United States Patent (19) 11 Patent Number: 5,798,392 Moss 45) Date of Patent: Aug
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USOO5798392AIII United States Patent (19) 11 Patent Number: 5,798,392 Moss 45) Date of Patent: Aug. 25, 1998 54 SULFONYL FLUORDES FOR THE Primary Examiner-Kimberly Jordan TREATMENT OF A LZHEMERS DSEASE Attorney, Agent, or Firm-Benjamin Aaron Adler 75 Inventor: Donald Eugene Moss, El Paso, Tex. 57 ABSTRACT 73 Assignee: The Board of Regents of the University of Texas System, Austin, The present invention provides a pharmaceutical Tex. composition, comprising a sulfonyl fluoride and a pharma ceutically acceptable carrier. Also provided is a method of (21) Appl. No.: 705,858 treating Alzheimer's disease in an individual in need of such 22 Filed: Aug. 28, 1996 treatment, comprising the step of administering to said (51) Int. Cl. ..................... A61K 31/135; A6K 31/10 individual a therapeutically effective dose of methanesulfo 52 U.S. Cl. ........................................... 514/649; 514/709 nyl fluoride. Further provided is a method of enhancing (58) Field of Search .................................. 514/649, 709 cognitive performance in an individual in need of such 56) References Cited treatment, comprising the step of administering to said PUBLICATIONS individual a therapeutically effective dose of methanesulfo nyl fluoride. CA 118: 183249. Palacios-Esquivel et al., 1993. CA 1.10: 147634, Moss et al., 1988. CA 106: 188458. Moss et al., 1986. 13 Claims, 9 Drawing Sheets U.S. Patent Aug. 25, 1998 Sheet 1 of 9 5,798.392 U 2. IOO u ap eas as o is a p (f) i BA SELNE H21. BEFORE 5 O L C) MSF t Ol DAYS FIGURE U.S. Patent Aug. 25, 1998 Sheet 2 of 9 5,798.392 8 O RESYNTHESS 6 O 4 O NATURA 2 O URAL LOSS O 2 3. 4. 5 6 7 HALF - T MES FIGURE 2 U.S. Patent Aug. 25, 1998 Sheet 3 of 9 5,798,392 - O.3O LOGo NH) = f/2 (TIME) + NTCP T ME FGURE 3 U.S. Patent Aug. 25, 1998 Sheet 4 of 9 5,798,392 a of it w y an as a wamp in a 2 - U (f) too a suWY- up a many - P. spe NM-ysu up a gap up ap as an up i BA SELNE DURING z 50 BEFORE DOSING y MSF 1. O O 5 O 5 2 O 25 3 O DAYS FIGURE 4 U.S. Patent Aug. 25, 1998 Sheet S of 9 5,798,392 O 6 O J O 5 O U D O 4 O O U O 3 O O - H 2 O Z 1. O O U Cl 2.5 O 4 O 8O DAYS AFTER MSF FIGURE 5 U.S. Patent Aug. 25, 1998 Sheet 6 of 9 5,798,392 gool - l Of) 5O Z L O 1. L - O 3 6 2 8 8 8 MSF mg/kg x IO-2 DOSES 3 x WEEK FIGURE 6 U.S. Patent Aug. 25, 1998 Sheet 7 of 9 5,798,392 co placebo 92 - 6 O T - - - (f) a 4 MSF O -2 Co Z MSF Os +2or vplacebo Y O 8 6 FIGURE 7 U.S. Patent Aug. 25, 1998 Sheet 8 of 9 5,798,392 - 2 PLACEBO MSF FIGURE 8 U.S. Patent Aug. 25, 1998 Sheet 9 of 9 5,798.392 2 gn 4. H 4 3 O o Z2 2 LL CD CD 2 2. at a C O No O Change PLACEBO MSF FIGURE 9 5,798.392 1 2 SULFONYL FLUOR DES FOR THE therapeutic pharmaceutical will be clinically efficacious in TREATMENT OF ALZHEMERS DISEASE humans. For example, Schwarz et al. reviewed the use of cholinesterase inhibitors for the treatment of Alzheimer's BACKGROUND OF THE INVENTION disease and concluded that irreversible inhibitors, specifi cally including methanesulfonyl fluoride, were too danger 1. Field of the Invention ous and toxic and that physicians are more confortable with The present invention relates generally to the fields of reversible drugs. Adem (1993) while reviewing the "next neurology and the pharmacotherapy of Alzheimer's Disease. generation of cholinesterase inhibitors" omitted discussing More specifically, the present invention relates to the novel the sulfonyl fluorides while focusing on noncholinesterase use of sulfonyl fluorides for the treatment of Alzheimer's O inhibiting effects. Disease. The prior art is deficient in the lack of effective and 2. Description of the Related Art improved means of treating individuals with Alzheimer's Neuropathological evidence demonstrating an extensive Disease. The present invention fulfills this longstanding loss of cholinergic function in the basal forebrain and cortex need and desire in the art. in senile dementia of the Alzheimer type (SDAT) has been 15 confirmed by many investigators and is a relatively common SUMMARY OF THE INVENTION feature of the disease 1.2.3). The reduction in cholinergic The novel treatment strategy with an irreversible acetyl function may, at least in part, be responsible for cognitive cholinesterase inhibitor is based on the brain recovering decline in this disease 4.5). One treatment strategy that has from inhibition (resynthesizing the enzyme) more slowly attracted considerable attention is the use of cholinesterase than peripheral tissues. Using this special quality of brain (ChE) inhibitors to increase the concentration of acetylcho tissue, small doses of methanesulfonyl fluoride administered line in the brain, thereby increasing cholinergic function and over time can accumulate very high levels of inhibition in improving cognitive performance 4,6,7,8}. the brain without toxic cholinergic effects in peripheral The problem, however, has been to develop an effective, tissues. The peripheral tissues are protected because they relatively nontoxic inhibitor for acetylcholinesterase 25 resynthesize the enzyme relatively quickly (11,12). Using (acetylcholinesterase EC 3.1.1.7), the enzyme widely this strategy, therefore, it was expected that methanesulfonyl accepted as involved in memory functions 5.9). Cholinest fluoride could produce more than 50% inhibition in the erase inhibitors, in general, are a relatively toxic compounds brain, the minimum therapeutic window (7,14.15), without because significant inhibition of these enzymes in peripheral toxic effects in peripheral tissues. A minimum of 50% tissues are associated with nausea, vomiting, diarrhea, 30 inhibition also corresponds to strong methanesulfonyl excessive salivation, and other signs of excessive cholin fluoride-induced enhancement of animal memory without ergic activity. In addition, there is some evidence that toxicity 16, 17.18). inhibition of butyrylcholinesterase (BChE, E.C. 3.1.1.8), In one embodiment of the present invention, there is concurrently with acetylcholinesterase (AChE. E.C. provided a composition of matter comprising a pharmaceu 3.1.1.7), potentiates the toxicity of cholinesterase inhibitors 35 tical composition, comprising a sulfonyl fluoride and a in peripheral smooth muscle 10). The ideal cholinesterase pharmaceutically acceptable carrier. inhibitor to be used for the treatment of a chronic disease In another embodiment of the present invention, there is such as SDAT would therefore, be selective for the CNS provided a method of treating Alzheimer's disease in an (compared to peripheral tissues), be long acting, and have a individual in need of such treatment, comprising the step of high degree of selectivity for acetylcholinesterase administering to said individual a therapeutically effective (compared to butyrylcholinesterase). dose of a sulfonyl fluoride. Methanesulfonyl fluoride (MSF) is a long-acting irrevers In yet another embodiment of the present invention, there ible inhibitor of acetylcholinesterase that shows excellent is provided a method of enhancing cognitive performance in selectivity for the CNS 11.12). This selectivity seems to be an individual in need of such treatment, comprising the step due, in part. to the irreversible mechanism of action. Recov 45 of administering to said individual atherapeutically effective ery from inreversible inhibition is a simple function of the dose of a sulfonyl fluoride. rate of new synthesis of acetylcholinesterase in each tissue. Other and further aspects, features, and advantages of the Fortunately, acetylcholinesterase in the brain is resynthe present invention will be apparent from the following sized at a rate much slower than peripheral tissues 11.12). 50 description of the presently preferred embodiments of the Therefore, methanesulfonyl fluoride can be used to accu invention given for the purpose of disclosure. mulate up to 80-90% inhibition of rodent and monkey brain acetylcholinesterase with minimum inhibition of peripheral BRIEF DESCRIPTION OF THE DRAWINGS enzyme and without toxicity by using relatively small doses So that the matter in which the above-recited features, of the drug over a long period of time 11.12. 55 advantages and objects of the invention, as well as others Methanesulfonyl fluoride also has high selectivity as an which will become clear, are attained and can be understood inhibitor of acetylcholinesterase in comparison to butyryl in detail, more particular descriptions of the invention cholinesterase and is much better with regard to this quality briefly summarized above may be had by reference to than tacrine, metrifonate, and physostigmine which do not certain embodiments thereof which are illustrated in the show this high degree of selectivity (13). This may also be appended drawings. These drawings form a part of the one mechanism by which methanesulfonyl fluoride avoids specification. It is to be noted, however, that the appended peripheral toxicity. In summary, therefore, methanesulfonyl drawings illustrate preferred embodiments of the invention fluoride is a long-acting, acetylcholinesterase-selective and therefore are not to be considered limiting in their scope. inhibitor that can produce up to 80-90% inhibition in the FIG. 1 shows the effects of methanesulfonyl fluoride brain without toxicity. 65 (mg/kg) on erythrocyte acetylcholinesterase. Despite the research discussed supra, there are significant FIG. 2 shows the synthesis and loss of enzyme at steady problems in this art in determining whether a potential State. 5,798.392 3 4 FIG.