US 20140057869A9 (19) United States (10) Pub. No.: US 2014/0057869 A9 (12) Patent Application Publication (48) Pub. Date: Feb. 27, 2014 Christian CORRECTED PUBLICATION (54) NOVEL PHARMACEUTICAL AGENTS Publication Classification CONTAINING CARBOHYDRATE MOETIES AND METHODS OF THEIR PREPARATION (51) Int. Cl. AND USE A613 L/7008 (2006.01) A6IP 25/6 (2006.01) (76) Inventor: Samuel T. Christian, Alabaster, AL A6IP 9/2 (2006.01) (US) A6IP3/00 (2006.01) A6IP 25/08 (2006.01) A6IP3I/00 (2006.01) (21) Appl. No.: 12/913,543 A6IP3L/2 (2006.01) A613 L/7048 (2006.01) (22) Filed: Oct. 27, 2010 A6IP 23/00 (2006.01) (52) U.S. Cl. Prior Publication Data USPC ............................................................ 514/62 (15) Correction of US 2011/0237544A1 Sep. 29, 2011 See (63) Related U.S. Application Data. (57) ABSTRACT Hydrophilic N-linked pharmaceutical compositions, meth (65) US 2011/0237544A1 Sep. 29, 2011 ods of their preparation and use in neuraxial drug delivery comprising a glycosyl CNS acting prodrug compound covalently N-linked with a saccharide through an amide oran Related U.S. Application Data amine bond and a formulary consisting of an additive, a (63) Continuation of application No. 1 1/343.266, filed on stabilizer, a carrier, a binder, a buffer, an excipient, an emol Jan. 30, 2006, now abandoned, which is a continuation lient, a disintegrant, a lubricating agent, an antimicrobial of application No. 09/547,201, filed on Apr. 12, 2000, agent or a preservative, with the proviso that the saccharide now abandoned. moiety is not a cyclodextrin or a glucuronide. US 2014/0057869 A9 Feb. 27, 2014 NOVEL PHARMACEUTICAL AGENTS tiourinary dyantonomia, hypotension and cognitive decline CONTAINING CARBOHYDRATE MOETIES (Hurtig, 1997). Often after 3-5 years of treatment patients AND METHODS OF THER PREPARATION reportedly develop complex dose-related unpredictable AND USE response fluctuations leading to a progressive decrease in therapeutic efficacy and also possible onset of serious side CROSS REFERENCE TO RELATED effects such as abnormal involuntary movements, end-of APPLICATIONS dose deterioration and abrupt near instantaneous on-off changes in patient disability. "Adaptation’ by neural tissues 0001. This application claims the benefit of U.S. applica to chronic administration is complex, and may include down tion Ser. No. 09/547,501 filed Apr. 12, 2000, which is hereby regulation of dopamine receptor expression as well as meta incorporated herein by reference in its entirety. bolic changes in post-striatal neurons. In addition to these neurologic side effects, metabolism of oral dopa compounds FIELD OF THE INVENTION to dopamine in the stomach and gastrointestinal tract (even in 0002 The invention relates generally to compositions and the presence of decarboxylase inhibitors) can often lead to methods for treating peripheral and central neurological dys unwanted side effects including severe nausea and hypoten functions including e.g. infectious diseases, epilepsy, Sion. Levodopa methyl and ethyl esters given orally Suffer impaired motor dysfunction, Schizophrenia, cognition, many of these same problems. Thus, all current therapies for depression, behavior and mood disorders. treating Parkinsonism suffer from serious side effects, bio availability problems, or both, and there has been a long-felt BACKGROUND OF THE INVENTION need for improved pharmaceutically active agents for meta 0003. It is estimated that mental disorders account for 10 bolic replacement therapy in Parkinson's and related diseases percent of the global burden of disease with four disorders (Hurtig, 1997). ranking among the 10 leading causes of disability worldwide: 0006. In pharmacologic studies conducted over the past 20 namely, unipolar major depression, bipolar disorder, Schizo years, the results seem to suggest relatively stringent struc phrenia and obsessive-compulsive disorder (National Insti tural requirements for activation of the D1 receptors, particu tute of Mental Health, Report of the National Advisory Men larly in regard to any nitrogenatoms present in the compound tal Health Council Behavioral Science Workgroup, March (e.g., see Seiler et al., 1991; Berger et al., 1989; Brewster et 2000). Unfortunately, the fundamental basis by which neuro al., 1990; Kaiseret al., 1982; Dandridge et al., 1984: Brewster biologic function translates into behaviors such as cognition, et al. 1990; Weinstock et al., 1985; Riggs et al.; Seiler et al., emotion, motivation, development, personality and social 1982: Shah et al., 1996: Knoerzeret al., 1994). In addition, the interaction are (at present) largely unknown. nature of the terminal group (i.e., amino), or presence or 0004 Delivery of drugs from the blood and into neural length of an n-alkyl chain (Iorio et al., 1986) may reportedly tissues (neuraxial delivery) is a key aspect complicating clini influence binding interactions at D1 sites. Based on experi cal rehabilitation and intervention techniques. The blood ence with different pharmacophores, several receptor models brain barrier effectively limits access of many classes of have been proposed (Seiler and Markstein, 1989; Petersson known and potentially useful pharmaceutical agents. For et. al., 1990; Brewster et. al., 1990; Knoerzer et al., 1994; instance, in Parkinson's disease it has long been understood Snyder et. al., 1995; Minor et. al., 1994). By comparison, that the disease results from a defect in dopamine biosynthe pharmacologic Studies of D2-like receptors suggest some sis, but it has proven exceptionally difficult to effect proper what less rigid overall structural requirements, but also delivery of therapy across the bloodbrain barrier into affected restrictions around any nitrogen atoms (e.g., see McDermed nigrostriatal tissues. Catecholamines including dopamine, et al. 1979: Freeman and McDermed, 1982; Liljefors et al., norepinephrine and epinephrine are produced by chromaffin 1986; van de Waterbeemdet al., 1987). cells in the adrenal medulla responding as a specialized gan 0007. The Na"/Cl dependent dopamine transporter, glion to sympathetic enervation from preganglionic fibers of DAT1, granule system mediates calcium-dependent outward the splanchic nerve. However, catecholamines do not cross dopamine release into the synaptic cleft and inward energy the blood-brain barrier, hence, the need for synthesis within dependent dopamine vesicular re-uptake into the cytoplasm the CNS. Although metabolic replacement therapy in Parkin of presynaptic neurons. Loading of biosynthetic dopamine sons might theoretically be effected with L-Dopa, the pre into granules is effected by the vesicular monoamine trans cursor of dopamine and a compound, which readily crosses porter (VMAT2: reviewed in Miller et al., 1999). DAT may the blood-brain barrier, the compound is highly unstable and also control movements of other monoamines in braintissues. rapidly inactivated in blood. Cocaine, amphetamines, phencyclidine and certain anti-de 0005 L-dopa, Levodopa, Cardiodopa (an inhibitor of pressants and uptake inhibitors interfere with dopamine dopa decarboxylase), Deprenyl (inhibiting dopamine degrad transport by DAT (e.g., see Jones et al., 1999; Giros et al., ing monoamine oxidase), Sinemet (a controlled release form 1992). DAT function may be regulated by steroid hormones, of Levodopa) and their combinations and derivatives suffer has second order dependence on Na" (Earles et al., 1999) and from many major disadvantages common also in certain other may be coupled (or uncoupled) to modulatory second mes drugs which might be used in neuraxial therapies, e.g. poor senger systems, (e.g., down-regulation of DAT accompany aqueous solubility, poor brain penetrability, relatively short ing activation of protein kinase C by phorbolesters), and ionic half-lives, dosing fluctuations and numerous side effects. currents (Melikian et al., 1999; reviewed in Figlewicz, 1999). Observed side effects accompanying chronic use in Parkin Radiotracer imaging methods have been used to localize DAT son’s patients include motor fluctuation, dysfunctions, peak (e.g., within the nucleus accumbens and mid-brain regions) dose dyskinesia, requirements for frequent dosing, involun and D1 and D2 receptors (e.g., in nigrostrial pathways) in the tary movements, psychosis, confusion, visual hallucinations, brains of normal subjects, as well as in patients with Parkin bradykinesia, rigidity, tremors, gastrointestinal and gen son's disease and neuropsychiatric diseases such as Schizo US 2014/0057869 A9 Feb. 27, 2014 phrenia (reviewed in Verhoeff, 1999). Structure activity stud glycoside derivatives with alkyl chains or carbonyl groups (as ies of antagonists have Suggested that: (i) the DAT transporter an aglycone Substituent) may act as non-penetrating inhibi may be sensitive to N-substitution (Choi et al., 2000); (ii) tors of glucose transport (Ramaswamy et al., 1976); and (iii) N-phenyl-substituted analogues may inhibit transport 1-5-anhydroglucitol and 6-deoxyglucose may be transport (Prakash et al., 1999: Husbands, et al., 1999); (iii) certain able (Alvarado et al., 1960). Thus, like dopaminergic receptor energetically unfavored boat conformations of rings may binding, the art Suggests that special chemical structural have high affinity for DAT (Prakash et al., 1999); (iv) struc requirements may exist for intestinal transport. tural rearrangement of the DAT protein may occur and be 0010 Metabolic replacement therapy using compounds required for inward transport (Chen et al., 2000:); (v) the DAT that