Samuel O. Nortey

Topiramate: Preclinical Evaluation of a Structurally Novel Anticonvulsant

Summary: Topiramate [TPM, 2,3:4,5‐his‐O‐(1‐methyl‐ethylidene)‐β‐D‐fructopyranose sulfamate] (RWJ‐17021‐000, formerly McN‐4853) is a structurally novel antiepileptic drug (AED). The preclinical anticonvulsant profile suggests that TPM acts primarily by blocking the spread of seizures. TPM was highly effective in the maximal electroshock (MES) seizure test in rats and mice. Activity was evident 0.5. h after oral administration and lasted at least 16 h. The ED50 values 4 h after oral dosing were 13.5 and 40.9 mg/kg in rats and mice, respectively. TPM blocked pentylenetetrazol (PTZ)‐induced clonic seizures at high doses in mice (ED50= 1,030 mg/kg orally, p.o.). With motor incoordination and loss of righting reflex used as indicators of neurologic impairment, the neuroprotective index (TD50/MES ED50) for TPM was equivalent or superior to that of several approved AEDs. In mice pretreated with SKF‐525A (a P450 enzyme inhibitor), the anticonvulsant potency was either increased or unaffected when TPM was tested 0.5, 1, or 2 h after i.p. administration, suggesting that TPM rather than a metabolite was the active agent. In mice pretreated with reserpine or tetrabenazine, the activity of TPM in the MES test was markedly reduced. TPM was inactive in a variety of receptor binding, neurotransmitter uptake, and ion channel tests. TPM weakly inhibited erythrocyte carbonic anhydrase (CA) activity. However, the anticonvulsant activity of TPM appears to differ mechanistically from that of acetazolamide.

ARYLSULFONATE ESTERS IN SOLID PHASE ORGANIC SYNTHESIS. I. CLEAVAGE WITH AMINES, THIOLATE, AND IMIDAZOLE

Abstract The arylsulfonate ester functionality connecting an alkyl chain to a polystyrene resin is cleaved with neat volatile primary or secondary amines to give secondary or tertiary amines, respectively, in high yields and purity. Non-volatile secondary amines, thiols, and imidazole also cleave the alkyl chain efficiently to afford the expected products which can be readily purified by an ion-exchange resin work-up method.

Arylsulfonate esters in solid phase organic synthesis. II. Compatibility with commonly-used reaction conditions

Abstract The arylsulfonate ester functionality connecting an alkyl chain to a polystyrene resin is compatible with Grignard additions, stabilized Wittig, sodium borohydride reduction, reductive aminations, acylations and addition of various electrophiles, and Suzuki coupling. Cleavage of the resin-bound substrate with amines and other nucleophiles can provide diverse compound libraries.

Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

Stereoselectivity in the electrophile-promoted cyclizations of a hydroxyolefin derived from arabinose. Synthesis of a phosphonate isostere of β-(=D)-arabinose-1, 5-diphosphate

Abstract Cyclization of droxyolefin 3, either with NBS or Hg(OAc)2, gives predominantly the β isomer of a C -arabinofuranoside structure. Carbohydrate phosphonate 1 was synthesized from bromide 4a in six steps.

Synthesis of C-arabinofuranosyl compounds. Phosphonate and carboxylate isosteres of d-arabinose 1,5-bisphosphate☆

Abstract Electrophile-mediated cyclization of 3,4,6-tri- O -benzyl-1,2-dideoxy- d - arabino -hex-1-enitol with N -bromosuccinimide yielded primarily 2,5-anhydro-3,4,6-tri- O -benzyl-1-bromo-1-deoxy- d -glucitol ( 10 ). This apparently kinetically controlled reaction was of key importance in the successful synthesis of a phosphonate analog of β- d -arabinose 1,5-bisphosphate ( 1 ), namely, 2,5-anhydro-1-deoxy-1-phosphono- d -glucitol 6-phosphate ( 4 ), whith high stereoselectivity. By contrast, condensation of the sodium salt of tetraethyl methylenediphosphonate and 2,3,5-tri- O -benzyl- d -arabinose ( 7 ) gave a phosphonate compound slightly enriched in the 2,5-anhydro- d -mannitol (α) isomer. In the Wittig—Michael reaction of stabilized phosphoranes with 7 , the α isomer preponderated. Since equilibration of methyl 3,6-anhydro-4,5,7-tri- O -benzyl-2-deoxy- d - glycero - d - galacto - ( 33 ) and - d - gulo -heptonate ( 34 ) (5:1) resulted in a 1:1 α:β ratio, the preference for the 2,5-anhydro- d -mannitol (α) isomer probably reflects a kinetic bias. The carbomethoxy anomers were converted independently into the α and β carboxylate isosteres ( 5 and 6 , respectively) of d -arabinose 1,5-diphosphate. Empirical force field calculations (MMP2) and n.m.r. experiments were conducted on the pairs of diastereomers 9 and 10 , and 33 and 34 . The calculations predict that the α and β anomers of each pair have similar energies, differing by only 2.1 kJ/mol. Compounds 4, 5 , and 6 were evaluated for biological activity.

Synthesis of phosphates and phosphate isosteres of furanose sugars as potential enzyme inhibitors

Abstract Various D-furanose monosaccharides were synthesized as possible inhibitors of the gluconeogenic enzyme fructose 1,6-bisphosphatase. These included sulfamate, phosphoramidate, and epoxy analogues of the natural substrate, fructose 1,6-diphosphate (1), and arabinose and ribose analogues of a natural inhibitor, fructose 2,6-diphosphate (2). NMR studies were conducted to establish the stereochemistry of phosphate displacenent at C1 in the synthesis of arabinose 1-phosphate derivatives. β-Ribose 1,5-diphosphate (35b) was prepared with >95% stereoselectivity.

Synthesis of hydroxylated derivatives of topiramate, a novel antiepileptic drug based on d-fructose: Investigation of oxidative metabolites

To corroborate the structures of two monohydroxylated metabolites of topiramate (1), we synthesized four monosaccharide derivatives from D-fructose: 4,5-O-[(1R)- and 4,5-O-[(1S)-1-hydroxymethylethylidene]-2,3-O-isopropylidene-beta-D -fructopyranose sulfamates (2a and 2b); 2,3-O-[(1R)- and 2,3-O-[(1R)-1-hydroxymethylethylidene]-4,5-O-isopropylidene-beta-D -fructopyranose sulfamates (3a and 3b). The route to 2a and 2b was brief and straightforward, while that to 3a and 3b was more involved. In the latter case, the D-fructose bis-acetal 10 was benzylated and converted to a monoacetal dibenzoate (14) (50% yield), which was then transacetalized to give a mixture of 4,5-dibenzoyl-2,3-O-[(1R)- and 4,5-dibenzoyl-2,3-O-[(1S)-1-benzyloxymethylethylidene]- beta-D-fructopyranose (16a and 16b) (22%). The individual diastereomers were separated and processed via ester saponification, acetonation, sulfamoylation, and hydrogenolysis into 3a (36%) and 3b (27%). Structure 2b was confirmed for one oxidative metabolite, but the other metabolite was found not to correspond with either 2a, 3a, or 3b. On the basis of CI-MS and 1H NMR data, a (2-hydroxy-1,4-dioxano)pyran structure, 4, is proposed for this unidentified metabolite.

New directions in anxiolytic drug research

Agents to treat anxiety have gained in acceptance and importance in the fast pace of life in the second half of this century. The discovery and refinement of the benzodiazepines represented a quantum leap in therapy from early compounds which were essentially sedatives. With the advent of molecular biology, an understanding of the basic mechanism by which the benzodiazepines exert their effects was revealed through the discovery and isolation of the GABAA receptor and its benzodiazepine binding site. This, in turn, has enabled benzodiazepines to be classified into a broad spectrum of pharmacological types ranging from agonist to inverse agonist, thus allowing fine tuning with respect to side-effects. Consequently, newer, more promising agents have emerged which bind at the GABAA BZD site and have reduced side-effects. An example of this is RWJ-51204 (92), a member of a novel structural type which is superior to several marketed benzodiazepines in animals in terms of efficacy and side-effects. The cost-conscious environment of managed health care presents continuing challenges to the discovery and development of safe, highly efficacious, and cost-effective anxiolytic agents.

Stereochemical observations in the synthesis of novel 1,4,5,9b-tetrahydro-5-phenyl-2H-azeto[2,1-a]isoquinolin-2-one derivatives

Imine (5),4-phenyl-3,4-dihydroisoquinoline, reacted with Cl 2 CHC(O)Cl in the presence of Et 3 N to give β-lactams, azeto[2,1-a]isoquinolin-2-one derivatives, (7a) and (7b) in a 4:1 ratio. The stereochemistry of cycloadduct (7a) was confirmed by X-ray analysis. Uncyclized intermediates were identified. Reduction of dichloro β-lactam (7a) with Zn/HOAc gave mostly exo monochloride (13a), with high stereoselectivity (10:1) ratio. Reduction of a mixture of exo and endo monochlorides (13a) and (13b) with Zn/HOAc indicated that the more sterically hindered endo chlorine is preferentially attacked. Reduction of (7a) with Bu 3 SnH gave β-lactam (14a) as the major product