosyl 5-mem doses Such as , , glucose, , , bered ring, pyranosyl 6-membered Sugar ring, and , galactose, , , glucono-1,4-lactone, glu Straight and branched chains composed of caro-1,4:6,3-dilactone, gluconofuranono-6,3-lactone; the Sugar residues, as Set forth further below. ketoseS ribo-heXulose, arabino-heXulolose, Xylo-heXulose 0.027 “Anti-infective prodrug”, when used in regard to and lyXO-heXulose, and derivatives thereof. Representative the “A” moiety of FORMULA I is intended to mean a 7-membered residues (i.e., heptosyl residues) include e.g., Sulfonyl-amidyl or Sulfonyl-aminyl pharmaceutical agent and derivatives thereof, and, representative exerting a growth inhibitory effect on an infectious disease 9-membered residues (i.e., nonosyl residues) include agent, i.e., a microbe as defined below. Representative N-acetylneuraminic acid and derivatives thereof. Also rep examples of anti-infective Sulfonyl-amidyl prodrug entities resentative are, 2-deoxy-ribose, 6-deoxyglucose and include Sulfamethoxazole, Sulfathiazole, Sulfamerazine, Sul 2-deoxyglucose, Xyloascorbyllactone, digitoxose (2-deoxy fadiazine, Sulfademethoxine, Sulfamethizole, Sulfamoxole, altromethylose), (6-deoxy-galactose), gluconolac Sulfapyridine, Sulfamethazine, Sulfamethoxidiazine, Sul tone, galaconolactone, (6-deoxy-mannose), fruc famethoxipyridazine, Sulfisomidine, Sulfadoxine and the tose (2-keto-arabohexose), aldaric acids, alditols, aldonic acids, ketoaldonic acids, and amino Sugars, with the proviso like. that the Sugar is not a cyclodextrin. Representative alditols 0028 “N-linked glycosyl prodrug”, when used herein in includes e.g., erythritol, threitol, ribitol, arabinitol, Xylitol, regard to a pharmaceutical agent, is intended to mean an ly Xitol, glucitol, alloSitol, altrositol, mannositol, gulositol, “A”-moiety anti-infective prodrug compound linked idositol, galactositol, talositol and their derivatives. Repre through an aminyl or amidyl D-moiety nitrogen to a sac Sentative aldonic acids include erythronic acid, threonic charide E-moiety, according to FORMULA I, Supra. Rep acid, ribonic acid, arabinonic acid, Xylonic acid, lyxonic resentative N-linked glycosyl prodrug compounds are also acid, gluconic acid, allonic acid, altronic acid, mannonic disclosed (below) and illustrated (see the EXAMPLES sec acid, gulonic acid, idonic acid, galactonic acid, tolonic acid tion, below). and their derivatives. Representative ketoaldonic acids 0029 "Saccharide” is intended to mean a mono-, di-, tri include erythro-tetrauloSonic acid, threo-tetrauloSonic acid, or oligosaccharide made up of n Sugar Subunits linked to ribo-pentuloSonic acid, arabino-pentuloSonic acid, Xylo each other by glycosidic bonds, which Subunits, when n is pentuloSonic acid, lyZo-pentuloSonic acid, gluco-heXu greater than 1, may be the Same or different in respect to the loSonic acid, allo-heXuloSonic acid, altro-heXuloSonic acid, localization of axial and equatorial ring Substituents, number manno-heXuloSonic acid, gulo-heXuloSonic acid, ido-heXu of carbon atoms and ring carbon locations and orientations loSonic acid, galacto-heXuloSonic acid, talo-heXuloSonic of hydroxyl groups. acid and their derivatives. Representative aldaric acids include erythraric acid, threaric acid, ribaric acid, arabinaric 0030 “Monosaccharide', when used in regard to the “E” acid, Xylaric acid, lyxaric acid, allaric acid, altraric acid, moiety of FORMULAI, is used interchangeably with Sugar glucaric acid, mannaric acid, gularic acid, idaric acid, galac to mean a Sugar residue. Representative examples of Sugar taric acid, talaric acid and their derivatives. Representative residues include the following: namely, polyhydroxy C-al of include erhtyrosamine, threosamine, dehydes (e.g. aldoses and ketoaldoses); polyols resulting ribosamine, arabinosamine, Xylosamine, lyxosamine, from e.g., reduction of the C aldehyde carbonyl to a allosamine, altrosamine, glucosamine, N-acetylglu hydroxyl (e.g., alditols and ketoses); polyhdyroxy acids cosamine, N-methlglucosamine mannosamine, gulosamine, resulting e.g., from oxidation of the Caldehyde and/or the idosamine, galactosamine, talosamine and their derivatives. chain terminal hydroxyl (e.g., aldonic, ketoaldonic, aldaric Representative uronic acids include erythroSuronic acid, and ketoaldaric); amino-Sugars resulting from replacement threoSuronic acid, riboSuronic acid, arabinoSuronic acid, of any hydroxyl in the chain with an amino group (e.g., XyloSuronic acid, lyxoSuronic acid, alloSuronic acid, altro aldosamines and ketosamines); aldehydo-acids resulting e.g. Suronic acid, glucuronic acid, mannoSuronic acid, guloSu from oxidation of only the chain terminal hydroxyl in an ronic acid, idoSuronic acid, galactoSuronic acid, taloSuronic aldehydo-Sugar (e.g., uronic acids and keto-uronic acids); acid and their derivatives. Representative keto-uronic acids and their various lactones, i.e., cyclic esters of hydroxy include keto-erythroSuronic acid, keto-threoSuronic acid, carboxylic acids containing one 1-oxacycloalkan-2-one keto-ribosuronic acid, keto-arabinoSuronic acid, keto-Xylo Structure. The Subject SugarS may be Straight chains and/or Suronic acid, keto-lyxoSuronic acid, keto-alloSuronic acid, cyclic 3-, 4-, 5-, 6-, 7-, 8- and 9-membered Sugar residues keto-altroSuronic acid, keto-glucuronic acid, keto-mannoSu (e.g., hemiacetals and acetals) optionally Substituted and ronic acid, keto-guloSuronic acid, keto-idoSuronic acid, linked with the pharmaceutical agent as Set forth according keto-galactoSuronic acid, keto-taloSuronic acid and their to FORMULA I, Supra. Representative triosyl residues derivatives. Representative lactones include erythrolactone, US 2003/0130205 A1 Jul. 10, 2003

threolactone, ribolactone, arabinolactone, XyloSlactone, arabinosides, XyloSides, lyxoSides, alloSides, altroSides, glu ly XOslactone, allolactone, altrolacone, glucolactone, manno cosides (e.g., , (Glc-?31,4Frc), galactosides (e.g., lac lactone, gulolactone, idolactone, galactolactone, talolactone tose; Gal-f1,4-Glc), mannosides, gulosides, idosides, talo and their derivatives. sides and their substituted derivatives. Other representative include the following: namely, Sucrose, 0.031 Preferred sugar residues for use according to the , fucosidolactose, , lactobionic acid, amy instant methods comprises or pentosyl or lose, fructose, fructofuranose, Scillabiose, panose, , hexosyl SugarS Selected from the group consisting of D- and , hyaluronic acid, chondroitin Sulfate, heparin, L- enantiomers of ribose, glucose, galactose, mannose, laminarin, lichenin and . Preferably, the Subject Sugar, arabinose, allose, altrose, gulose, idose, talose and their when present as an oligosaccharide, is Selected from the substituted derivatives. Most preferably, the subject sugar group consisting of glucosyl and galactosyl homo- and comprises an aldose pentosyl or hexosyl Sugar Selected from heteropolymers, e.g., , , glucosides and ribose, glucose, galactose, glucosamine, galactosamine, galactosides. The Subject Sugar is not a cyclodextrin or N-acetylglucosamine, N-acetylgalactosamine, N-acetyl derivative thereof. The subject E-moiety is not a cyclodex ribosamine, Xylose, mannose and arabinose. trin or derivative thereof. 0.032 “Di-saccharide', when used in regard to the subject 0037 “Aldose” is intended to mean a polyhydroxyalde Sugar residue, is intended to mean a polymeric assemblage hyde of the sugar of the general form HICH(OH),C(=O)H, of 2 Sugar residues. Representative examples of disaccha wherein n is an integer greater than one; preferably, the rides include homo-polymeric (e.g., and ) Subject aldose is in equilibrium with furanosyl and pyrano and hetero-polymeric (e.g., lactose and Sucrose) assem blages of Sugars as Set forth Supra. syl forms. 0038 “Ketose', also known as ketoaldose, is intended to 0.033 “Tri-saccharide', when used in regard to the Sub mean a Sugar containing both an aldehydic group and a ject Sugar residue, is intended to mean a polymeric assem ketonic carbonyl group; preferably, the Subject ketose is in blage of 3 Sugar residues, e.g., as Set forth Supra. equilibrium with intramolecular hemiacetal forms. 0034 Preferably, the subject di- and tri-saccharide Sugar 0039) “Aldaric acid” is intended to mean a polyhydroxy moieties are metabolizable and/or acid hydrolyzable to dicarboxylic acid of a Sugar having the general formula mono- and di-Saccharides transportable by Saccharide trans HOC(=O)CH(OH)nC(=O)CH, wherein n is greater than porters in mammals. 1 and Such as may be derived from an aldose by Oxidation 0035 “Oligosaccharide”, when used in relation to the of both terminal carbon atoms to carboxyl groups. subject E-moiety residue of FORMULA I, is intended to 0040 “Alditol' is intended to mean an acyclic polyol mean a polymeric assemblage of about 4 to about 10 having the general formula HOCHICH(OH), CHOH, glycosidically linked constituent homo-monosaccharide wherein n is greater than one. Sugars (i.e., all the same constituent) or hetero-monosaccha ride (i.e., different constituent) Sugars. Each of the Subject 0041) “Aldonic acid” is intended to mean a polyhydroxy constituent SugarS is linked one-to-another in a Serial array acid having the general formula HOCHICH(OH) through a Series of glycosyl bonds formed between the C C(=O)CH, wherein n is greater than one and Such as may and C carbon atoms, or alternatively, between the C and C. be derived from an aldose by oxidation of the aldehyde carbon atoms, or alternatively, between the C and C carbon function. atOmS. 0042 “Amino Sugar" is intended to mean a sugar 0.036 The Subject oligosaccharides may be homo-poly (defined Supra) having one alcoholic OH group replaced by meric, i.e., all the same Sugar constituent, or hetero an amino group. monosaccharide, i.e., different constituent SugarS. Prefer 0043 “Glycosyl is intended to mean a hexose sugar ably, the Subject oligosaccharide is Selected from Substituent group; preferably, a glucosyl or galactosyl Sub metabolizable and/or acid hydrolyzable oligosaccharides Stituent. which following hydrolysis yield mono-, di- and tri-saccha rides, and most preferably, the resultant constituent Sugars 0044) “Glycosylamine”, also known as N-glycosides, is are transportable by a Saccharide transporter in a mammal. intended to mean glycosyl group attached to an amino Representative oligosaccharides include lactose, maltose, -NR, group; preferably, an N-linked glucosyl or galactosyl , Sucrose, glycogen, cellobiose, fucosidolactose, Substituent. lactulose, , fructose, fructofuranose, Scillabiose, 0045 "' is intended to mean a cyclic hemiacetal panose, raffinose, amylopectin, hyaluronic acid, chondroitin form of a Sugar in which the ring is five membered. Sulfate, heparin, laminarin, lichenin and inulin. Preferably, the Subject E-moiety, when present as an oligosaccharide, is 0046 “' is intended to mean a cyclic hemiacetal Selected from the group consisting of glucosyl and galacto form of a hexose Sugar in which the ring is six membered. Sylhomo- and heteropolymers. Most preferably, the Subject E-moiety when present as an oligosaccharide, is Selected 0047 As used herein the following additional terms are from the group of metabolizable Saccharides consisting of intended to have meaning as follows: namely, (i) homopolymerS Such as an erythran, a threan, a riban, an 0048 “Saccharide transporter” is intended to mean a arabinan, a Xylan, a lyxan, an allan, an altran, a (e.g. cellular membrane protein capable of binding a Saccharide maltose, isomaltose, cellobiose), a mannan, a gulan, an idan, and transporting that Saccharide from one location to another a , a talan and their Substituted derivatives; (ii) on/in the cell. Representative examples of Saccharide trans heteropolymerS Such as erythroSides, threosides, ribosides, porters include a glucose transporters (e.g., GLUT 1, 2, 3, 4 US 2003/0130205 A1 Jul. 10, 2003 and 5), galactose transporters, a mannose transporters, fruc nervous System relating to infection), ii) Vascular impair tose transporters, arabinose transporters and the like. Those ment e.g. resulting from infectious and/or inflammatory skilled in the art are cognizant of methods by which test damage to nervous tissues, iii) central nervous System compounds may be shown capable of binding to a Saccha degeneration or peripheral nerve degeneration, and iv) ner ride transporter, i.e., and examples of which are provided Vous System lesions induced by infectious agents. Repre below. Sentative illness, diseases, and conditions having neurologic 0049. “Pharmaceutical composition”, is intended to mean dysfunction have been classified and codified (“International a composition containing one or more N-linked glycosyl Classification of Diseases, Washington D.C., 1989). prodrug compounds according to FORMULAI and a for 0055 “Subject in need thereof" is intended to mean a mulary effective to provide a dosage form Suitable for mammal, e.g., humans, domestic animals and livestock. administration to man or a domestic animal. Representative Representative examples of Subjects in need thereof include examples of formularies and dosage forms So Suitable are humans and domestic animals having an infection. Repre provided below. Sentative infections include pulmonary infections, nasal 0050 “Formulary” is intended to mean an agent added to infections, bronchial infections, dermal infections, infec a pharmaceutical composition comprising Said hydrophilic tions of dense tissues, (e.g., muscle, connective tissues, N-linked prodrug compound according to FORMULA I. tendons and ligaments), and infections of the peripheral and Representative examples of formulary agents include addi central nervous System. tives, Stabilizers, carriers, binders, buffers, excipients, emol 0056 “Intestinal cell' is intended to mean a columnar lient water-in-oil and oil-in-water emulsions, disintegrants, epithelial cell, e.g., a microVillus luminal cell, lining the lubricating agents, antimicrobial agents, preservative and Small or large intestine, or lining the colon. the like; as disclosed further below. 0057 “Endothelial cell' is intended to mean a cell lining 0051) “Dosage form” is intended to mean a form of a a blood vessel, e.g., a capillary cell or a cell of an artery or pharmaceutical composition Suitable for administration to a vein. man or a domestic animal. Representative dosage forms 0.058 “Neural cell” is intended to mean cells of the include Solids and liquids, e.g., perenteral and injection nervous System, including neurons, glial cells, Schwann Solutions, powders and granules, emollient creams, Syrups cells and the like. and elixirs, nasal and ophthalmic drops, intrabronchial inhal ants, timed-release capsules, lozenges, troches, Supposito 0059) “Transportable in an intact form” is intended to ries, dermal patches, impregnated bandages and the like. mean that the instant N-linked glycosyl prodrug compound is not an inhibitor of a Saccharide transporter, and is not 0.052 “Treatment” is intended to mean a method of Substantially chemically altered during transport, e.g., it is delivering to a Subject in need thereof, i.e., man or a not methylated or metabolized to an inactive form or con domestic animal, a pharmaceutical preparation with the aim verted to a glucuronide during transport, Such that when the of ameliorating or preventing one or more indicia of an instant compound is transported from one side of a cell to the infection in the subject. The subject methods include deliv ering the preparation to a patient i) before the infection has another Side it remains Substantially chemically and func been diagnosed, (e.g., prophylactic protocols delivered with tionally unchanged. the aim of preventing development of the infection), as well 0060 “Neuraxial delivery” is intended to mean that as, ii) after the infection has been diagnosed, (e.g., thera administration of one or more of the instant pharmaceutical peutic protocols). That the subject treatments have fulfilled compositions, according to FORMULA I, at one or more the intended aim will be evident to a skilled practitioner by Sites outside the central nervous System results in measur a change (increase or decrease) or complete elimination of able levels of the A-moiety drug within a neural tissue or a one or more clinical indicia of the infectious disease. neural tissue fluid. Representative neural tissues include myelinated and non-myelinated nerves, brain and Spinal 0.053 “Indicia of dysfunction” is intended to mean a sign cord. Representative neural tissue fluids include cerebrospi or Symptom of an infectious disease as may be evident to a nal fluid and tissue homogenates and expressates obtained trained professional, e.g., a clinician or Specialist, in View of from myelinated and non-myelinated nerves. Representative one or more patient clinical Symptoms, or in View of a methods for measuring levels of the instant prodrugs in combination of laboratory test results and observations. Representative indicia of infection include clinical Symp biological fluids are known to those of skill in the art. toms of inflammation, i.e., fever, redness, Swelling and the 0061 “Substantially chemically unchanged” means that like; neurologic dysfunction resulting from peripheral and only conservative modifications of certain R group Substitu central nervous System infection, e.g., motor and Sensory ents of the A, B, D or E-moieties (FORMULAI, below) may dysfunction, disorientation and the like; as well as diagnos occur during transport, e.g., removal of a halogen atom and tic test results and results from microbiological culture and replacement with a hydrogen, conversion of a hydroxyl to a isolation. methoxy and the like. 0.054 “Neurologic dysfunction” is intended to mean a 0062) “Brain penetration index”, abbreviated BPI, is pathophysiologic or psychologic condition of a central or intended to mean the mathematical ratio calculated as the peripheral nervous System tissue, which condition is evi amount of one or more of the instant compounds in brain denced by a difference relative to a function of a nervous tissue per gram of brain tissue, divided by the amount of the System activity in a normal healthy control Subject. For compound (or compounds) in liver tissue per gram liver example, the Subject conditions include, but are not limited tissue. The liver being chosen as a reference organ because to, i) toxic dystrophy, (e.g., Secondary dystrophy in the of its intimate contact with blood and relative lack of US 2003/0130205 A1 Jul. 10, 2003

barriers. Measurements of BPI may be made for instance at 0067. In other embodiments, the invention provides 5-60 minutes after administration of a test compound, e.g., methods for treating a Subject in need thereof by the Step of by oral, Subcutaneous or intravenous routes. The Subject administering one or more of the instant pharmaceutical mathematical ratio is commonly expressed as a percentage, compositions comprising an N-linked glycosyl prodrug i.e., by multiplying the ratio by 100%. This procedure has the advantage that even for a sparingly Soluble lipophilic compound according to FORMULAI to the subject. Pref drugs, (which tend to remain largely at an injection site with erably, the instant methods involve treatment regimens use Slow diffusion into the circulation), the amounts of drug in ful for ameliorating one or more indicia of disease in a the liver will reflect the actual amount which is systemically Subject having an infectious disease, as Set forth Supra. available and not the initial dose injected. Certain of the According to the instant disclosure, pharmaceutical compo preferred compounds according to the instant invention have Sitions administered according to the instant method provide BPIs in the range of about 2% to about 500%, most preferred N-linked glycosyl prodrug compounds which when released compounds have a BPI of about 10% to about 200%. from the instant pharmaceutical compositions are transport 0.063 “Microbial infection” is intended to mean infection able across the gastrointestinal tract, transportable in blood, of a mammalian host with a bacteria, Virus, fungus, rickets and transportable acroSS the blood brain barrier, or acroSS sia, mycoplasma, prion agent, or parasite. endothelial barriers in dense tissues, in a Substantially intact 0.064 Embodiments of the invention provide pharmaceu form. Preferably, within the latter tissue sites the instant tical compositions containing a hydrophilic N-linked pro N-linked glycosyl prodrug compounds are activatable by a drug compound, according to FORMULA I, and a formu tissue amidase, e.g., a glucosaminidase, a galactosaminidase lary, preferably in a dosage form as defined Supra. The and the like, to release the A-moiety prodrug from its instant N-linked Sulfonyl prodrug compounds contain an covalent linkage with the B-D-E-moiety. Most preferably, A-moiety prodrug linked through an aminyl or amidyl bond the A-moiety prodrug, when released, comprises and active with a Saccharide moiety, preferably a mono-, di- or tri drug exerting a growth inhibitory effect on an infectious Saccharide. The instant pharmaceutical compositions are Suitable for treating a neurological infection in a Subject in disease agent, i.e., a microbe. need thereof without resort to combination therapy, e.g., a 0068. In yet other embodiments, the invention provides treatment with the instant compound an a monoamine oxi methods for improving the aqueous Solubility and blood dase or decarboxylase inhibitor. Despite N-linkage between brain barrier penetrability of a prodrug compound by the Subject prodrug compound and the Saccharide moiety, covalently linking that prodrug compound through an ami the compounds and compositions according to the invention nyl or amidyl nitrogen bond to a Saccharide. In certain when administered in an oral dosage form are: (i) transport preferred embodiments, the Subject prodrug compound com able in a Substantially intact form acroSS the gastrointestinal prises a prodrug according to FORMULAI, and the instant lumen and into blood, i.e., by endogenous active transport methods are effective to both increase acqueous Solubility and mechanisms; then, (ii) transportable in blood to the blood improve blood-brain-penetrability. While it may be common brain barrier (i.e., unassociated or associated with erythro in the art to add hydrocarbon chains to prodrug compounds cyte Saccharide transporters); and, (iii) transportable across to increase lipid Solubility, (i.e., often at the expense of the blood brain barrier into myelinated and unmyelinated decreased acqueous Solubility), the instant methods provide neural tissues (i.e., by facilitative transporters in endothelial an alternative, which Simultaneously offers advantages of cells). high aqueous Solubility and good blood brain barrier pen 0065. In other embodiments, the invention provides etrability. methods and processes for preparing a variety of hydrophilic N-linked glycosyl prodrug compounds, each of which meth 0069. In certain presently preferred embodiments, the ods and processes contains a Synthetic Step, or Series of invention provides methods for administering a anti-infec Steps, which result in the formation of an aminyl or an tive therapy to a subject in need thereof. The instant method amidyl nitrogen bond between a Saccharide moiety and a involves administering to the Subject one or more of the prodrug compound according to FORMULA I, Supra. instant pharmaceutical preparations consisting of an 0.066. In other embodiments, the invention provides pro N-linked glycosyl prodrug compound according to FOR ceSSes for preparing pharmaceutical compositions compris MULA I, with the requirement that the instant compound, ing hydrophilic N-linked glycosyl prodrug compounds, when So administered, is capable of inhibiting the growth of according to FORMULA I, Suitable for neuraxial delivery. a microbial agent, e.g., inhibiting one or more microbial The processes comprise the Steps of first linking a prodrug cellular metabolic processes. compound, according to FORMULA I, Supra, with a sac charide moiety through an aminyl or amidyl nitrogen atom. 0070. In other embodiments, the invention provides Representative conditions suitable for formation of amidyl methods for producing prodrug compositions with improved or aminyl nitrogen bonds between the Subject prodrug bioavailability, CNS penetrability and adsorption enhancing compounds and the Saccharide E-moiety are illustrated activity. The methods involve the Step (or steps) of linking below. Next, formulary compounds (Supra) are added to the a Saccharide through an amidyl or aminyl nitrogen bond resultant N-linked glycosyl prodrug to form the instant with a Sulfonyl prodrug compound to form the instant pharmaceutical composition. Representative formulary compound according to FORMULA I. compounds, as disclosed Supra, additives, Stabilizers, carri ers, binders, buffers, excipients, emollients, disintegrants, 0071. In certain presently preferred embodiments, the lubricating agents, antimicrobial agents, preservatives and invention provides improved methods for treating infectious the like. diseases. The instant methods employ one or more of the US 2003/0130205 A1 Jul. 10, 2003 instant N-linked glycosyl prodrug anti-infective compounds 0076 Presently preferred pharmaceutical A-moiety (Supra), i.e., having improved bioavailability and aqueous (FORMULAI) drug compounds according to the methods Solubility, fewer toxic Side effects and fewer allergic and of the invention are anti-infective drugs of the general class hyperSensitivity reactions. of chemical compounds disclosed in TABLE B, below. 0.072 In certain other preferred embodiments, the inven tion provides pharmaceutical compositions containing TABLE B N-linked glycosyl Sulfonyl anti-infective prodrug com pounds according to FORMULA I that are effective to ANT-MICROBIAL AGENTS: inhibit one or more microbial biosynthetic processes at a site Sulfamethoxazole of infection at lower dosages than the parent A-moiety (FORMULA I) sulfonyl-amidyl or -aminyl anti-infective O drug. 9N N-S NH2 0073. In yet other embodiments, the invention provides S. H || anti-infective pharmaceutical compositions with improved CH O aqueous Solubility and transportability by Saccharide trans porters and methods for their use in neuraxial delivery of Sulfamethiazole anti-infective therapy across the intestine (e.g., in timed release dosage forms) and rectum (e.g., in Suppositories). R it 0.074. Unlike sulfamethoxazole, presently preferred S. X--H || NH2 embodiments of the invention according to FORMULA I S O provide anti-infective Sulfonyl-amidyl and -aminyl prodrug compositions that offer advantages of possible decreased Penciclovir tissue ulceration, irritation and toxicity when injected or applied locally (e.g., onto a skin or mucosal Surface) or when O delivered into the gastrointestinal lumen via an oral route. N N 0075. In addition to Sulfonyl-amidyl and aminyl pro drugs, the instant methods of the invention find particular us y other uses for improving the properties of other, (non NH; 4. N-- Sulfonamide), classes of sparingly water-Soluble anti-infec CH2OH tive prodrug compounds Such as may have undesirable toxicological or pharmacokinetic profiles, e.g., trimethop Sulfamerazine rim. Representative classes of anti-infective pharmaceutical drug compounds that may contain sparingly water Soluble, CH lipophilic and/or water-labile drugs which may prove Suit able for use according to the instant methods are disclosed R it in TABLE A and TABLE B on the following pages. Rep / )-N- NH2 resentative pharmaceutical drug compounds contemplated FN | for improvement according to the instant methods include O those set forth in TABLE A, as well as derivatives thereof, Sulfadiazine with the presently preferred drug compounds disclosed in TABLE B, below.

TABLE A Class of Agent: Representative Examples: Antimicrobial Agents ampicillin, penicillin G, ketoconazole, itraconazole, metronidazole, miconazole, co-trimoxazole, amoxicillin, oxacillin, carbenicillin, benzylpenicillin, phenoxymethylpenicillin, methicillin, nafcillin, ticarcillin, bacampicillin, epicillin, hetacillin, pivampacillin, the methoxymethyl ester of hetacillin, ampicillin, chlortetracycline, demeclocycline, minocycline, doxycycline, Oxytetracycline, tetracycline, methacycline, clindamycin, lincomycin, nalidixic acid, Oxolinic acid, phenazopyridine, dicloxacillin, cephalothin, cephalexin, cefazolin, cefoxitin, moxalactam, ceforanide, cefroxadine, cephapirin, imidazole-type antifungal agents, econazole, clotrimazole, Oxiconazole, bifonazole, metronidazole (metronidazole benzoate), fenticonazole, miconazole, Sulconazole, tioconazole, isoconazole, butoconazole, ketoconazole, doconazole, parconazole, orconazole, Valconazole and lombazole, trizole-type antifungal agents, terconazole, itraconazole, co-trimoxazole, sulfadiazine, sulfonamide Antiprotozoal Agents imidazole-type antiprotozoals, metronidazole, ornidazole, carnidazole, ipronidazole, tinidazole, nimorazole, benzimidazole-type antifungals, flubendazole Antihelminthic Agents benzimidazole-type, thiabendazole, Oxibendazole, cambendazole, fenbendazole, flubendazole, albendazole, Oxfendazole US 2003/0130205 A1 Jul. 10, 2003

TABLE B-continued TABLE B-continued

ANT-MICROBIAL AGENTS: ANT-MICROBIAL AGENTS: R it Melarsoporol / )-N- NH2 =s, " O| Sulfamethoxine

CHO 2 N M N \/ --(|| )—s. O Penicillins: CHO H S CH Trimethoprim O CH OCH N R N COOH s's OCH H O N 21 OCH3 e.g. Amoxicillin

NH2 WHERER = Cephalosporins: e.g. Cefepime HO CH H OCH3- N V S CH\ N NH2 N N-4 le Anti-tuberculosis Agents: \ N C e.g. Ethionamide

sit-4, O O OSNH2

Anti-Fungal Compounds: OSNH e.g. Flucytosine N 2 NY 2 l Cycloserine

Anti-Parasitic Agents: e.g. Trimetrexete NH2SR NH2 OMe - N N N OMe Amino-salicylic acid NH e N COOH N e N OMe OH Pentamidine

NH HN O NH2 O NH2 NH2 Cycloguanil US 2003/0130205 A1 Jul. 10, 2003 10

TABLE B-continued -continued FORMULA IVb ANT-MICROBIAL AGENTS: is R14n1 L YMa 1 R 16 )= N R131. r n R17 c-()- )-NH. R-- CH -- CH R2 R4 Pyrimethamine 1. X Y. n R1 Rs ? Rs' R0 CHCH ny1 N n. / )-Nil, N Ya FN E/ SR, NH2 0078 wherein, Ring 1 and Ring 2 each independently 0077. In certain presently preferred embodiments, the comprise an optionally Substituted cyclic or heterocyclic A-B-D-E compound of FORMULA I, comprises a com ring, or an optionally Substituted aromatic ring, Ring 1 being pound according to FORMULAS IVa-IVb, wherein, the composed of about 4 to about 8 carbon atoms, among which A-moiety' prodrug is depicted linked through the “B” and are counted “X” and “Y” and Ring 2 composed of about 4 “D’-moieties with the “E”-moiety as set forth and described to about 6 atoms among which are counted “G”, “J”, “L’, further below: namely, “O'” and optional ring components “M” and “R”;

FORMULA IV a 0079 preferably, Ring 1 comprises an optionally substi - R. R 15 tuted aryl or heteroaryl ring and Ring 2 comprises an v J-11 optionally Substituted 5-membered ring or a heteroaryl; and

1. {2 \, a 0080 most preferably, Ring 1 comprises a substituted R13 Y R 16 aryl ring, wherein, R, R2, R and R comprise the Subject R-N-R optional ring Substituents and X and Y each comprise a "A" carbon atom; 0081 most preferably Ring 2 comprises an optionally R2 R4 substituted 5-membered ring, i.e., as depicted in FORMULA 1. IVa, or 6-membered ring, i.e., as depicted in FORMULA X Y. R1 n R0 IVb; and, - Rs n, 1 Rs' 0082 wherein the instant 5-membered Ring 2 (FOR "B" MULA IVa) is selected from among the compounds num R6 R6 bered 1A through 17E of TABLE C, and the instant 6-mem N n bered Ring 2 (FORMULA IVb) is selected from among the "D" / SR E compounds numbered 1A through 19F of TABLE D (below).

TABLE C Alternative Ring 2 Groups: 5-membered Compound Class No. “G” “J” “L” “M” “Q” Representative Ring Strucutres 1A C C N C C pyrrolyl, pyrrolidinyl 1B C N C C C pyrrolyl, pyrrolidinyl US 2003/0130205 A1 Jul. 10, 2003 11

TABLE C-continued Alternative Ring 2 Groups: 5-membered Compound Class No. s' cL “M “Q Representative Ring Strucutres pyrrolyl, pyrrolidinyl pyrrolyl, pyrrolidinyl pyrrolyl, pyrrolidinyl thiophenyl thiophenyl thiophenyl thiophenyl thiophenyl furanyl furanyl furanyl furanyl furanyl imidazolyl, imidazolidinyl imidazolyl, imidazolidinyl imidazolyl, imidazolidinyl imidazolyl, imidazolidinyl imidazolyl, imidazolidinyl pyrazolyl, pyrazolidinyl pyrazolyl, pyrazolidinyl pyrazolyl, pyrazolidinyl pyrazolyl, pyrazolidinyl pyrazolyl, pyrazolidinyl Oxazolyl, oxazolidinyl Oxazolyl, oxazolidinyl Oxazolyl, oxazolidinyl SMO: Oxazolyl, oxazolidinyl Oxazolyl, oxazolidinyl isooxazolyl, isooxazolidinyl isooxazolyl, isooxazolidinyl isooxazolyl, isooxazolidinyl isooxazolyl, isooxazolidinyl SMX: isooxazolyl, isooxazolidinyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl Oxathiolanyl, Oxathiolyl thiazolidinyl, thiazolyl thiazolidinyl, thiazolyl thiazolidinyl, thiazolyl thiazolidinyl, thiazolyl thiazolidinyl, thiazolyl isothiazolidinyl, isothiazolyl isothiazolidinyl, isothiazolyl isothiazolidinyl, isothiazolyl isothiazolidinyl, isothiazolyl isothiazolidinyl, isothiazolyl triazolidinyl, triazolyl triazolidinyl, triazolyl triazolidinyl, triazolyl triazolidinyl, triazolyl triazolidinyl, triazolyl oxadiazolyl, oxadiazolidinyl oxadiazolyl, oxadiazolidinyl oxadiazolyl, oxadiazolidinyl oxadiazolyl, oxadiazolidinyl oxadiazolyl, oxadiazolidinyl thiadiazolyl, thiadiazolidinyl thiadiazolyl, thiadiazolidinyl thiadiazolyl, thiadiazolidinyl thiadiazolyl, thiadiazolidinyl thiadiazolyl, thiadiazolidinyl oxadiazolidinyl, oxadiazolyl oxadiazolidinyl, oxadiazolyl oxadiazolidinyl, oxadiazolyl

US 2003/0130205 A1 Jul. 10, 2003 13

TABLE D-continued Alternative Ring 2 Groups: Aryl Compound Class No. s' cL “M “Q Representative Ring Strucutres Oxazinanyl, oxazinyl Oxazinanyl, oxazinyl Oxazinanyl, oxazinyl Oxathianyl, Oxathiinyl Oxathianyl, Oxathiinyl Oxathianyl, Oxathiinyl Oxathianyl, Oxathiinyl Oxathianyl, Oxathiinyl Oxathianyl, Oxathiinyl C ithianyl, dithiinyl C ithianyl, dithiinyl C ithianyl, dithiinyl C ithianyl, dithiinyl C ithianyl, dithiinyl C ithianyl, dithiinyl C ithiazinanyl, dithiazinyl C ithiazinanyl, dithiazinyl C ithiazinanyl, dithiazinyl C ithiazinanyl, dithiazinyl C ithiazinanyl, dithiazinyl C ithiazinanyl, dithiazinyl hiomorpholinyl, thiazinyl hiomorpholinyl, thiazinyl hiomorpholinyl, thiazinyl hiomorpholinyl, thiazinyl hiomorpholinyl, thiazinyl hiomorpholinyl, thiazinyl hiazinanyl, thiazinyl hiazinanyl, thiazinyl hiazinanyl, thiazinyl hiazinanyl, thiazinyl hiazinanyl, thiazinyl hiazinanyl, thiazinyl riazinanyl, triaziny riazinanyl, triaziny riazinanyl, triaziny riazinanyl, triaziny riazinanyl, triaziny riazinanyl, triaziny Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl Oxadiazinanyl, oxadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl thiadiazinanyl, thiadiazinyl US 2003/0130205 A1 Jul. 10, 2003

0084 Ro, R, R, R and Reach independently comprise and, representative 9-membered residues (i.e., nonosyl resi a group Selected from among hydrogen, hydroxyl, halogen, dues) include N-acetylneuraminic acid and derivatives halo-lower alkyl, alkoxy, alkoxy-lower alkyl, halo-alkoxy, thereof. Also representative are, 2-deoxy-ribose, 6-deoxy thioamido, amidoSulfonyl, alkoxycarbonyl, carboxamide, glucose and 2-deoxyglucose, Xyloascorbyllactone, digitox amino-carbonyl, and alkylamine-carbonyl; preferably, each ose (2-deoxyaltromethylose), fucose (6-deoxy-galactose), comprises a group Selected from hydrogen, hydroxyl, lower gluconolactone, galaconolactone, rhamnose (6-deoxy-man alkyl and alkoxyl-lower alkyl, most preferably, each com nose), fructose (2-keto-arabohexose), aldaric acids, alditols, prises hydrogen; aldonic acids, ketoaldonic acids, and amino Sugars, with the 0085 R. R., RS, R, each independently comprise a proviso that the E-moiety is not a cyclodextrin. Represen group Selected from among hydrogen, hydroxyl, lower alkyl tative alditols include e.g., erythritol, threitol, ribitol, ara and alkoxyl-lower alkyl, preferably, each is independently binitol, Xylitol, lyxitol, glucitol, alloSitol, altrositol, man hydrogen or lower alkyl, and, most preferably, each is nositol, gulositol, idositol, galactositol, talositol and their independently hydrogen or lower alkyl, derivatives. Representative aldonic acids include erythronic acid, threonic acid, ribonic acid, arabinonic acid, Xylonic 0.086 Z is optional and when present comprises a lower acid, lyxonic acid, gluconic acid, allonic acid, altronic acid, alkyl optionally Substituted with Rs and Rs, preferably, Z is mannonic acid, gulonic acid, idonic acid, galactonic acid, absent or a lower alkyl comprising 1 or 2 carbon atoms, most tolonic acid and their derivatives. Representative ketoal preferably, Z is absent or a one carbon atom; and, Rs and donic acids include erythro-tetrauloSonic acid, threo-tetrau Rs (when present) and R and R(when present) are groups loSonic acid, ribo-pentuloSonic acid, arabino-pentuloSonic Selected from among hydrogen, hydroxyl, alkoxyl, carboxyl, acid, Xylo-pentuloSonic acid, lyxo-pentuloSonic acid, gluco alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and heXuloSonic acid, allo-heXuloSonic acid, altro-heXuloSonic dialkylamino-carbonyl, acid, manno-heXuloSonic acid, gulo-heXuloSonic acid, ido heXuloSonic acid, galacto-heXuloSonic acid, talo-heXu 0.087 N comprises a nitrogen atom of a primary or loSonic acid and their derivatives. Representative aldaric Secondary amine or an amide, preferably R-7 is a hydrogen or acids include erythraric acid, threaric acid, ribaric acid, methyl, most preferably, R-7 is hydrogen; and, arabinaric acid, Xylaric acid, lyxaric acid, allaric acid, 0088 E comprises a saccharide moiety as set forth above altraric acid, glucaric acid, mannaric acid, gularic acid, and below. idaric acid, galactaric acid, talaric acid and their derivatives. Representative of amino Sugar include erhtyrosamine, 0089 Representative examples of E-moiety saccharide threosamine, ribosamine, arabinosamine, Xylosamine, lyx residues include the following: namely, polyhydroxy C, osamine, allosamine, altrosamine, glucosamine, N-acetyl aldehydes (e.g. aldoses and ketoaldoses); polyols resulting glucosamine, N-methlglucosamine mannosamine, from e.g., reduction of the C aldehyde carbonyl to a gulosamine, idosamine, galactosamine, talosamine and their hydroxyl (e.g., alditols and ketoses); polyhdyroxy acids derivatives. Representative uronic acids include erythroSu resulting e.g., from oxidation of the Caldehyde and/or the ronic acid, threoSuronic acid, ribosuronic acid, arabinoSu chain terminal hydroxyl (e.g., aldonic, ketoaldonic, aldaric ronic acid, XyloSuronic acid, lyxoSuronic acid, alloSuronic and ketoaldaric); amino-Sugars resulting from replacement acid, altroSuronic acid, glucuronic acid, mannoSuronic acid, of any hydroxyl in the chain with an amino (e.g., guloSuronic acid, idoSuronic acid, galactoSuronic acid, talo aldosamines and ketosamines); aldehydo- acids resulting Suronic acid and their derivatives. Representative keto e.g. from oxidation of only the chain terminal hydroxyl in an uronic acids include keto-erythroSuronic acid, keto-threoSu aldehydo-Sugar (e.g., uronic acids and keto-uronic acids); ronic acid, keto-ribosuronic acid, keto-arabinoSuronic acid, and their various lactones, i.e., cyclic esters of hydroxy keto-XyloSuronic acid, keto-lyxoSuronic acid, keto-alloSu carboxylic acids containing one 1-oxacycloalkan-2-one ronic acid, keto-altroSuronic acid, keto-glucuronic acid, Structure. The Subject SugarS may be Straight chains and/or keto-mannoSuronic acid, keto-guloSuronic acid, keto-idoSu cyclic 3-, 4-, 5-, 6-, 7-, 8- and 9-membered Sugar residues ronic acid, keto-galactoSuronic acid, keto-taloSuronic acid (e.g., hemiacetals and acetals) optionally Substituted and and their derivatives. Representative lactones include eryth linked with the D-moiety as Set forth, Supra. Representative rolactone, threolactone, ribolactone, arabinolactone, Xylo triosyl residues include the aldoses D- and L-glyceraldehyde Slactone, lyxOSlactone, allolactone, altrolacone, glucolac and derivatives thereof e.g., glyceraldehyde and glyceric tone, mannolactone, gulolactone, idolactone, galactolactone, acid phosphates, the keto-SugarS D- and L-dihydroxyac talolactone and their derivatives. etone and derivatives thereof. Representative tetraoSyl resi dues include the aldoses D- and L-erythrose, threose, Strep 0090 Preferably, the subject E-moiety comprises an tose and apiose, the keto-SugarS D- and L-erythrulose; and aldose or ketose or hexose Sugar Selected from the derivatives thereof. Representative pentosyl residues group consisting of D- and L- enantiomers of ribose, glu include the D- and L-aldoses ribose, arabinose, Xylose and cose, galactose, mannose, arabinose, allose, altrose, gulose, lyxose; the D- and L-ketoseS ribulose and Xylulose, and, idose, talose and their substituted derivatives. Most prefer derivatives thereof. Representative hexosyl residues include ably, the Subject E-moiety comprises an aldose pentosyl or aldosyl, furanosyl and pyranosyl Sugars, e.g., cyclic and hexosyl Sugar Selected from ribose, glucose, galactose, glu acyclic D- and L-aldoses Such as allose, altrose, glucose, cosamine, galactosamine, N-acetylglucosamine, N-acetyl mannose, gulose, idose, galactose, talose, fructose, glucono galactosamine, N-acetyl ribosamine, Xylose, mannose and 1,4-lactone, glucaro-1,4:6,3-dilactone, gluconofuranono-6, arabinose. 3-lactone; the ketoseS ribo-heXulose, arabino-heXulolose, 0091 “Halogen' is intended to mean a fluorine, chlorine, Xylo-heXulose and lyxo-heXulose; and derivatives thereof. bromine, or Sulfur atom or ion or group. Preferred halo Representative 7-membered residues (i.e., heptosyl resi groups are chlorine, bromine, thiol and Sulfonyl and most dues) include e.g., Sedoheptulose and derivatives thereof; preferred, chlorine. US 2003/0130205 A1 Jul. 10, 2003

0092 “Lower alkyl is intended to mean a hydrocarbon 0105. “Alkylaminocarbonyl' is intended to mean a chain containing fewer than Six carbon atoms, preferably -C(O)NHR substituent group wherein R is a lower alkyl. fewer than four and most preferably two or 3 carbon atoms. Representative lower alkyl groups include methyl, ethyl, 0106 “Alkoxycarbonyl” is intended to mean a n-propyl, i-propyl, n-butyl, t-butyl and i-butyl. Presently -C(O)OR Substituent group. preferred alkyls are methyl, ethyl or i-propyl, and most 0107 “Carboxamide" is intended to mean a –NR'COR preferably, ethyl. Substituent group. 0093. “Substituted lower alkyl” is intended to mean a 0.108 “Dialkylaminocarbonyl' is intended to mean a lower alkyl in which one or more of the hydrogen atoms are -C(O)NR'R substituent group, wherein R' and R constitute replaced by a Substituent group. Representative Substituent lower alkyl groups. groups include hydroxy, alkoxy, halogen, amino, amido, carboxyl, thiol, Sulfonyl, methoxy and the like. 0109) “Haloalkoxy” is intended to mean a -OR Sub Stituent group where R is a haloalkyl. 0094) “Halo-lower alkyl is intended to mean a lower alkyl in which one or more of the hydrogen atoms on the 0110 “Oxyamido” is intended to mean a-OC(O)NH hydrocarbon chain has been replaced by a halogen atom. or -HNC(O)O-substituent. 0.095 “Cycloalkyl is intended to mean a closed saturated 0111 "Thioamido” is intended to mean a-SC(O)NH monocyclic hydrocarbon ring made up of about 4 to about or -HNC(S)- Substituent. 9 carbon atoms, preferably about 5 to about 7 carbon atoms 0112 “Amidosulfonyl” is intended to mean a and most preferably 6 carbon atoms. Representative -NHSO-substituent. examples of cycloalkyl compounds include phenyl, pip eridyl, piperazinyl, diazinyl, morpholinyl, isooxazoanyl and 0113. In other embodiments, the invention provides the like. methods of using pharmaceutical compositions containing one or more compounds according to FORMULA I, Supra, 0.096 “Heterocyclic” is intended to mean a close satu in combination with optional Stabilizers, carriers, binders, rated monocyclic ring made up of about 4 to about 8 carbon buffers, excipients, emollients, disintegrants, lubricating atoms and about 1 to about 2 non-carbon atoms, preferably, agents, antimicrobial agents and the like. For oral adminis about 5 to about 6 carbon atoms and 1 non-carbon halogen tration, the instant methods may employ pharmaceutical or oxygen atom; and, most preferably 5 carbon atoms and 1 compositions that are liquid, Solid or encapsulated. For non-carbon halogen or oxygen atom. perenteral administration, the instant methods may employ 0097 “Aromatic”, and “aryl', are used interchangeably pharmaceutical compositions that are Sterile liquids or Sol to mean a closed unsaturated monocyclic hydrocarbon ring ids, e.g., as provided in a powdered or granulated form System made up of about 3 to about 9 carbon atoms having Suitable for reconstitution. a delocalized L-electron system. Preferably, the Subject aryl 0114. In other embodiments, the invention provides ring is made up of about 5 to about 7 carbon atoms and most methods of using pharmaceutical compositions containing preferably, 6 carbon atoms. Representative aromatic rings one or more compounds according to FORMULA I, Supra, include benzyl, pyranyl, pyridyl, pyrimidinyl, thiadiazinyl in combination with an optional Second anti-infective agent, and pyridazinyl, with benzyl preferred. and also optional Stabilizers, carriers, binders, buffers, 0.098 “Amine” is intended to mean an -NHR substitu excipients, emollients, disintegrants, lubricating agents, ent group. antimicrobial agents and the like. For oral administration, the instant methods may employ pharmaceutical composi 0099) “Amide” is intended to mean an–C(O)N-(R')R" tions that are liquid, Solid or encapsulated. For perenteral or -HNC(O) substituent group, where R' and R" are administration, the instant methods may employ pharma hydrogen or a Substituent Such as hydroxy, lower alkyl, ceutical compositions that are Sterile liquids or Solids, e.g., amino, or the like. Preferred amino groups are those wherein as provided in a powdered or granulated form Suitable for R' or R" is hydrogen. reconstitution. In one presently preferred embodiment one compound according to FORMULAI, Supra, is administered 0100 “Alkoxy” is intended to mean an -OR substituent in an admixed formulation with the anti-infective drug grOup. trimethoprim. 0101 “Halo-lower alkyl is intended to mean a halogen Substituted lower alkyl, preferably, a halogen Substituted 0115 The instant methods may employ compounds to be lower alkyl having 2 to 6 carbon atoms, most, preferably, a administered alone or in combination with pharmaceutically chlorine or fluorine substituted lower alkyl having 2 to 4 acceptable carriers, e.g. in either Single or multiple doses. carbon atoms. Suitable pharmaceutical carriers may include inert Solid diluents or fillers, Sterile aqueous Solutions, and various 0102) “Alkoxy-lower alkyl is intended to mean an nontoxic organic Solvents. The pharmaceutical compositions alkoxy compound, Supra, wherein R comprises a lower formed by combining a compound according to FORMULA alkyl, preferably a 2 to 6 carbon lower alkyl; and most I with a pharmaceutically acceptable carrier may be admin preferably, a 2 to 4 carbon lower alkyl. istered according to the instant methods in a variety of dosage forms Such as tablets, lozenges, Syrups, injectable 0103 “Thioalkoxy” is intended to mean an -SOR Sub Solutions, and the like. The Subject pharmaceutical carriers Stituent group. can, if desired, contain additional ingredients Such as fla 0104 “Aminocarbonyl' is intended to mean a Vorings, binders, excipients, and the like. Thus, for purposes -C(O)NH, substituent group. of the instant oral administration, tablets containing various US 2003/0130205 A1 Jul. 10, 2003

excipients Such as Sodium citrate, calcium carbonate, and borate, benzoate, lactate, phosphate, to Sulate, citrate, male calcium phosphate may be employed along with various ate, furmarate, Succinate, tartrate, and the like. disintegrants Such as , and preferably potato or tapioca Starch, alginic acid, and certain complex Silicates, together 0118 For use in the instant methods, freely-soluble salts with binding agents Such as polyvinylpyrolidone, Sucrose, of a compound according to FORMULAI may be converted gelatin, and acacia. Additionally, lubricating agents, Such as to a salt of a lower solubility in a body fluid, e.g. by magnesium Stearate, Sodium lauryl Sulfate, and talc may be modification with a slightly water-Soluble pharmaceutically useful for tableting purposes. Solid compositions of a simi acceptable Salt Such as tannic or palmoic acid, or by inclu lar type may also be employed as fillers in Salt and hard Sion in a time-release formulation Such as covalently filled gelatin capsules. Preferred materials for this purpose coupled to a larger carrier, or in timed-release capsules and include lactose or milk Sugar and high molecular weight the like. In general, the acid addition Salts of the Subject polyethylene glycols. When aqueous Suspensions of elixirs compounds with pharmaceutically acceptable acids will be are desired for oral administration according to the instant biologically equivalent to the compounds themselves. Phar methods, the compound therein may be combined with maceutically acceptable Salts can be prepared from the various Sweetening or flavoring agents, colored matter or compounds by conventional methods. Thus, Such Salts are, dyes, and if desired, emulsifying or Suspending agents, for example, prepared by treating with an aqueous Solution together with diluents Such as water, ethanol, propylene of the desired pharmaceutically acceptable metallic hydrox glycol, glycerin, and combinations thereof. For parenteral ide or other metallic base and evaporating the resulting administration according to the instant methods, Solutions Solution to dryness, preferably under reduced pressure in a may be prepared in Sesame or peanut oil or in aqueous nitrogen atmosphere. Alternatively, a Solution of a com polypropylene glycol, as well as Sterile aqueous Saline pound is mixed with an alkoxide to the desired metal, and Solutions of a corresponding water-Soluble pharmaceutically the Solution Subsequently evaporated to dryneSS. The phar acceptable metal Salt, e.g. as disclosed Supra. The Subject maceutically acceptable hydroxides, bases, and alkoxides aqueous Solution is preferably Suitably buffered if necessary include those with cations for this purpose, including (but and the liquid diluent first rendered isotonic with sufficient not limited to), potassium, Sodium, ammonium, calcium, Saline or glucose. Such acqueous Solutions of compounds and magnesium. Other representative pharmaceutically according to FORMULAI may be particularly suitable for acceptable Salts include hydrochloride, hydrobromide, Sul intravenous, intramuscular, Subcutaneous, and intraperito fate, bisulfate, acetate, oxalate, Valarate, oleate, laurate, neal injection. The Subject Sterile aqueous media employed borate, benzoate, lactate, phosphate, tosylate, citrate, male are obtainable by Standard techniques well known to those ate, furmarate, Succinate, tartrate, and the like. skilled in the art. 0119) The preferred pharmaceutical compositions for 0116 For use in one or more of the instant methods, it inocula and dosage for use in the instant methods will vary may prove desirable to Stabilize a compound according to with the clinical indication. The inocula may typically be FORMULA I, e.g. to increase shelf life and/or pharmaco prepared from a dried compound by Suspending the com kinetic half-life. Shelf-life stability may be improved by pound in a physiologically acceptable diluent Such as water, adding excipients Such as: a) hydrophobic agents (e.g., Saline, or phosphate-buffered Saline. Some variation in dos glycerol); b) non-linked Sugars (e.g., Sucrose, mannose, age will necessarily occur depending upon the condition of Sorbitol, rhamnose, Xylose); c) non-linked complex carbo the patient being treated, and the physician will, in any hydrates (e.g., lactose); and/or d) bacteriostatic agents. For event, determine the appropriate dose for the individual use in the instant methods, pharmacokinetic half-lives may patient. The effective amount of the instant compound per vary depending upon the Saccharide moiety Selected, e.g., unit dose depends, among other things, on the body weight, whether a Sugar or a digestible oligosaccharide, or the nature physiology, and chosen inoculation regimen. A unit dose of of the Sugar R-group constituents. For use in the instant a compound according to FORMULAI refers to the weight methods, pharmacokinetic half-life and pharmacodynamics of the Subject compound without the weight of carrier (when may also be modified e.g. by: a) encapsulation; b) control carrier is used). Generally, the amount of active ingredient ling the degree of hydration; and, c) controlling the electro administered to a Subject in need thereof according to the Static charge and hydrophobicity of the Sugar constituents. practice of the invention will be in the range of about 1 0117 For use according to the instant methods, pharma mg/day to about 2.5gm/day. Single unit dosage forms and ceutically acceptable Salts can be prepared from the instant multi-use dosage forms are considered within the Scope of compounds by conventional methods. Thus, Such Salts may, the invention, as disclosed further below. for example, be prepared by treating a compound according 0120 Pharmaceutically acceptable carriers may be to FORMULA I with an aqueous solution of the desired formed, filled and Sealed for ease of use according to the pharmaceutically acceptable metallic hydroxide or other methods of the invention. Representative forming, filling metallic base and evaporating the resulting Solution to and Sealing methods are known in the pharmaceutical arts. dryneSS, preferably under reduced pressure in a nitrogen For instant, the Subject compositions may be formulated atmosphere. Alternatively, a Solution of the Subject com with pharmaceutically acceptable carriers into pharmaceu pound may be mixed with an alkoxide to the desired metal, tical preparations Suitable for inclusion in timed-release and the Solution Subsequently evaporated to dryneSS. The capsules, tablets, lozenges, Syrups and the like. pharmaceutically acceptable hydroxides, bases, and alkOX ides include those with cations for this purpose, including 0121 For treatments of local infections, the subject com (but not limited to), potassium, Sodium, ammonium, cal pounds may be provided in an emollient cream. Represen cium, and magnesium. Other representative pharmaceuti tative examples of emollient pharmaceutically acceptable cally acceptable Salts include hydrochloride, hydrobromide, carriers include oil-in-water and water-in-oil emulsions, i.e., Sulfate, bisulfate, acetate, oxalate, Valarate, oleate, laurate, as are known to those skilled in the pharmaceutical arts. US 2003/0130205 A1 Jul. 10, 2003

0122) Pharmaceutically acceptable salts may be prepared according to FORMULA I. In certain embodiments, the from the subject compounds by conventional methods. For invention provides improved treatment methods using rela example, Such Salts may be prepared by treating one or more tively high concentrations of the Subject drugs in multi-dose, of the Subject compounds with an aqueous Solution of the time-release, Subcutaneous and intradermal, buccal, trouch, desired pharmaceutically acceptable metallic hydroxide or and Suppository preparations. In other embodiments, the other metallic base and evaporating the resulting Solution to instant treatment methods may also be especially useful for dryneSS, preferably under reduced pressure in a nitrogen achieving Steady State plasma levels in Subjects in need atmosphere. Alternatively, a Solution of the Subject com thereof. Where conventional methods of administration may pound may be mixed with an alkoxide to the desired metal, be ineffective in certain patients, the instant methods, i.e., and the Solution Subsequently evaporated to dryneSS. The employing high Solubility compounds according to FOR pharmaceutically acceptable hydroxides, bases, and alkOX MULA I, make it feasible to administer anti-infective ides include those with cations for this purpose, including therapy in a multi-dosage form, e.g. via an implantable (but not limited to), potassium, Sodium, ammonium, cal mini-pump (Such as used for delivery of insulin in patients cium, and magnesium. Other representative pharmaceuti with Type 1 insulin-dependent diabetes mellitus). cally acceptable Salts include hydrochloride, hydrobromide, 0.126 Embodiments of the invention provide methods for Sulfate, bisulfate, acetate, oxalate, Valarate, oleate, laurate, improving the aqueous Solubility of poorly Soluble pharma borate, benzoate, lactate, phosphate, to Sulate, citrate, male ceutical agents. The compositions prepared according to the ate, furmarate, Succinate, tartrate, and the like. methods of the invention have improved acqueous Solubility. 0123. In alternative embodiments, the invention provides The instant compositions have improved bioavailability different routes for delivery of compounds according to providing a pharmacologically effective therapeutic unit FORMULA I as may be suitable for use in the different dosage at a lower level of administered drug compound. The infectious disease States and Sites where treatment is instant methods thus provide novel formulations and result required. For topical, intrathecal, intramuscular or intra ant pharmaceutical compositions wherein lower concentra rectal application it may prove desirable to apply the Subject tions of pharmaceutical agents provides cost-Savings, and at compounds as a Salve, ointment or emollient pharmaceutical the same time, improvements in efficacy. Bioavailability, in composition at the local Site, or to place an impregnated this context, is intended to mean improved pharmacokinetic bandage or a dermal timed-release lipid-Soluble patch. For rates of delivery occassioned e.g., by more effective trans intra-rectal application it may prove desirable to apply the port from the gastrointestinal System into blood, or by Subject compounds e.g. in a Suppository. In other embodi greater Solubility in bodily fluids, as well as, improved ments, it may prove desirable to administer the Subject stability of drug levels in bodily fluids. In addition to compositions by intranasal or intrabronchial instillation delivery rate improvements, the instant methods provide (e.g., as pharmaceutical compositions Suitable for use in a novel pharmaceutical compositions not previously possible nebulizer), or by gastrointestinal delivery (e.g., with a cap with poorly Soluble pharmaceutical agents. Sule, tablet, trouch or Suppository). Also contemplated are 0127 Embodiments of the invention provide treatments Suppositories for urethral and vaginal use. In one preferred for neurologic infections. According to the instant methods, embodiment, the Subject pharmaceutical compositions are a purpose of therapy in an acute Setting may be to rapidly administered via Suppository taking advantage of Saccharide increase the concentration of one or more of the instant transporters in the rectum for transport into the blood Stream composition in a tissue, e.g., by a bolus intravenous injec in a timed-release type manner e.g. providing possible tion. Alternatively, in other cases it may desirable to deliver anti-infective therapy in a patient with an immunodeficiency the composition over a longer period of time, e.g., by Syndrome and a Pneumocystis carinii infection. infusion. The route of delivery according to the instant methods is determined by the infectious disease and the Site 0.124. Embodiments of the invention provide treatments where treatment is required. For topical application, it may for infectious diseases with several different microbes prove desirable to apply the compositions at the local Site including e.g., Pseudomonas aeruginosa, Escherichia coli, (e.g., by placing a needle into the tissue at that Site) or by Klebsiella Species, Enterobacter Species, Morganella mor placing a timed-release dermal patch), while in a more acute ganii, Proteus mirabilis, Proteus vulgaris, Haemophilus disease clinical Setting it may prove desirable to administer influenzae, Streptococcus, Shigella flexneri, Shigella Sonnei, the compositions Systemically. For other indications the Shigella dysenteriae, Pneumocystis carinii and antibiotic instant compounds may be delivered by intravenous, intra resistant Strains thereof. Infections that may be amenable to peritoneal, intramuscular, Subcutaneous and intradermal treatments according to the instant invention include, e.g., injection, as well as, by intranasal and intrabronchial instil pulmonary infections (pneumonia, chronic bronchitis, infec lation (e.g., with a nebulizer), transdermal delivery (e.g., tions in cystic fibrosis patients, Pneumocystis carinii infec with a lipid-Soluble carrier in a skin patch), or gastrointes tions in HIV infected patients and the like); urinary tract tinal delivery (e.g., with a capsule or tablet). The preferred infections, vaginal infections; middle ear infections (otitis therapeutic compositions for inocula and dosage will vary media); gastrointestinal infections (e.g., Shigellosis, entero with the clinical indication. The inocula may typically toxic E. coli enteritis and the like; central and peripheral prepared from a dried compound, e.g. by Suspending the nervous System infections, and, infections of dense tissues, compound in a physiologically acceptable diluent Such as e.g., connective tissues, tendons, ligaments and the like. water, Saline, or phosphate-buffered Saline. Some variation 0.125. In yet other embodiments, the invention provides in dosage will necessarily occur depending upon the con therapeutic methods in which a relatively high concentration dition of the patient being treated, and the physician will, in of active ingredients (e.g., up to about 4 to about 5 mg/ml) any event, determine the appropriate dose for the individual is included in a relatively Small Volume taking advantage of patient. Since the pharmacokinetics and pharmacodynamics the Special aqueous Solubility of the prodrug compounds of the instant compounds will vary somewhat in different US 2003/0130205 A1 Jul. 10, 2003 patients, the most preferred method for achieving a thera assayS. For example, a representative Selection of five patho peutic concentration in a tissue is to gradually escalate the genic bacteria may be chosen from among the agents of dosage and monitor the clinical effects. The initial dose, for bacterial meningitis, i.e., StreptococcuS pneumoniae, Neis Such an escalating dosage regimen of therapy, will depend Seria meningitidis, Haemophilis influenza, Group B Strep upon the route of administration. tococcus and Escherichia coli (Medical Microbiology, 3" Edition, Murray, et al., 1998; CDC, http://cdc.gov/ncidod// 0128. In other embodiments, the invention provides dbmd). The minimal inhibitory concentration (MIC) of a test methods prophylactic and therapeutic uses in treatment of an compound may be determined on Such bacteria by microdi infectious disease in a man or domestic animal, involving lution following established guidelines (National Committee the Step of administering to the Subject in need thereof a for Clinical Laboratory Standards, 3" Edition, 1998). Such compound according to FORMULA I, Supra. In certain testing determines the lowest concentration of a test com alternative embodiments, the method may involve adminis pound capable of preventing visible growth of a bacteria. In tration of an intravenous bolus injection or perfusion, or may addition, it is possible to determine the minimum bacteri involve administration during (or after) Surgery, or a pro cidal concentration (MBC) of a test compound by counting phylactic administration. In certain other embodiments, the bacterial colonies growing on microbiological plates, e.g., instant administration may involve a combination therapy, according to established methods as Set forth in guidelines e.g., a compound according to FORMULAI and a Second established by the FDA (FDA Bacteriological Analytical drug, e.g., an anti-coagulant, a Second anti-infective agent, Manual, 8" Edition, 1998). In addition, disk-plate-diffusion an anti-Viral agent and/or an anti-hypertensive agent. bioassays of a test compound may be conducted with the 0129. The route of delivery of the subject preparations, Size of an inhibitory Zone (mm) giving a relative in vitro according to the instant methods, determined by the particu measure of anti-microbial activity of the Subject test com lar disease. For topical application it may be useful to apply pound (Lannette, E. H., Manual of Clinical Microbiology, the instant compounds at the local site (e.g., by injection, 4 Edition: American Association for Microbiology, Wash while for other indications the preparations may be delivered ington, D.C.). For comparative purposes, it prove worth by intravenous, intraperitoneal, intramuscular, Subcutane while to compare the activity of a test compound according ous, intranasal, and intradermal injection, as well as, by to the invention with the activity of Sulfamethoxizole. In the transdermal delivery (e.g., with a lipid-Soluble carrier in a art, it is appreciated that the combination of MIC value, Size skin patch placed on the skin), or even by oral and/or of the Zone of inhibition in disk-plate-diffusion assays, and gastrointestinal delivery (e.g., with a capsule, tablet or MBC are effective in predicting antimicrobial activity of a Suppository). test compound. Test compounds may also be evaluated in experimental animals, e.g., to determine an EDso, e.g., in 0130. In certain preferred embodiments, the invention rats at an oral dosage of about 0.1-30 mg/kg. provides methods for administering to a Subject in need thereof one or more anti-infective agents according to FOR 0.132. In one embodiment, a pharmaceutical composition MULAI in combination with an agent capable of stimulat for use in humans comprises a therapeutic unit dose effective ing intestinal or neural glucose transporter activity, e.g., to delivery to the subject in need thereof about 0.08 mg/kg IGF-1, glucagon, Vascular infusions of glucose and the like. to about 8 mg/kg of trimethoprim, or a trimethoprim The instant combination treatments may be effected by the gluconamide according to FORMULA I, and about 0.04 same route, (e.g., both administered orally), or alternatively, mg/kg to about 40 mg/kg of a compound according to either by different routes. Instruction is provided that intestinal of FORMULA IVa or FORMULA IVb per 24 hrs. An glucose Saccharide co-transporters exhibit circadian period illustrative use of the latter composition being therapy in icity and expression is inducible by dietary carbohydrate children with otitis media. (e.g., see Rhoads et al., 1998), and negatively regulated by 0133. In a second embodiment, a pharmaceutical com leptin (e.g., see Lostao et al. 1998). Thus, in certain embodi position for use in humans comprises a therapeutic unit dose ments, treatment regimens for oral administration may effective to delivery to the subject in need thereof about 0.02 include instructions to take one or more of the Subject mg/kg to about 20 mg/kg of trimethoprim, or trimethoprim compounds orally with a feeding that includes dietary car gluconamide according to FORMULA I, and about 1.0 bohydrate, and preferably, in the morning within about 5 to mg/kg to about 100 mg/kg of a compound according to about 20 minutes after the first meal, and in the evening either of FORMULA IVa or FORMULA IVb per 24 hrs. An before, during or within about 5 to about 20 minutes after an illustrative use of the latter composition being treatment of evening meal. Instruction is also provided that during the patients with pulmonary Pneumocystis carinii infections. instant treatment the following are to be avoided because they may alter Saccharide transporter activity: namely, (i) 0.134. In a third alternative embodiment, a pharmaceuti high cholesterol diet; (ii) co-administration with oral cal cal tablet for use in humans comprises about 1.60 mg to cium channel blockers (e.g., see Hyson et al. 1996, 1997); about 160 mg of trimethoprim, or a trimethoprim-glucona (iii) erythromycin (Navarro et al., 1993); and, (iv) barbitu mide according to FORMULA I, and about 8 mg to about rates (Haspel et al., 1999). 800 mg of a compound according to either of FORMULA IVa or FORMULA IVb. 0131 Methods for determining that a test compound according to FORMULA I, i.e., with a drug selected from 0135) In a fourth embodiment, a pharmaceutical tablet for TABLE A or TABLE B, is Suitable for use in one or more use in humans comprises about 0.8 mg to about 80 mg of of the instant methods, (i.e., for treating infectious disease), trimethoprim, or a trimethoprim-gluconamide according to are known to those skilled in the art of neuropsychophar FORMULA I, and about 4 mg to about 400 mg of a macology, immunology and microbiology. For instance, the compound according to either of FORMULA IVa or FOR test compound may be evaluated in tests in microbiological MULA IVb. US 2003/0130205 A1 Jul. 10, 2003

0136. The following EXAMPLES illustrate synthetic methods which may prove useful in preparation of the TABLE E instant N-linked Sulfonyl-amine and -amide drugs according Component Amount to FORMULA I, FORMULA IVa and FORMULA IVb. Compound #1 or #2 2.5 gm Additional disclosure of the N-linked glycosyl prodrug Methyl-p-aminobenzoic acid 0.014 gm pharmaceutical compositions is contained within Appli Propyl-p-aminobenzoic acid 0.020 gm cant's copending U.S. patent application Ser. Nos. 09/547, Saccharin sodium 0.050 gm Flavoring agent 0.001 gm 506 and 09/547,501, both filed on Apr. 12, 2000, and both Citric acid 0.200 gm incorporated herein by reference in their entirety. Sodium citrate 0.320 gm Distilled water USP q.s. to 100 ml EXAMPLE 1.

Preparation of N-linked Glycosyl Prodrug EXAMPLE 3 Compounds: Dopamine Gluconamide and Illustrative Powder Composition for Reconstitution Dopamine Gluconamine Prior to Use 0137) Synthesis of representative alternative N-linked 0141 Powder composition suitable for reconstitution glycosyl prodrug compounds is disclosed in applicants co before use were prepared according to TABLE F. pending U.S. patent application Ser. Nos. 09/547,506 and 09/547,501, both filed on Apr. 12, 2000, both incorporated TABLE F herein by reference in their entirety. Briefly, gluconolactone and 3-hydroxytryamine were reacted slowly in methanol to Component Amount form a white Solid dopamine gluconamide precipitant. The Compound #1 or #2 2.5 mg Sodium citrate 20.0 mg product was collected by filtration, Washing and drying in Sorbitol 2.0 mg vacuo (i.e., dopamine gluconamide, Compound #1, below). Flavoring agent 0.1 mg Distilled water USP for 10.0 ml 0138 Synthesis of dopamine gluconamine from the reconstitution dopamine gluconamide Compound #1 involved first protect ing the dopamine aromatic hydroxyl groups by addition of acetone, Stirring, refluxing and cooling to form the isopro EXAMPLE 4 pylidine-protected product as a white Solid. The Solid was removed by filtration and dried in vacuo. Second, the Illustrative Tablets for Oral Administration dopamine gluconamide carbonyl group was reduced by 0.142 Tablets for oral administration were prepared addition of Borane in THF, and after refluxing, cooling, and according to TABLE G. solvent removal by rotary evaporation methanolic HCl was added and the Solution was again refluxed. Solvent was TABLE G removed by evaporation and the Solid dopamine glucon Component Amount amine product was recrystalized using a mixture of aceto Compound #1 or #2 250 mg nitrile and ethanol. The recrystalized reduced dopamine Starch 17 mg gluconamine product (i.e., referred to below as Compound Sodium glycolate (starch) 40 mg Polyvinal pyrrollidene 7.0 mg #2) was dried in vacuo. Microcrystalline 45 mg 0.139. By way of non-limiting illustration, using Appli Magnesium sterate 2.0 mg cant's methods amide and amine products were prepared e.g., for at least the following pharmaceutical agents: namely, dopamine ribonamine and ribonamide, p-ami EXAMPLE 5 nobenzoic acid gluconamine and gluconamide, p-aminoSali cyclic acid gluconamine and gluconamide, acyclovir glu Illustrateive Tablets for Sublingual Administration conamine and gluconamide; tryptamine gluconamine and 0.143 Tablets for Sublingual administration were pre gluconamide, Sulfamethoxazol gluconamine and glucona pared according to TABLE H. mide, SulfaSalazine gluconamine and gluconamide, phen ethylamine gluconamine and gluconamide, and, benzocaine TABLE H gluconamine and gluconamide. Component Amount Compound #1 or #2 250 mg EXAMPLE 2 Gum arabic 10 mg Lactose 90 mg Ammonium glycyrrhiznate 20 mg Illustrative Ready Solution For Administration as a Sodium saccharin 2 mg Measured Dose Flavor 10 mg Magnesium sterate 7 mg 0140. Ready solutions for administration as a measured dose were prepared according to TABLE E, below. US 2003/0130205 A1 Jul. 10, 2003 20

EXAMPLE 6 0154) Findlay, J., Levy, G. A. and C. A. Marsh. 1958. Inhibition of glycosidases by aldonolactones or correspond Preparation of N-linked Glycosyl Prodrug ing configuration. 2. Inhibitors of B-N-acetylglucosamini Compounds: Preparation of Sulfamethoxazole dase. Biochemical J. 69: 467-476. Gluconamide-1 0155 Fodor et al. 1961. Acta Chim. Acad. Sci. Hung. 28 0144) Sulfamethoxazole (1.42 g, 5.6 mmol) was added (4): 409. with stirring to a 100 mL round bottom flask containing 8-gluconolactone (1.00 gm, 5.6 mmol), triethylamine (5.7 0156 Gee, J. M., DuPont, M. S., Rhodes, M.J. and I. T. gm, 5.6 mmol) and 30 mL of acetonitrile. The mixture as Johnson. 1998. Quercetin glucosides interact with the intes refluxed for 4.5 hr. during which time the reaction mixture tinal glucose transporter pathway. Free Radic. Biol. Med. 25 became homogeneous. After allowing the Solution to cool to (1): 19-25. room temperature, Solvent was removed by rotary evapora 0157 Green, M.D. and T. R. Tephly. 1996. Glucuronida tion. The resultant reaction product was rinsed with cold tion of amines and hydroxylated Xenobiotics and endobiotics acetonitrile to give a white Solid Sulfamethoxazole glucona catalyzed by expressed human UGT1.4 protein. Drug mide (1.36 gm, about 56.2% yield) having a melting point Metab. Dispos. 24(3): 356-363. of 154-155° C. 0158 Haspel, H. C., Stephenson, K. N., Davies-Hill, T., 0145 Analysis Calculated for CHNOS (431.42): El-Barbary, A., Lobo, J. F., Croxen, R. L., Mougrabi, W., C, 44.55; H, 4.91; N, 9.74; S, 7.43. Found: C, 44.6; H, 4.91; Koehler-Stec, E. M., Fenstermacher, J.D. and I. A. Simpson. N, 9.73; S, 7.34. 1999. Effects of barbiturates on facilitative glucose trans porters are pharmacologically Specific and isoform Selective. EXAMPLE 7 J. Membr. Biol. 169 (1): 45-53. Preparation of N-linked Glycosyl Prodrug 0159) Horton, D. 1969. Monosaccharide Amino Sugars. Compounds: Preparation of Sulfamethoxazole In: “The Amino Sugars': The Chemistry and Biology of Gluconamide-2 Compounds Containing Amino Sugars. Vol. 1A. Ed. R. W. 0146 Alternatively, sulfamethoxazole (1.42g, 5.6 mmol) Jeanloz. Academic Press, N.Y. pp. 4-18. was added with stirring to a 100 mL round bottom flask 0160 Huang, X., Xu, R., Hawley, M.D., Hopkins, T. L. containing 6-gluconolactone (1.00 gm, 5.6 mmol) and 30 and K. J. Kramer. 1998. Electrochemical oxidation of mL of methanol. The mixture as refluxed for 4.5 hr. during N-acyldopamines and regioSelective reactions of their which time the reaction mixture became homogeneous. quinones with N-acetylcysteine and thiourea. Arch. Bio After allowing the Solution to cool to room temperature, chem. Biophys. 352 (1): 19-30. solvent was removed and the product collected by filtration. The resultant reaction product was rinsed with cold aceto 0.161 Hyson, D. H., Thomson, A. B. and C. T. Kappa nitrile to give a white Solid Sulfamethoxazole gluconamide goda. 1996. Calcium channel blockerS modify jejunal uptake (1.36 gm, about 60% yield) having a melting point of of D-galactose in rabbits. Dig. Dis. Sci. 41 (9): 1871-1875. 154-155° C. 0162 Hyson, D. H., Thomson, A. B., Keelan, M. and C. 0147 Analysis Calculated for CHNOS (431.42): T. Kappagoda. 1997. A high cholesterol diet blocks the effect C, 44.55; H, 4.91; N; 9.74; S, 7.43. Found: C, 44.6; H, 4.91; of calcium channel blockers on the uptake of Sugars in rabbit N, 9.73; S, 7.34. intestine. Can. J. Physiol. Pharmacol. 75 (1): 57-64. 0163 Kerwin, J. L. 1996. Negative ion electrospray mass Citations Spectrometry of polyphenols, catecholamines and their oxi 0148 Bodor et al., 1978. J. Pharm. Sci, 67 (5): 685. dation products. J. Mass Sprectrom. 31: 1429-1439. 0149 Bodor, 1976. “Novel Approaches for the Design of 0164. Kerwin, J. L. 1997. Profiling peptide adducts of Membrane Transport Properties of Drugs'. In: “Design of oxidized N-acetyldopamine by electrospray mass spectrom Biopharmaceutical Properties Through Prodrugs and Ana etry. Rapid Commun. Mass Sprectrom. 11:557-566. logs”, Ed. E. B. Roche et al. APhA Academy of Pharma 0165 Kerwin, J. L., Whitney, D. L. and A. Sheikh. 1999. ceutical Sciences, Washington, D.C., pp. 98-135 Mass spectrometry of glucosamine, glucosamine polymers 0150 Bodor et al., 1981. Science 214: 1370-1372. and their catecholamine adducts. Model reactions and cuticular hydrolysates of Toxorhynchites amboinensis (Culi 0151. Bodor et al., 1983. Pharmacology and Therapeutics cidae) pupae. Insect Biochem. Mol. Biol. 29 (7): 599–607. 19 (3): 337-386. 0166 Kumagai, A. K. 1999. Glucose transport in brain 0152 Curtis, B. R., McFarland, J. G., Guo-Guang, W., and retina: Implications in the management and complica Visentin, G. P. and R. H. Aster. 1994. Antibodies in Sulfona mide-induced immune thrombocytopenia recognize cal tions of diabetes. Diabetes Metab. Res. Rev. 15(4): 261-273. cium-dependent epitopes on the glycoprotein IIb/IIIa com 0.167 Lostao, M. P., Urdaneta, E., Martinez-Anso, E., plex. Blood 84 (1): 176-183. Barber, A. and J. A. Martinez. 1998. Presence of leptin 0153 Duport, S., Robert, F., Muller, D., Grau, G., Parisi, receptors in rat Small intestine and leptin effect on Sugar L. and L. Stoppini. 1998. An in vitro blood-brain barrier absorption. FEBS Lett. 423 (3): 302-306. model: Cocultures between endothelial cells and organo 0168 Manzi, A. E. and A. Varki. 1993. In: Glycobiology: typic brain slice cultures. Proc. Natl. Acad. Sci. USA 95 (4): A Practical Approach. Eds. M. Fukuda and A. Kobata. IRL 1840-1845. Press, Oxford University, Oxford. pp. 29-31. US 2003/0130205 A1 Jul. 10, 2003

0169 Martin, M. G., Turk, E., Lostao, M. P., Kerner, C. Solution, an injection Solution, a Syrup, an elixir, a nasal and E. M. Wright. 1996. Defects in Na+/glucose cotrans Solution, a intrabronchial Solution, an ophthalmic Solution, a porter (SGLT1) trafficking and function cause glucose dermal patch and a bandage. galactose malabsorption. Nat. Genet. 12 (2): 216-220. 3. The pharmaceutical composition of claim 1, wherein 0170 Mauri-Hellwig, D., Bettens, F, Mauri, D., Brander, Said hydrophilic N-linked glycosyl prodrug compound fur C., Hunziker, T. and W. J. Pichler. 1995. Activation of ther comprises a compound according to FORMULA I: drug-specific CD4+ and CD8+ T cells in individuals allergic to Sulfonamides, phenytoin and carbamazepine. J. Immu Formula I nool. 155: 462. wherein, each of "-" comprises a Single bond; A, com 0171 Mizuma, T., Ohta, K. and S. Awazu. 1994. The prises an anti-infective prodrug compound; B, com beta-anomeric and glucose preferences of glucose transport prises a lower alkyl, D, comprises a nitrogen linker carrier for intestinal active absorption of monosaccharide amine or amide, and, E comprises a Saccharide, with conjugates. Biochim. Biophys. Acta 1200 (2): 117-122. the proviso that E is not a cyclodextrin or a glucu 0172 Navarro, H., Arruebo, M. P., Alcalde, A. I. and V. ronide. Sorribas. 1993. Effect of erythromycin on D-galactose 4. The pharmaceutical composition of claim 3 wherein absorption and Sucrase activity in rabbit jejunum. Can. J. Said A-moiety comprises a Sulfonamide anti-infective pro Physiol. Pharmacol. 71 (3-4): 191-194. drug compound. 5. The pharmaceutical composition of claim 4, wherein 0173 Rhoads, D. B., Rosenbaum, D. H., Unsal, H., Said Sulfonamide is Selected from the group consisting of Isselbacher, K. J. and L. L. Levitsky. 1998. Circadian Sulphamethoxazole, Sulphamerazine, Sulfathiazole, Sulfa periodicity of intestinal Na+/glucose cotransporter 1 mRNA troxazole, Sulfadiazine, SulfasaleZine, Sulfadimethoxine and levels is transcriptionally regulated. J. Biol. Chem. 273 (16): Sulfapyridine. 9510-9516. 6. The pharmaceutical composition of claim 5, wherein 0174 Schauer, R. 1978. In: Methods in Enzymology, Ed. Said anti-infective prodrug comprises Sulfamethoxazole. V. Ginsberg. Academic Press, NY. pp. 64-89. 7. A process for preparing a hydrophilic N-linked glycosyl 0175 Vannucci, S.J., Clark, R. R., Koehler-Stec, E., Li, prodrug compound for neuraxial delivery, comprising the K., Smith, C. B., Davies, P., Maher, F. and I. A. Simpson. Step of reacting an anti-infective prodrug compound with a 1998. Glucose transporter expression in brain: Relationship Saccharide moiety under conditions Suitable for formation of to cerebral glucose utilization. Dev. Neurosci. 20 (4-5): an amide or amine bond between said anti-infective prodrug 369-379. compound and Said Saccharide moiety. 8. The process of claim 7, wherein said hydrophilic 0176 von Greyerz, S., Zanni, M.P., Frutig, K., Schnyder, N-linked glycosyl prodrug compound comprises a com B., Burkhart, C. and W. J. Pichler. 1999. Interaction of pound according to FORMULA I: Sulfonamide derivatives with the TCR of Sulfamethoxazole Specific human CfB+ T cell clones. J. Immunology 162: 595-6O2. Formula I 0177. Wright, E. M., Hirsch, J. R., Loo, D. D. and G. A. wherein, each of "-" comprises a Single bond; A, com Zampighi. 1997. Regulation of Na+/glucose cotransporters. prises said anti-infective prodrug, B, comprises an J. Exp. Biol. 200 (2): 287-293. optional lower alkyl, D, comprises said N-linker amine or amide, and, E comprises Said Saccharide, with the 0178 While the preferred embodiment of the invention proviso that E is not a cyclodextrin or a glucuronide. has been illustrated and described, it will be appreciated that 9. A proceSS for preparing a pharmaceutical composition various changes can be made therein without departing from comprising hydrophilic N-linked glycosyl prodrug com the Spirit and Scope of the invention. pound for neuraxial delivery, comprising the Steps of react ing an anti-infective prodrug compound with a Saccharide I claim: moiety under conditions Suitable for formation of an amide 1. A pharmaceutical composition for neuraxial delivery or amine bond between said anti-infective prodrug com comprising both a hydrophilic N-linked glycosyl prodrug pound and Said Saccharide moiety; and formulating Said compound and a formulary, wherein Said hydrophilic N-linked glycosyl prodrug compound into Said pharmaceu N-linked glycosyl prodrug compound comprises an anti tical composition by addition of an agent Selected from the infective prodrug compound covalently linked with a sac group consisting of an additive, a Stabilizer, a carrier, a charide through an amide or an amine bond and Said binder, a buffer, an excipient, an emollient, a disintegrant, a formulary comprises an agent Selected from the group lubricating agent, an antimicrobial agent and a preservative. consisting of an additive, a Stabilizer, a carrier, a binder, a 10. A method for treating a neurological infection in a buffer, an excipient, an emollient, a disintegrant, a lubricat Subject in need thereof comprising the Step of administering ing agent, an antimicrobial agent and a preservative, to the Subject a pharmaceutical composition comprising a with the proviso that Said Saccharide moiety is not a compound according to FORMULA I: cyclodextrin or a glucuronide. 2. The pharmaceutical composition of claim 1, further comprising a dosage form Selected from the group consist Formula I ing of a powder, a granule, an emollient cream, a tablet, a wherein, each of "-" comprises a Single bond; A, com capsule, a lozenge, a trouch, a Suppository, a perenteral prises an anti-infective prodrug, B, comprises a lower US 2003/0130205 A1 Jul. 10, 2003 22

alkyl, D, comprises a nitrogen linker amine or amide; N comprises a nitrogen atom of a primary or Secondary and, E comprises a Saccharide, with the proviso that E amine or an amide and R7 comprises hydrogen or is not a cyclodextrin. methyl, 11. A pharmaceutical composition comprising an anti E comprises a Saccharide moiety; infective prodrug compound according to either of FOR Ro, R, R2, R and R. each independently comprise a MULA IVa or FORMULA IVb, group Selected from among hydrogen, hydroxyl, halo gen, halo-lower alkyl, alkoxy, alkoxy-lower alkyl, halo-alkoxy, thioamido, amidoSulfonyl, alkoxycarbo FORMULA IV a nyl, carboxamide, amino-carbonyl, and alkylamine R14 R15 Y-1/ carbonyl; and, / 2 \ R13, R1, Ris, R16 each independently comprise a group Selected from among hydrogen, hydroxyl, lower alkyl and alkoxyl-lower alkyl. 12. The anti-infective pharmaceutical composition of claim 11, wherein Z is absent or a lower alkyl comprising 1 OFSFO or 2 carbon atoms. 13. The anti-infective pharmaceutical composition according to claim 12, wherein Z is absent or a one carbon atOm. 14. The anti-infective pharmaceutical composition of claim 11, wherein each of Rs and Rs, when present, and each of R and R, when present, independently comprise a group Selected from among hydrogen, hydroxyl, alkoxyl, carboxyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and dialkylamino-carbonyl. D / nSR 15. The anti-infective pharmaceutical composition of E claim 11, wherein R, comprised a hydrogen atom. FORMULA IVb 16. The anti-infective pharmaceutical composition of s claim 11, wherein Ro, R, R2, R and Reach independently R14 LN - R16 comprise a group Selected from hydrogen, hydroxyl, lower n1 NM alkyl and alkoxyl-lower alkyl. 17. The anti-infective pharmaceutical composition of 1. n claim 16, wherein Ro, R, R, R and Reach independently R13 N R17 comprise hydrogen. 18. The anti-infective pharmaceutical composition of R-- claim 11, wherein Ring 2 comprises a 5-membered ring. 19. The anti-infective pharmaceutical composition of R2 R4 claim 11, wherein Ring 2 comprises an aryl or heteroaryl ring. 1. X Y. 20. The anti-infective pharmaceutical composition of R1 n Ro claim 11, wherein Ra, R1, Ris, R16 each independently R5 Rs' comprise hydrogen or lower alkyl. ny 1 21. The anti-infective pharmaceutical composition of claim 11, wherein Ra, R1, Ris, R16 each independently N. comprise hydrogen or lower alkyl. N n 22. The anti-infective pharmaceutical composition of / R. E claim 11, wherein said Rs and Rs are selected from the group consisting of hydrogen, hydroxyl, alkoxyl, carboxyl, alkoxylcarbonyl, aminocarbonyl, alkylamino-carbonyl and wherein, Ring 1 and Ring 2 each independently comprise dialkylamino-carbonyl. an optionally Substituted cyclic or heterocyclic ring, or 23. The anti-infective pharmaceutical composition of claim 11, wherein said E. Substituent is selected from the an optionally Substituted aromatic ring, Ring 1 com group consisting of a radical of a monosaccharide, a disac prising about 4 to about 8 carbon atoms, among which charide, a and an oligosaccharide are counted “X” and “Y” and Ring 2 comprising about 24. The anti-infective pharmaceutical composition of 4 to about 6 atoms, among which are counted “G”, “J”, claim 1, wherein Said E monosaccharide comprises a radical “L”, “O'” and optional ring components “M” and “R”; of a Sugar Selected from the group consisting of aldose, the constituent atoms of Ring 2 being Selected accord ketoaldose, alditols, ketoses, aldonic acids, ketoaldonic ing to either of TABLE C or TABLED; “X” and “Y” acids, aldaric acids, ketoaldaric acids, amino Sugars, keto each comprise a carbon atom; amino Sugars, uronic acids, ketouronic acids, lactones and keto-lactones. Z is optional and when present comprises a lower alkyl 25. The anti-infective pharmaceutical composition of optionally Substituted with Rs and Rs. claim 24, wherein Said radical of a Sugar is further Selected US 2003/0130205 A1 Jul. 10, 2003 from the group consisting of triosyl, tetraoSyl, pentosyl, Side, alloSide, altroSide, glucoside, mannoside, guloside, hexosyl, heptosyl, octosyl and nonosyl radicals and deriva idoside, galactoside, taloSide, fructoside and derivatives tives thereof. thereof. 26. The anti-infective pharmaceutical composition of 36. The anti-infective pharmaceutical composition of claim 25, wherein Said pentosyl Sugar radical comprises a claim 35, wherein Said Sugar heteropolymer further com Straight carbon chain, a furanosyl ring or a derivative prises a glycoside metabolized in a mammal to a glucosyl or thereof. a galactosyl monosaccharide. 27. The anti-infective pharmaceutical composition of 37. The anti-infective pharmaceutical composition of claim 25, wherein Said hexosyl Sugar radical comprises a claim 34, wherein Said glycoside further comprises a riban, Straight carbon chain, a furanosyl ring, a pyranosyl ring or an arabinan, a glucan, a galactan, a mannan and derivatives a derivative thereof. thereof. 28. The anti-infective pharmaceutical composition of 38. The anti-infective pharmaceutical composition of claim 25, wherein said hexosyl radical is further selected claim 35, wherein Said glycoside further comprises a ribo from the group consisting of allose, altrose, glucose, man Side, an arabinoside, a glucoside, a galactoside, a manno nose, gulose, idose, galactose, talose, fructose, ribo-heXu Side, a fructoside and derivatives thereof. lose, arabino-heXulose, lyxo-heXulose and derivatives 39. The anti-infective pharmaceutical composition of thereof. claim 36, wherein Said glucan comprises maltose, amylose, 29. The anti-infective pharmaceutical composition of glycogen, cellobiose, amylopectin, heparin and derivatives claim 25, wherein Said pentosyl radical is further Selected thereof. from the group consisting of ribose, arabinose, Xylose, 40. The anti-infective pharmaceutical composition of lyxose, ribulose, Xylulose and derivatives thereof. claim 37, wherein Said glucoside comprises Sucrose and 30. The anti-infective pharmaceutical composition of derivatives thereof. claim 25, wherein Said heptosyl residue comprises Sedohep 41. The anti-infective pharmaceutical composition of tulose and derivatives thereof. claim 37, wherein Said fructoside comprises fucosidolactose 31. The anti-infective pharmaceutical composition of and derivatives thereof. claim 25, wherein Said nonosyl residue comprises N-acetyl 42. The anti-infective pharmaceutical composition of , N-glycolylneuraminic acid, diacetyl claim 37, wherein Said galactoside comprises lactose, hyalu neuranminic acid, and derivatives thereof. ronic acid, and derivatives thereof. 32. The anti-infective pharmaceutical composition of 43. A method for improving the aqueous Solubility and claim 28, wherein Said compound further comprises glucose, blood brain barrier penetrability of a drug, comprising the galactose, fructose or derivatives thereof. Step of forming a covalent chemical bond between the drug 33. The anti-infective pharmaceutical composition of and a Sugar or oligosaccharide, wherein Said drug comprises claim 23, wherein Said , trisaccharide and oli an amide or amine group and Said drug bonded to Said Sugar gosaccharide comprise a Sugar homopolymer or a Sugar or oligosaccharide comprises a compound according to heteropolymer. FORMULA I: 34. The anti-infective pharmaceutical composition of claim 33, wherein Said Sugar homopolymer comprises a glycoside Selected from the group consisting of erythran, Formula I threan, riban, arabinan, Xylan, lyXan, allan, altran, glucan, wherein, each of "-" comprises a Single bond; A, com mannan, gulan, idan, galactan, talan, and derivatives prises a Anti-infective prodrug, B, comprises a lower thereof. alkyl, D, comprises a nitrogen linker amine or amide; 35. The anti-infective pharmaceutical composition of and, E comprises a Saccharide, with the proviso that E claim 33, wherein Said Sugar heteropolymer further com is not a cyclodextrin. prises a glycoside Selected from the group consisting of erythroside, threoside, riboside, arabinoside, XyloSide, lyXo