US 2005O182044A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0182044 A1 Bruinsma (43) Pub. Date: Aug. 18, 2005 (54) COMBINATORIAL THERAPY WITH AN Related U.S. Application Data ACETYLCHOLINESTERASE INHIBITOR AND (3AR)-1,3A,8-TRIMETHYL-1,2,3,3A,8,8A- (60) Provisional application No. 60/545,046, filed on Feb. HEXAHYDROPYRROLOI2,3,-BINDOL-5-YL 17, 2004. PHENYLCARBAMATE Publication Classification (76) Inventor: Gosse B. Bruinsma, Leiden (NL) (51) Int. C.7 - - - - - - - - - - - - - - - - - - - - - - - A61 K 31/55; A61 K 31/473; A61K 31/407 Correspondence Address: (52) U.S. Cl. ..................... 514/214.03; 514/290; 514/411 TRASK BRITT P.O. BOX 2550 (57) ABSTRACT SALT LAKE CITY, UT 84110 (US) The present invention relates to an improved method of treating, reducing or delaying cognitive impairments asso (21) Appl. No.: 11/059,191 ciated with the B-amyloid peptide, either in combination with treatment by cholinomimetic replacement therapy or as (22) Filed: Feb. 15, 2005 a prophylactic treatment. Patent Application Publication Aug. 18, 2005 Sheet 1 of 7 Patent Application Publication Aug. 18, 2005 Sheet 2 of 7 US 2005/0182044 A1 S2 2 e HE C 9. d O O cN O ea o c Cd cs (uu 06v e d'O) HS-N-XS useme-Ol C O V 1 O. S. ap 3xxx3 c) CN es wS. o o N O (9 CD & 5 S. Sg S 9 O E s (Ad) Seo HS-N-S J0 epau use AagW S S E 9 cs CD a O 8C is 1.E a gs E C s H ) s E C 9. M XO ? N g g O k (Ionuo Jo 9) slie HS-N-Xs useAal (Ieneos.u.) 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For HEXAHYDROPYRROLOI2,3,-BINDOL-5-YL example, rivastigmine, and galantamine are both prepared as PHENYLCARBAMATE the desired enantiomer, and considerable attention is paid to avoiding the alternative enantiomer or purifying the desired CROSS-REFERENCE TO RELATED enantiomer. This resolution of enantiomerS Substantially APPLICATIONS increases the cost of manufacturing the drug. 0001) This application claims the benefit of U.S. Patent 0008 (-)-Phenserine, the (-) enantiomer, was initially Application 60/545,046, filed Feb. 17, 2004, the entirety of prepared as the pure (-) enantiomer for use in the treatment which is incorporated by reference. of cognitive impairments, Since this enantiomer inhibits acetylcholinesterase activity, while the (+) enantiomer, TECHNICAL FIELD POSIPHENTM, does not. 0002 The invention relates to generally to biotechnology, and more particularly to various methods and compositions DISCLOSURE OF INVENTION for the treatment of cognitive disorders. 0009. The present invention provides combinatorial therapy for the treatment of cognitive disorders, Such as BACKGROUND those associated with accumulation of a B-amyloid peptide. 0003. Since defects in the cholinergic system have been 0010. The present invention relates to an improved Suggested to underlie cognitive impairments associated with method of therapy for cognitive impairments, comprising normal aging and Alzheimer's disease (AD) (Bartus et al., treating a Subject with an effective amount of a compound Science 217:408-417 (1982); Fischer et al., Neurobiol. lacking Significant cholinergic activity, but having B-APP or Aging 13:9-23 (1992)), much research has focused on the AB inhibitory activity (which may be determined, for development of cholinomimetic replacement therapy as a example, by the method described in Examples II and/or V), potential treatment of these impairments. Among them, and a compound having cholinergic activity, for example, cholinesterase inhibitors, such as physostigmine (Phy) and (-) and (+)-N-phenylcarbamoyl eSeroline, and/or one or tetrahydroaminoacridine (THA), have been investigated for more pharmaceutically acceptable Salts of each. In particu memory-enhancing effects in both animals (Rupniak et al., lar, cognitive disorders associated with the B-amyloid pep Neurobiol. Aging 11:09-613 (1990); Murray et al. Psychop tide production and/or accumulation and Susceptible to harmacology 105:134-136 (1991)) and human subjects treatment by cholinomimetic replacement therapy may be (Mohs et al., J.A. Geriatr. Soc. 33:749-757 (1985); Summers treated. et al., N. Engl. J. Med. 315:1241-1245 (1986)). 0011. The present invention relates to an improved 0004 Additional cholinesterase inhibitors that are, or method of treating cognitive disorders comprising treating a have been, used for treating cognitive disorders, Such as Subject with an effective amount of an acetylcholinesterase Alzheimer's disease, included donepezil, rivaStigmine, and inhibitor (AChEI) and a compound lacking significant galantamine, see, U.S. Pat. No. 5,409,948. In addition, AChEI activity, but being capable of reducing the produc (-)-phenserine, the negative optical enantiomer (-)-phenyl tion of B-APP and/or accumulation of AB, for example, carbamoyleSeroline, which has the Structure: (+)-phenserine, POSIPHENTM. In particular, cognitive dis orders associated with the 3-amyloid peptide and Susceptible to treatment by cholinomimetic replacement therapy may be benefited treated by the method of the invention. 0012. The invention further relates to co-administration s of (+)-phenserine or a similar compound and at least one NH CH acetylcholinesterase inhibitor Selected from the group con sisting of (-)-phenserine, donepezil, rivastigmine, metri HC fonate, tacrine, physostigmine, (-) carbamates, eptastig mine, galantamine, huperzine A and pharmaceutically acceptable Salts and esters thereof. 0013 The invention further relates to coadministration of 0005 (3aS)-1,3a,8-trimethyl-1,2,3,3a,8.8a-hexahydropy (+)-phenserine and an AchEI for the Symptomatic treatment rrolo2,3-bindol-5-yl phenylcarbamate and its salts, pro of AD. vides another acetylcholinesterase inhibitor that may be used 0014. In a preferred embodiment, the invention further clinically for treating cognitive disorders. relates to the coadministration of (+)-phenserine and (-)- 0006 (-)-Phenserine is a potent acetylcholinesterase phenserine, preferably in non-equal molar amounts, includ inhibitor having Significantly reduced negative side effects ing between about 2:1 to about 100:1. relative to other acetylcholinesterase inhibitors. Due to the 0015 The invention further relates to a method of reduc chronic nature of treatment for cognitive disorders, it has ing the Subject's risk of developing or further developing a long been desired to provide an agent that is effective and cognitive impairment and/or providing a prophylactic treat does not produce the undesirable side effects that may be ment for Subject comprising co-administering (+)- caused by the use of acetylcholinesterase inhibitors. phenserine to a Subject thought to be at risk for the devel US 2005/0182044 A1 Aug. 18, 2005 opment of a cognitive impairment associated with increased BRIEF DESCRIPTION OF DRAWINGS levels of B-APP or AB, for example, in combination with an 0022 FIG. 1 illustrates the effect of three weeks of daily AChE inhibitor. oral administration of donepezil (1.5 mg/kg) on brain levels 0016 Typically, treatment of cognitive disorders associ of B-APP in adult rats (N>6). The levels of B-APP were ated with accumulation of AB, Such as Alzheimer's disease, measured by 22C11 (epitope APP 66-81). Similar elevations are initiated when the Subject's cognitive impairment has were seen with Elan 266 (epitope AB 13-28) for B-APPY. progressed to a point where cognitive ability displayS Sig *Significantly different from controls (p<0.05). nificant impairment that can be attributed to a disease State, 0023 FIG. 2 illustrates the effect of donepezil treatment Such as Alzheimer's disease. The fact that many of the on B-APP and AB levels. Donepezil reduces intracellular Subjects are elderly and may be simply Suffering from other B-APP without altering AB levels, except at toxic doses, as effects of aging hinders the diagnosis of AD and delayS measured by LDH. treatment. The present invention overcomes this difficulty and provides a method of treating an elderly Subject or a 0024 FIG. 3 illustrates the elevated secretion of B-APP Subject having a perceived risk of developing a cognitive by rivastigmine in human neuroblastoma cells. Human impairment without the necessity of awaiting manifestations neuroblastoma cells were incubated with rivastigmine at 2 LiM, 10 uM and 50 uM, and secreted ?-APP and AB were of actual cognitive decline. measured. No Statistically significant change in the AB 0.017. The present invention also relates to co-adminis peptide levels was seen. tration of effective amounts of N-phenylcarbamoyleseroline 0025 FIG. 4 illustrates time- and concentration-depen enantiomers, or a pharmaceutically acceptable Salt of one or dent actions of (-)-phenserine on cellular (intracellular) and more enantiomers. In an exemplary embodiment, the (-) secreted (extracellular) levels of B-APP and secreted levels enantiomer is administered at a dosage appropriate for of AB in human neuroblastoma (SK-N-SH) cell culture, cholinomimetic replacement therapy and the (+) enantiomer as assessed by Western blot analysis of B-APP levels (mAb is administered at a dosage appropriate for the reduction or 22C11) and ELISA analysis of AB in the absence of cellular further reduction of B-APP synthesis when co-administered toxicity, as assessed by measurement of lactase dehydroge with the (-) enantiomer.