STRUCTURE-ACTIVITY STUDIES ON ANTICONVULSANT SUGAR SULFAMATES RELATEDTO TOPIRAMATE - ENHANCED POTENCY WITH CYCLIC SULFATE DERIVATIVES

We have explored the structure-activity relationship (SAR) surrounding the clinically efficacious antiepileptic drug topiramate (1), a uniqu e sugar sulfamate anticonvulsant that was discovered in our laboratori es. Systematic structural modification of the parent compound was dire cted to identifying potent anticonvulsants with a long duration of act ion and a favorable neurotoxicity index. In this context, we have prob ed the pharmacological importance of several molecular features: (1) t he sulfamate group (6-8, 22-25, 27, 84), (2) the linker between the su lfamate group and the pyran ring (9, 10, 21a,b), (3) the substituents on the 2,3- (58-60, 85, 86) and 4,5-fused (30-38, 43, 45-47, 52, 53) 1 ,3-dioxolane rings, (4) the constitution of the 4,5-fused 1,3-dioxolan e ring (2, 54, 55, 63-68, 76, 77, 80, 83a-r, 84-87, 90a, 91a, 93a), (5 ) the ring oxygen atoms (95, 96, 100-102, 104, 105), and (6) the absol ute stereochemistry (106 and 107). We established the C1 configuration as R for the predominant alcohol diastereomer from the highly selecti ve addition of methylmagnesium bromide to aldehyde 15 (16:1 ratio) by single-crystal x-ray analysis of the major diastereomer of sulfamate 2 1a. Details for the stereoselective syntheses of the hydrindane carboc yclic analogues 95, 96, 100, and 104 are presented. We also report the synthesis of cyclic imidosulfites 90a and 93a, and imidosulfate 91a, which are rare examples in the class of such five-membered-ring sulfur species. Imidosulfite 93a required the preparation and use of the nov el sulfur dichloride reagent, BocN=SCl2. Our SAR investigation led to the impressive 4,5-cyclic sulfate analogue 2 (RWJ-37947), which exhibi ts potent anticonvulsant activity in the maximal electroshock seizure (MES) test (ca. 8 times greater than 1 in mice at 4 h, ED50 = 6.3 mg/k g; ca. 15 times greater than 1 in rats at 8 h, ED50 = 1.0 mg/kg) with a long duration of action (>24 h in mice and rats, po) and very low ne urotoxicity (TD50 value of >1000 mg/kg at 2 h, p0 in mice). Cyclic sul fate 2, like topiramate and phenytoin, did not interfere with seizures induced by pentylenetetrazole, bicucculine, picrotoxin, and strychnin e; also, 2 was not active in diverse in vitro receptor binding and upt ake assays. However, 2 turned out to be a potent inhibitor of carbonic anhydrase from different rat tissue sources (e.g., IC50 of 84 nM for the blood enzyme and 21 nM for the brain enzyme). An examination of se veral analogues of 2 (83a-r, 85-87, 90a, 91a, 93a) indicated that pote nt anticonvulsant activity is associated with relatively small alkyl s ubstituents on nitrogen (Me/H, 83a; Me/Me, 83m; Et/H, 83b; allyl/H, 83 e; c-Pr/H, 83j; c-Bu/H, 83k) and with limited changes in the cyclic su lfate group, such as 4,5-cyclic sulfite 87a/b. The potent anticonvulsa nts 83a and 83j had greatly diminished carbonic anhydrase inhibitory a ctivity; thus, inhibition of this enzyme may not be a significant fact or in the anticonvulsant activity. The alpha-L-sorbopyranoses 67, 68, and 80, which mainly possess a skew conformation (ref 29), were nearly twice as potent as topiramate (1). The L-fructose enantiomers of 1 (1 06) and 2 (107), synthesized from L-sorbose, were found to have modera te anticonvulsant activity, with eudysmic ratios (MES ED50 in mice at 4 h, p0) of 1:106 = 1.5 and 2:107 = 3.5. The log P values for 1 and 2 were determined experimentally to be 0.53 and 0.42, respectively, whic h are less than the optimal 2.0 for CNS active agents. However, analog ues with more favorable calculated log P (clogP) values, in conjunctio n with just minor steric perturbation according to the developed SAR p rofile, such as 47 (clog P = 2.09), 83m (1.93), and 86 (1.50), did not display improved potency: 47 is less potent than 1, 83m is equipotent with 2, and 86 is less potent than 2. Although the measured log P val ue for diethyl analogue 31 is 1.52, this did not translate into enhanc ed potency relative to 1. The 400-MHz H-1 NMR studies of 1 and 2 indic ated that the skew (3)So conformer predominates at ambient temperature in nonaqueous and aqueous media; 95 strongly populates a skew (3)So c onformer in benzene and (as reported in ref 29) 67 mainly adopts this skew conformation in various solvents. X-ray crystal structures for 1, 2, and 95 (as well as 67) depict the skew (3)So conformer in the soli d state. Solution IR studies with 1, 2, and 83b showed an absence of i ntramolecular hydrogen bonding, in contrast to what has been observed for alcohol 4 (ref 73).