US008592458B2

(12) United States Patent (10) Patent N0.: US 8,592,458 B2 Kem et a]. (45) Date of Patent: *Nov. 26, 2013

(54) ALPHA7 NICOTINIC RECEPTOR (56) References Cited SELECTIVE LIGANDS U.S. PATENT DOCUMENTS

(75) Inventors: William Reade Kem, Gainesville, FL 5,741,802 A 4/1998 Kem et al. (US); Ferenc Soti, Gainesville, FL (US) 5,977,144 A 11/1999 Meyer et al. 7,244,745 B2 7/2007 Herbert et al. Assignee: University of Florida Research 8,093,269 B2 * 1/2012 Kem et al...... 514/333 (73) 2007/0232651 A1 10/2007 Habgood et a1. Foundation, Inc., Gainesville, FL (U S) FOREIGN PATENT DOCUMENTS Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 WO WO-2004/019943 A 3/2004 USC 154(b) by 0 days. OTHER PUBLICATIONS This patent is subject to a terminal dis West, Anthony R., Solid State Chemistry and its Applications, Wiley, claimer. NeWYork, 1988, pp. 358 & 365* Wu et al, Toxicology, vol. 236, 2007, pp. 1-6.* Arendash. G.W. Brain Research. 1995, vol. 674. No. 2, pp. 252-259, (21) Appl. No.: 13/328,841 see especially p. 253, 2nd column. de Fiebre CM, et al. Characterization of a series of anabaseine (22) Filed: Dec. 16, 2011 derived compounds reveals that the 3-(4)-dimethylaminocin namylidine derivative is a selective agonist at neuronal nicotinic Prior Publication Data alpha 7/125l-alpha-bungarotoxin receptor subtypes. Mol Pharmacol. (65) Jan. 1995;47(1):164-71. US 2012/0094943 A1 Apr. 19, 2012 Kem et. al., Mol. Pharmacol. 2004, vol. 65. No. 1, pp. 56-67. Kem, Behav. Brain Res. 2000, vol. 113, pp. 169-181. Papke et al., Br. J. Pharmacol. 2002, vol. 137, pp. 49-61. Stokes et al., Mol. Pharmacol. 2004, vol. 66. No. 1, pp. 14-24. Related US. Application Data (63) Continuation of application No. 11/921,832, ?led as * cited by examiner application No. PCT/US2006/022136 on Jun. 7, 2006, Primary Examiner * Zinna Northington Davis noW Pat. No. 8,093,269. (74) Attorney, Agent, or Firm * Edwards Wildman Palmer (60) Provisional application No. 60/688,216, ?led on Jun. LLP; Jeffrey D. Hsi; Peter F. Corless 7, 2005. (57) ABSTRACT The invention relates to the design and synthesis of (51) Int. Cl. 3-arylidene-anabaseine compounds that exhibit enhanced C07D 401/14 (2006.01) selectivity toWard alpha7 nicotinic receptors. The compounds A61K 31/44 (2006.01) are expected to be useful in treating a Wide variety of condi (52) US. Cl. tions, including neurodegenerative conditions such as Alzhe USPC ...... 514/333; 514/334; 546/256; 546/257 imer’s Disease, neurodevelopmental diseases such as schizo phrenia, and certain peripherally located in?ammations (58) Field of Classi?cation Search None mediated by macrophage in?ltration. See application ?le for complete search history. 37 Claims, No Drawings US 8,592,458 B2 1 2 ALPHA7 NICOTINIC RECEPTOR nervous system, these non-neuronal cells include microglia SELECTIVE LIGANDS and astrocytes; outside the nervous system non-neuronal cells expressing alpha7 receptors include macrophages, vascular CROSS-REFERENCE TO RELATED endothelium and pulmonary epithelial cells. APPLICATIONS All knoWn mammalian nAChRs are cation selective ligand-gated ion channels that form pentameric structures in The present application is a Continuation of US. patent the plasma membrane. Each subunit of the pentamer contains application Ser. No. 11/921,832, ?led Feb. 17, 2009, now four transmembrane domains. There are at least seventeen US. Pat. No. 8,093,269, Which is a US. national phase appli different nAChR subunit genes, including ?ve found in stri cation, pursuant to 35 USC §371, of PCT International ated muscle (otl, [31, y, 6, e) and tWelve neuronal nAChR Application Ser. No. PCT/US2006/022136, ?led Jun. 7, subunits (a2-10, [32-4). These channels can be composed of a 2006, designating the United States and published in English number of different combinations of subunits. Examples of on Dec. 14, 2006 as publication WO 2006/ 133303 A1, Which the most abundant subtypes in the brain include the (X7 sub claims priority under 35 I/S/C/ §119(e) to US. Provisional type (ot-bungarotoxin sensitive) and the (x4[32 subtypes (a4 Application 60/688,216, ?led Jun. 7, 2005, each ofWhich are (2) [32(3) or 0L4(3) 92(2)). There is strong evidence support hereby incorporated by reference in its entirety. ing the idea that most (X7 receptors are expressed as homopentamers. Functional bungarotoxin sensitive channels STATEMENT AS TO FEDERALLY SPONSORED are expressed in Xenopus oocyles When only (X7 cDNA is RESEARCH injected. HoWever, rat hippocampal interneurons have 20 (x7-containing nAChRs that exhibit pharmacological and This invention Was made With US. government support functional properties different from those of homomeric (X7 under grant number MH-61412 aWarded by the National receptors. The co-expression of the (X7 subunit With the [32 Institutes of Health. The US. government may have certain subunit in Xenopus oocyles has produced functional hetero rights in the invention. meric channels With similar properties to the rat hippocampal 25 interneuron (x7-containing receptor (Khiroug et al. 2004 J. BACKGROUND OF THE INVENTION Physiol. (London) 540:425-434). In addition to its ability to assemble into homomeric channels, the (X7 nAChR channel Several types of nicotinic acetylcholine receptors displays much greater permeability to calcium ions than other (nAChRs) are knoWn to play a role in central nervous system nAChRs or the NMDA glutamate receptor subtype. activity and as such are involved in cognition, mood and 30 Neuronal nAChR de?cits have been implicated in several neuroprotection. The various types of knoWn nicotinic diseases including AD and schizophrenia. Until recently, the ligands appear to have different combinations of effects on study of neurodegenerative diseases focused on the muscar nicotine-modulated functions, depending on the subtypes of inic type neuronal acetylcholine receptor (mAChR) because nAChRs affected, some affecting all receptors, others having of its abundance in the brain When compared to the population more selective actions. A multitude of compounds has been 35 of neuronal nicotinic receptors (nAChRs). HoWever, the dis investigated, including quinuclidines (AR17776 and conge covery of a greater relative loss of nicotinic receptors than of ners); aZabicycyclic compounds for treating dementia (US. muscarinic receptors in the AlZheimer’s brain, as Well as Pat. No. 5,217,975); 2-aroylaminothiaZole derivatives that evidence that nicotinic agonists enhance cognition has may be useful for treating cognitive disorders (US. Pat. No. spurred interest in nAChRs. This is supported by the obser 5,510,478); and 5-hydroxytryptophan receptor antagonists 40 vation of enhanced attentiveness and rapid information pro based on 1-aZabicyclo nonane derivatives (U .S. Pat. No. cessing in humans receiving nicotine or DMXBA (GTS-21) 4,798,829). Published US. application (2004/0087616) dis treatment. The tWo major brain nAChRs alpha4beta2 ((>t4[32) closes 1H-pyraZole and 1H-pyrrole-aZabicyclic compounds and alpha 7 are important for cognitive processes such as reported to have alpha7 (a7) nicotinic acetylcholine receptor attention, learning and memory. Since brain alpha7 nicotinic agonist activity Which may be useful in treating the cognitive 45 receptors are spared relative to the alpha4beta2 nAChRs in and attention de?cit symptoms of AlZheimer’s disease (AD) AlZheimer’s disease and also possess exceptionally high cal and other degenerative CNS conditions. cium ion permeability, they are considered a particularly A large number of 3-arylidene-anabaseine compounds promising therapeutic target for treatment of AlZheimer’s have been prepared (WO 2004/019943) for potential use in disease. In addition to their direct involvement in synaptic treating neurodegenerative diseases, and particularly With the 50 transmission, certain nicotinic receptor subtypes, particularly hope that some compounds Would bind to nicotinic alpha7 alpha7, because of their very high calcium permeability also receptors. No particular nicotinic receptor activity (agonist or stimulate calcium-dependent intracellular signal transduc antagonist) or nicotinic receptor subtype selectivity has been tion processes that are neuroprotective by maintaining neu demonstrated for any of these anabaseine analogs, all of ronal integrity in the presence of stressful states such as Which contain fused-ring heteroaromatic moieties attached 55 ischemia or mechanical trauma. through a methylene group to the 3-position of anabaseine Central cholinergic neurons have been implicated in a Without substitutions on the tetrahydropyridyl ring in the number of neurodegenerative conditions including, AD and anabaseine molecule. schizophrenia. AD affects an estimated 15 million people Acetylcholine receptors can be divided into muscarinic WorldWide and accounts for approximately 50-60% of the (mAChR) and nicotinic (nAChR) subtypes in the mammalian 60 overall cases of dementia for people over the age of 65. The central nervous system (CNS). These subtypes are distin characteristic pathology of AD includes extracellular [3-amy guished based on their ability to be stimulated by either the loid plaques, intracellular neuro?brillary tangles, loss of neu mushroom toxin muscarine or the plant alkaloid nicotine. ronal synapes and pyramidal cells. The cholinergic dysfunc Nicotinic receptors are important in cholinergic transmission tion in AD is represented by a reduction in the activity of the in autonomic ganglia, striated muscles, the neuromuscular 65 ACh-synthesiZing enZyme cholineactyltransferase (ChAT) junction, and in brain and spinal synapses. Some nAChRs are and a loss in functional nAChRs. This alteration is possibly also expressed in non-neuronal or muscle cells. Within the attributable to a reduction in nAChR synthesis, and/or to US 8,592,458 B2 3 4 changes in nicotinic receptor pharmacology due to modi?ca including these anabaseine compounds and methods of using tions in the binding site. In schizophrenia, there is a disruption the anabaseine compounds, pharmaceutical formulations and in the normal brain mechanism that eliminates repetitive kits. stimuli in order to reduce the How of information. This mal Thus, in one aspect of the invention are provided novel function in the simple ?lter for sensory input causes an over 3-arylidene-anabaseine compounds as described in detail load of stimuli, Which may lead to misperceptions of sensory herein. These 3-arylidene-anabaseine compounds include stimuli producing delusions, or WithdraWal from stimuli particular 3-benZylidene-anabaseines (including 3-ben causing schiZoid behavior. Zylidene-anabaseines that are alkyl-substituted on the tet It is noW knoWn that selective alpha7 nicotinic receptor rahydropyridyl ring carbons, as Well as 3-benZylidene-ana agonists can improve memory-related behaviors and protect baseines With particular combinations of substituents (other against neurotoxicity induced by trophic factor deprivation, than hydrogen) on the phenyl ring of the benZylidene), 3-cin amyloid exposure, excitotoxicity, in viva ischemia and axo namylidene-anabaseines, 3-(benZofuran-2-ylmethylene) tomy (Li et al., 2000). The (x7nAChR subtype is knoWn to anabaseines, 3-(1H-indol-2-ylmethylene)-anabaseines, and 3-benZylidene-glucuronide-anabaseines as described herein. cause long-term synaptic modulation through its in?uence on In certain embodiments are provided 3-benZylidene-ana glutamatergic synapses. Strong, brief stimulation of presyn aptic (x7-containing nAChRs can enhance hippocampal baseines of the formula: glutamatergic synaptic transmission for some time after the nicotinic agonist has been removed (Radcliffe and Dani, 1 998). DMXBA, 3-(2,4-dimethoxy benZylidene)-anabaseine is a 20 Well-studied compound that selectively activates alpha7 receptors in rats and has shoWn promise in Phase I human clinical trials. It also is an antagonist at alpha4beta2 receptors. DMXBA is less toxic than nicotine and does not affect auto nomic and skeletal muscle systems at doses used to enhance 25 cognitive behavior. Clinical tests of DMXBA indicate that large doses could be safely administered orally Without adverse effects (KitagaWa et al., 2003. Neuropsychopharma cology 281542-551; Olincy et al., 2006. Arch. Gen. Psychial., in press). 30 Despite promising results in studies of anabaseine-related compounds such as DMXBA for potential treatment of cog nitive disorders, these compounds penetrate into all tissues of where R1 is, independently, acetoxy, acetamido, amino, dim the body, making them unsuitable for treating certain periph ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl eral diseases. The action of DMXBA, for example, cannot be 35 carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim restricted to peripheral (accessible from the blood compart ethylammoniumpropoxy, trimethylammoniumpentoxy, ment) alpha7 receptors, Which have recently been shoWn to Cl-C3 alkyl, Cl-C3 alkyl hydroxy, hydroxyl, Cl-C3 alkoxy, have therapeutic importance for treating certain diseases. tri?uoromethoxy, methylamino or thiomethoxy and n is 0-5; The importance of developing highly selective alpha7 R2 is independently C 1 -C3 alkyl and n' is 1-3, Wherein at least nicotinic receptor agonists has increased as the role of these 40 one R2 is present at position 4, 5, or 6; R3 is independently receptors in degenerative disease becomes clearer. There is a Cl-C3 alkyl, Cl-C3 alkylhydroxy, Cl-C3 alkoxy, cyano, halo, particular need for neW compounds useful in treating cogni phenoxy, phenyl, pyridyl or benZyl and n" is 0-4; R4 is hydro gen or C l-C3 alkyl or C l-C3 alkylhydroxy; or a pharmaceuti tive dysfunctions such as AD Where degenerative processes cally acceptable salt, solvate, clathrate, stereoisomer, enanti drastically interfere With cognitive and physiological pro omer, prodrug or combination thereof. cesses. Accordingly, compounds that are safe and are highly 45 In some embodiments of the 3-benZylidene-anabaseine, n selective as alpha7 nicotinic receptor agonists Wouldbe prime is 1-3. In particular embodiments, R2 is methyl. In certain of candidates for therapeutics to treat human diseases involving these embodiments, n is 1. In some embodiments, n is 2. In neurodegeneration or defective development of the brain. other embodiments, n is 3. While some anabaseine-related compounds hold promise In some embodiments of the 3-benZylidene-anabaseine, n as alpha7 agonist drugs, they are not completely selective and 50 is 1-3. In particular embodiments, R2 is ethyl. In certain of can have antagonistic effects on brain alpha4beta2 subtype these embodiments, n is 1. In some embodiments, n is 2. In nicotinic receptors, Which also participate in cognitive pro other embodiments, n is 3. cesses. Development of selective alpha7 agonists Would In some embodiments of the 3-benZylidene-anabaseine, n alloW less drug to be used, possibly With feWer side effects is 1-3. In particular embodiments, R2 is propyl. In certain of arising from interaction With other nicotinic receptor sub 55 these embodiments, n is 1. In some embodiments, n is 2. In types. other embodiments, n is 3. An additional advantage of neW alpha7 agonist drugs In some embodiments of the 3-benZylidene-anabaseines, Would be identi?cation of selective alpha7 agonists that do the anabaseine is enriched in one enantiomer and shoWs not penetrate into all tissues of the body, thus alloWing their greater relative selectivity for the (X7 nicotinic receptor versus use in selectively targeting peripheral (accessible from the the (x462 nicotinic receptor When compared to the anabaseine blood or pulmonary compartments) alpha7 receptors, Which enriched in the other enantiomer. have recently been shoWn to have therapeutic importance for In certain embodiments of the 3-benZylidene-anabaseines, treating certain diseases. the anabaseine is enriched in one enantiomer and shoWs greater relative selectivity for the (X7 nicotinic receptor versus SUMMARY OF THE INVENTION the (x462 nicotinic receptor When compared to a racemic 65 mixture of the anabaseine. Provided herein are novel 3-arylidene-anabaseine com In certain embodiments of the 3-benZylidene-anabaseines, pounds as Well as pharmaceutical formulations and kits R2 is at position 4. In some embodiments, R2 is at position 5. US 8,592,458 B2 5 6 In other embodiments, R2 is at position 6. In some of these DMXBA is enriched in one enantiomer and shoWs greater embodiments, n is 1. In others, n is 2 or 3. In certain embodi relative selectivity for the (X7 nicotinic receptor versus the ments, R2 is methyl. In others, R2 is ethyl. In still others, R2 is (x462 nicotinic receptor When compared to the other enanti propyl. omer of 6-methyl-DMXBA. In certain embodiments of the 3-benZylidene-anabaseines, In some embodiments of the 3-benZylidene-anabaseines, R1 is, independently, hydroxy, amino, methylamino, thi the anabaseine is 6-methyl-DMXBA and the 6-methyl omethoxy, or methoxy. In certain of these embodiments, n is DMXBA is enriched in one enantiomer and shoWs greater 1. In others, n is 2. In still others, n is 3. In particular of these relative selectivity for the (X7 nicotinic receptor versus the embodiments, each R1 is methoxy. In some embodiments, R1 (x462 nicotinic receptor When compared to the racemic mix is at the 2" and 4" positions. In particular embodiments, ture of 6-methyl-DMXBA. Wherein n is 1-5 and one of said Rls is, independently, at the In some embodiments of the 3-benZylidene-anabaseines, 2" or 4" position. In other embodiments, n is 1 and R1 is at the the anabaseine is 5 -methyl-DMXBA. In certain embodiments 4" position. the S-methyI-DMXBA is enriched in the one enantiomer that In certain embodiments are provided enantiomerically has a greater retention time on a Chiracel OJ-H column than enriched 3-arylidene-anabaseine compounds, Wherein the the other enantiomer. In certain embodiments, the greater anabaseine compound is Cl-C3 alkyl-substituted at one or retention time is about 27 minutes. In other embodiments, the more carbon atoms of the tetrahydropyridyl ring. In particular 5-methyl-DMXBA is enriched in the one enantiomer Which embodiments, the enantiomerically enriched 3-arylidene has a shorter retention time on a Chiracel OJ-H column than anabaseine compound is a 3-benZylidene-anabaseine as the other enantiomer. In certain embodiments, the shorter described herein. In certain embodiments, the 3-arylidene retention time is about 25 minutes. anabaseine compound is enriched in the R-isomer. In other 20 In some embodiments of the 3-benZylidene-anabaseines, embodiments, the 3-arylidene-anabaseine compound is the anabaseine is S-methyI-DMXBA and the 5-methyl enriched in the S-isomer. In particular embodiments, the DMXBA is enriched in one enantiomer and shoWs greater enantiomerically enriched 3-arylidene-anabaseine com relative selectivity for the (X7 nicotinic receptor versus the pound is 4-methyl-DMXBA, S-methyI-DMXBA, 6-methyl (x462 nicotinic receptor When compared to the other enanti DMXBA, 3-(4-hydroXybenZylidene)-4-methylanabaseine, 25 omer of S-methyI-DMXBA. or 3 -(4-hydroxybenZylidene)-6-methylanabaseine. In certain In some embodiments of the 3-benZylidene-anabaseines, embodiments, the enantiomerically enriched 3-arylidene the anabaseine is S-methyI-DMXBA and the 5-methyl anabaseine compound is 4-methyl-DMXBA, 5-methyl DMXBA is enriched in one enantiomer and shoWs greater DMXBA, or 6-methyl-DMXBA. In other embodiments, the relative selectivity for the (X7 nicotinic receptor versus the enantiomerically enriched 3-arylidene-anabaseine com (x462 nicotinic receptor When compared to the racemic mix pound is 3-(4-hydroxybenZylidene)-4-methylanabaseine or 30 ture of 5-methyl-DMXBA. 3 -(4-hydroxybenZylidene)-6-methylanabaseine. In certain of In some embodiments of the 3-benZylidene-anabaseines, these embodiments, the 3-arylidene-anabaseine compound is the 3-benZylidene-anabaseine is a (X7 nicotinic receptor ago enriched in the S-isomer. In others it is enriched in the R-iso nist. mer. In certain embodiments of the 3-benZylidene-anabaseines, In some embodiments of the 3-benZylidene-anabaseines, 35 the 3-benZylidene-anabaseine is a (X7 nicotinic receptor full the anabaseine is 4-methyl-DMXBA. In certain embodiments agonist. In particular embodiments, the 3-benZylidene-ana the 4-methyl-DMXBA is enriched in the one enantiomer that baseine is a (X7 nicotinic receptor partial agonist. has a greater retention time on a Chiracel OJ-H column than In some embodiments of the 3-benZylidene-anabaseines, the other enantiomer. In certain embodiments, the solvent the 3-benZylidene-anabaseine is a (X7 nicotinic receptor pro?le is as described herein. In certain embodiments, the 40 antagonist. greater retention time is about 26 minutes. In other embodi In certain embodiments are provided a 3-benZylidene-ana ments, the 4-methyl-DMXBA is enriched in the one enanti baseines of the formula: omer Which has a shorter retention time on a Chiracel OJ-H column than the other enantiomer. In certain embodiments, the shorter retention time is about 21 minutes. In some embodiments of the 3-benZylidene-anabaseines, 45 the anabaseine is 4-methyl-DMXBA and the 4-methyl DMXBA is enriched in one enantiomer and shoWs greater relative selectivity for the (X7 nicotinic receptor versus the (x462 nicotinic receptor When compared to the other enanti omer of 4-methyl-DMXBA. 50 In some embodiments of the 3-benZylidene-anabaseines, the anabaseine is 4-methyl-DMXBA and the 4-methyl DMXBA is enriched in one enantiomer and shoWs greater relative selectivity for the (X7 nicotinic receptor versus the (x462 nicotinic receptor When compared to the racemic mix 55 ture of 4-methyl-DMXBA. In some embodiments of the 3-benZylidene-anabaseines, the anabaseine is 6-methyl-DMXBA. In certain embodiments the 6-methyl-DMXBA is enriched in the one enantiomer that has a greater retention time on a Chiracel OJ-H column than 60 Where the 2"R and 4"R are, independently, acetoxy, aceta the other enantiomer. In certain embodiments, the greater retention time is about 29 minutes. In other embodiments, the mido, amino, methylamino, dimethylamino, dimethylcar 6-methyl-DMXBA is enriched in the one enantiomer Which bamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcarbam has a shorter retention time on a Chiracel OJ-H column than oyl, di?uoromethoxy, dimethylaminopropoxy, hydroxyl, the other enantiomer. In certain embodiments, the shorter Cl-C5 alkoxy, tri?uoromethoxy, methylamino or thi retention time is about 21 minutes. 65 omethoxy, provided that at least one of 2"R or 4"R is, inde In some embodiments of the 3-benZylidene-anabaseines, pendently, methylamino or dimethylcarbamoyl, diethylcar the anabaseine is 6-methyl-DMXBA and the 6-methyl bamoyl, ethylcarbamoyl, methylcarbamoyl; or a US 8,592,458 B2 7 pharmaceutically acceptable salt, solvate, clathrate, stereoi somer, enantiomer, prodrug or combination thereof. In certain embodiments of the 3-benZylidene-anabaseines, 2"R and 4"R are each methylamino. In some embodiments of the 3-benZylidene-anabaseines, 2"R is methylamino and 4"R is methoxy. In some embodiments of the 3-benZylidene-anabaseines, 2"R is methylamino and 4"R is isopropoxy. In some embodiments of the 3-benZylidene-anabaseines, 2"R and 4"R are each dimethylcarbamoyl. In some embodiments of the 3-benZylidene-anabaseines, 2"R is dimethylcarbamoyl and 4"R is methoxy. In some embodiments of the 3-benZylidene-anabaseines, 2"R is dimethylcarbamoyl and 4"R is isopropoxy. In some embodiments of the 3-benZylidene-anabaseines, the 3-benZylidene-anabaseine is a (X7 nicotinic receptor ago nist. In certain embodiments, the 3-benZylidene-anabaseine is a (X7 nicotinic receptor full agonist. In particular embodi ments the 3-benZylidene-anabaseine is a (X7 nicotinic recep tor partial agonist. where R1 is, independently, acetoxy, acetamido, amino, dim In some embodiments of the 3-benZylidene-anabaseines 20 ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl the 3-benZylidene-anabaseine is a (X7 nicotinic receptor carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim antagonist. ethylammoniumpropoxy, trimethylammoniumpentoxy, In certain embodiments are provided 3-cinnamylidene Cl-C3 alkyl, Cl-C3 alkylhydroxy, hydroxyl, Cl-C3 alkoxy, anabaseines of the formula: tri?uoromethoxy, methylamino or thiomethoxy and n is 0-4; R2 is independently C 1 -C3 alkyl and n' is 1-3, Wherein at least 25 one R2 is present at position 4, 5, or 6; R3 is independently Cl-C3 alkyl, Cl-C3 alkylhydroxy, Cl-C3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benZyl and n" is 0-4; R4 and R5 are, independently, hydrogen, Cl-C3 alkyl or Cl-C3 alkylhy droxy; or a pharmaceutically acceptable salt, solvate, clath 30 rate, stereoisomer, enantiomer, prodrug or combination thereof. In some embodiments of the 3-(benZofuran-2-ylmethyl ene)-anabaseines, n is 1-3. In certain embodiments, R2 is methyl. 35 In some embodiments of the 3-(benZofuran-2-ylmethyl ene)-anabaseines, the 3-(benZofuran-2-ylmethylene)-ana baseine is a (X7 nicotinic receptor agonist. In certain embodi ments, the 3-(benZofuran-2-ylmethylene)-anabaseine is a (X7 nicotinic receptor full agonist. In particular embodiments, the 3-(benZofuran-2-ylmethylene)-anabaseine is a (X7 nicotinic 40 receptor partial agonist. In some embodiments of the 3-(benZofuran-2-ylmethyl where R1 is, independently, acetoxy, acetamido, amino, dim ene)-anabaseines, the 3-(benZofuran-2-ylmethylene)-ana ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl baseine is a (X7 nicotinic receptor antagonist. carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim In certain embodiments are provided 3-(1H-indol-2-ylm ethylammoniumpropoxy, trimethylammoniumpentoxy, 45 ethylene)-anabaseines having the formula: Cl-C3 alkyl, Cl-C3 alkylhydroxy, hydroxyl, Cl-C3 alkoxy, tri?uoromethoxy, methylamino or thiomethoxy and n is 0-5; R2 is independently C 1 -C3 alkyl and n' is 1-3, Wherein at least one R2 is present at position 4, 5, or 6; R3 is independently Cl-C3 alkyl, Cl-C3 alkylhydroxy, Cl-C3 alkoxy, cyano, halo, 50 phenoxy, phenyl, pyridyl or benZyl and n" is 0-4; R4, R5 and R6 are, independently, hydrogen or Cl-C3 alkyl or Cl-C3 alkylhydroxy; or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomer, enantiomer, prodrug or combination thereof. 55 In some embodiments of the 3-cinnamylidene-ana baseines, n is 1-3. In certain embodiments, R2 is methyl. In some embodiments of the 3-cinnamylidene-ana baseines, the 3-cinnamylidene-anabaseine is a (X7 nicotinic receptor agonist. In certain embodiments, the 3-cin namylidene-anabaseine is a (X7 nicotinic receptor full agonist. 60 In particular embodiments, the 3-cinnamylidene-anabaseine is a (X7 nicotinic receptor partial agonist. In some embodiments of the 3-cinnamylidene-ana baseines, the 3-cinnamylidene-anabaseine is a (X7 nicotinic receptor antagonist. 65 where R1 is, independently, acetoxy, acetamido, amino, dim In certain embodiments are provided 3-(benZofuran-2-yl ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl methylene)-anabaseines of the formula: carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim US 8,592,458 B2 9 10 ethylammoniumpropoxy, trimethylammoniumpentoxy, In some embodiments are provided 3-benZylidene-glucu C l-C3 alkyl, C l-C3 alkylhydroxy, hydroxyl, C l-C3 alkoxy, ronide-anabaseines, Which include a modi?ed glucuronide, tri?uoromethoxy, methylamino or thiomethoxy and n is 0-4; of the formula: R2 is independently C 1 -C3 alkyl and n' is 1-3, Wherein at least one R2 is present at position 4, 5, or 6; R3 is independently Cl-C3 alkyl, Cl-C3 alkylhydroxy, Cl-C3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benZyl and n" is 0-4; R4 and R5 are, independently, hydrogen, Cl-C3 alkyl or Cl-C3 alkylhy droxy; R7 is hydrogen, Cl-C5 alkyl, Cl-C5 dialkoxy, or Cl-C5 alkoxy; or a pharmaceutically acceptable salt, solvate, clath rate, stereoisomer, enantiomer, prodrug or combination thereof. In some embodiments of the 3-(1H-indol-2-ylmethylene) anabaseines, n is 1-3. In certain embodiments, R2 is methyl. In some embodiments of the 3-(1H-indol-2-ylmethylene) anabaseines, the 3-(1H-indol-2-ylmethylene)-anabaseine is a (X7 nicotinic receptor agonist. In certain embodiments, the 3-(lH-indol-2-ylmethylene)-anabaseine is a (X7 nicotinic receptor full agonist. In particular embodiments, the 3-(1H indol-2-ylmethylene)-anabaseine is a (X7 nicotinic receptor 20 partial agonist. In some embodiments of the 3-(1H-indol-2-ylmethylene) anabaseines, the 3-(1H-indol-2-ylmethylene)-anabaseine is a (X7 nicotinic receptor antagonist. In certain embodiments are provided 3-arylidene-ana 25 baseines of the formula:

30 where R1 is, independently, acetoxy, acetamido, amino, dim ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim ethylammoniumpropoxy, trimethylammoniumpentoxy, Cl-C3 alkyl, Cl-C3 alkylhydroxy, hydroxyl, Cl-C3 alkoxy, 35 tri?uoromethoxy, methylamino, acylated glucuronidyl, or thiomethoxy andn is 0-4; R2 is independently C 1 -C3 alkyl and n' is 0-3; R3 is independently Cl-C3 alkyl, Cl-C3 alkylhy droxy, C 1 -C3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or

40 benZyl and n" is 0-4; R4 is hydrogen, Cl-C3 alkyl or Cl-C3 alkylhydroxy; glue is glucuronidyl optionally esteri?ed With a Cl-C4 alkylhydroxy and Where the glucuronidyl hydroxy groups can be acylated With a C l-C3 acyl group (e.g., acetyl, propionyl, butyryl, etc.); or a pharmaceutically acceptable 45 salt, solvate, clathrate, stereoisomer, enantiomer, prodrug or combination thereof. In some embodiments of the 3-benZylidene-glucuronide anabaseines, n' is 1-3 and an R2 is present at position 4, 5, or 6. 50 In some embodiments of the 3-benZylidene-glucuronide anabaseines, n is 1-3. In certain embodiments, R2 is methyl. In some embodiments of the 3-benZylidene-glucuronide anabaseines, the 3-benZylidene-glucuronide-anabaseine is a 55 (X7 nicotinic receptor agonist. In certain embodiments, the 3-benZylidene-glucuronide-anabaseine is a (X7 nicotinic receptor full agonist. In particular embodiments, the 3-ben Zylidene-glucuronide-anabaseine is a (X7 nicotinic receptor or a pharmaceutically acceptable salt, solvate, clathrate, ste 60 partial agonist. reoisomer, enantiomer, prodrug or combination thereof. In some embodiments of the 3-benZylidene-glucuronide In particular embodiments are provided 3-arylidene-ana baseines selected from the group consisting of 3-(3,4-(ethyl anabaseines, the 3-benZylidene-glucuronide-anabaseine is a enedioXy)benZylidene)-anabaseine, 3-(3,4-(methylene (X7 nicotinic receptor antagonist. dioXy)benZylidene)-anabaseine, 3-((6-methoXynaphth-2-yl) 65 In some embodiments are provided 3-benZylidene-glucu methylene)-anabaseine, and 3-((benZofuran-2-yl) ronide-anabaseines, Which include a modi?ed glucuronide, methylene)-anabaseine. of the formula: US 8,592,458 B2 11 12 and one or more pharmaceutically acceptable carriers, excipi H3COOC ents, diluents, stabiliZers or preservatives. In certain embodiments are provided pharmaceutically A00 acceptable compositions comprising at least one of the A00 A00 3-(benZofuran-2 -ylmethylene) -anabaseines described herein and one or more pharmaceutically acceptable carriers, excipi ents, diluents, stabiliZers or preservatives. In certain embodiments are provided pharmaceutically acceptable compositions comprising at least one of the-3 benZylidene-glucuronide-anabaseine described herein and one or more pharmaceutically acceptable carriers, excipients, diluents, stabiliZers or preservatives. In particular embodiments, the 3-arylidene-anabaseines may be used to selectively stimulate (X7 nicotinic receptors as described herein. In certain embodiments are provided methods of selec tively stimulating alpha7 nicotinic receptors, comprising the where R1 is, independently, acetoxy, acetamido, amino, dim step (a) administering a therapeutically effective amount of a ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl 3-benZylidene-anabaseine as described herein to an indi carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim 20 vidual in need thereof. ethylammoniumpropoxy, trimethylammoniumpentoxy, In certain embodiments are provided methods of selec Cl-C3 alkyl, Cl-C3 alkylhydroxy, hydroxyl, Cl-C3 alkoxy, tively stimulating alpha7 nicotinic receptors, comprising the tri?uoromethoxy, methylamino, acylated glucuronidyl, or step (a) administering a therapeutically effective amount of a thiomethoxy and n is 0-4; R2 is independently C 1 -C3 alkyl and 3-benZylidene-anabaseine as described herein to an indi n' is 0-3; R3 is independently Cl-C3 alkyl, Cl-C3 alkylhy 25 vidual in need thereof. droxy, C 1 -C3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or In certain embodiments are provided methods of selec benZyl and n" is 0-4; R4 is hydrogen, Cl-C3 alkyl or Cl-C3 tively stimulating alpha7 nicotinic receptors, comprising the alkylhydroxy; or a pharmaceutically acceptable salt, solvate, step (a) administering a therapeutically effective amount of a clathrate, stereoisomer, enantiomer, prodrug or combination 3-cinnamylidene-anabaseine as described herein to an indi thereof. 30 vidual in need thereof. In some embodiments of the 3-benZylidene-glucuronide In certain embodiments are provided methods of selec anabaseines, n' is 1-3 and an R2 is present at position 4, 5, or tively stimulating alpha7 nicotinic receptors, comprising the 6. step (a) administering a therapeutically effective amount of a In some embodiments of the 3-benZylidene-glucuronide 3-(benZofuran-2-ylmethylene)-anabaseine as described anabaseines, n is 1-3. In certain embodiments, R2 is methyl. 35 herein to an individual in need thereof. In some embodiments of the 3-benZylidene-glucuronide In certain embodiments are provided methods of selec anabaseines, the 3-benZylidene-glucuronide-anabaseine is a tively stimulating alpha7 nicotinic receptors, comprising the (X7 nicotinic receptor agonist. In certain embodiments, the step (a) administering a therapeutically effective amount of a 3-benZylidene-glucuronide-anabaseine is a (X7 nicotinic 3-(lH-indol-2-ylmethylene)-anabaseine as described herein receptor full agonist. In particular embodiments, the 3-ben 40 to an individual in need thereof. Zylidene-glucuronide-anabaseine is a (X7 nicotinic receptor In certain embodiments are provided methods of selec partial agonist. tively stimulating alpha7 nicotinic receptors, comprising the In some embodiments of the 3-benZylidene-glucuronide step (a) administering a therapeutically effective amount of a anabaseines, the 3-benZylidene-glucuronide-anabaseine is a benZylidene-glucuronide-anabaseine as described herein to (X7 nicotinic receptor antagonist. 45 an individual in need thereof. In another aspect of the present invention are provided In certain embodiments are provided methods of selec pharmaceutical formulations of the 3-arylidene-anabaseine tively inhibiting alpha7 nicotinic receptors, comprising the compounds described herein, comprising at least one of the step (a) administering a therapeutically effective amount of a 3-arylidene-anabaseines as described herein and one or more 3-benZylidene-anabaseine as described herein to an indi pharmaceutically acceptable carriers, excipients, diluents, 50 vidual in need thereof. stabiliZers or preservatives. In certain embodiments are provided methods of selec In still another aspect of the invention are provided meth tively inhibiting alpha7 nicotinic receptors, comprising the ods of using the 3-arylidene-anabaseine compounds, or phar step (a) administering a therapeutically effective amount of a maceutical formulations thereof, as described herein. 3-benZylidene-anabaseine of as described herein to an indi In certain embodiments are provided pharmaceutically 55 vidual in need thereof. acceptable compositions comprising at least one of the 3-ben In certain embodiments are provided methods of selec Zylidene-anabaseines described herein and one or more phar tively inhibiting alpha7 nicotinic receptors, comprising the maceutically acceptable carriers, excipients, diluents, stabi step (a) administering a therapeutically effective amount of a liZers or preservatives. 3-cinnamylidene-anabaseine as described herein to an indi In certain embodiments are provided pharmaceutically 60 vidual in need thereof. acceptable compositions comprising at least one of the 3-cin In certain embodiments are provided methods of selec namylidene-anabaseines described herein and one or more tively inhibiting alpha7 nicotinic receptors, comprising the pharmaceutically acceptable carriers, excipients, diluents, step (a) administering a therapeutically effective amount of a stabiliZers or preservatives. 3-(benZofuran-2-ylmethylene)-anabaseine as described In certain embodiments are provided pharmaceutically 65 herein to an individual in need thereof. acceptable compositions comprising at least one of the In certain embodiments are provided methods of selec 3-(lH-indol-2-ylmethylene)-anabaseines described herein tively inhibiting alpha7 nicotinic receptors, comprising the US 8,592,458 B2 13 14 step (a) administering a therapeutically effective amount of a etc.); cognition enhancement compound, etc.); additional 3-(lH-indol-2-ylmethylene)-anabaseine as described herein treatment modality, or combinations of the foregoing. Step to an individual in need thereof. (b) may be performed prior to, concomitantly With, or after In certain embodiments are provided methods of selec step (a). And, in some variations, step (b) may be performed tively inhibiting alpha7 nicotinic receptors, comprising the more than once (e. g., tWice, three times, etc.) (e. g., both prior step (a) administering a therapeutically effective amount of a to and after step (a), both concomitantly With and after step benzylidene-glucuronide-anabaseine as described herein to (a), both prior to and concomitantly With step (a), etc.). For an individual in need thereof. example, in certain variations, step (b) may be performed In certain embodiments the condition to be treated is a prior to or concomitantly With step (a). In other variations, neurological condition characterized by a reduced number of step (b) may be performed concomitantly With or after step (X7 nicotinic receptors. In some embodiments, the condition (a). In still other variations, step (b) may be performed prior to to be treated is a neurological condition characterized by or after step (a). In particular variations, step (b) may be degeneration or impairment of nicotinic alpha7 receptors. In performed prior to step (a). In some variations, step (b) may some embodiments, the neurological condition is Alzhe be performed concomitantly With step (a). In certain varia imer’s disease, Parkinson’s Disease, vascular dementia, age tions, step (b) may be performed after step (a). related cognitive decline (AACD), mild cognitive impair Where step (b) includes administration of a combination of ment (MCI), AIDS-related dementia, schizophrenia, bipolar a pharmaceutical agent and an additional treatment modality disorder, stimulant addiction (e.g., to cocaine, amphetamines, (ies), each may be independently administered prior to, con etc.), or psychoses (e.g., manic psychoses, etc.). comitantly With, or after step (a). In particular embodiments, In particular embodiments the methods of using the 20 step (b) includes a pharmaceutical agent. In particular 3-arylidene-anabaseine compounds described herein (or embodiments, step (b) includes an additional treatment pharmaceutical formulations thereof) include methods of modality (e.g., surgical intervention (e.g., in the treatment of enhancing cognitive behavior in an individual, comprising cancer, including tumors), radiation therapy, etc.). the step (a) administering to individual in need thereof, a In yet another aspect are provided kits including the therapeutically effective amount of a 3-arylidene-anabaseine 25 3-arylidene-anabaseine compounds or pharmaceutical for (or pharmaceutical composition thereof) described herein. mulations thereof as described herein. It is intended that any In particular embodiments, the cognitive behavior is leam of the 3-arylidene-anabaseine compounds or pharmaceutical ing or memory retention. formulations thereof described herein may be included in the Some embodiments of the methods of using the kits of the present invention. In certain embodiments are 3-arylidene-anabaseine compounds described herein (or 30 provided kits including any of the 3-arylidene-anabaseine pharmaceutical formulations thereof) include methods of compound(s) or pharmaceutical formulations thereof ameliorating glutamate-induced toxicity toWard cortical described herein, packaging and instructions for use. cells, comprising the step (a) administering to an individual in In some embodiments, the kits include one or more addi need thereof a therapeutically effective amount of a tional pharmaceutical agents (non-3-arylidene-anabaseine 3-arylidene-anabaseine compound (or pharmaceutical for 35 compound pharmaceutical agents). In certain embodiments, mulation thereof) as described herein. the kits may include one or more non-3 -arylidene-anabaseine Some embodiments of the methods of using the compound nicotinic acetylcholine receptor agonists. In cer 3-arylidene-anabaseine compounds described herein (or tain embodiments, the kits may include one or more non-3 pharmaceutical formulations thereof) include methods of arylidene-anabaseine compound nicotinic acetylcholine reducing or ameliorating in?ammation, comprising the step 40 receptor antagonists. In particular embodiments, the pharma (a) administering to an individual in need thereof, therapeu ceutical agent is provided in a separate container from the tically effective amount of a 3-arylidene-anabaseine com 3-arylidene-anabaseine compound or pharmaceutical formu pound (or pharmaceutical formulation thereof) as described lations thereof. herein to selectively stimulate alpha7 receptors in peripheral In certain embodiments, the 3-arylidene-anabaseine com macrophages. 45 pound(s) or pharmaceutical formulation(s) thereof is pro In certain embodiments, the in?ammation is peripheral. vided in a multi-dose form. Particular embodiments of the methods of using the In particular embodiments, the 3-arylidene-anabaseine 3-arylidene-anabaseine compounds described herein (or compound(s) or pharmaceutical formulation(s) thereof is pharmaceutical formulations thereof) include methods of provided in one or more single unit dose forms. reducing angiogenesis, comprising the step (a) administering 50 In some embodiments, su?icient 3-arylidene-anabaseine a therapeutically effective amount of a 3-arylidene-ana compound(s) or pharmaceutical formulation(s) thereof (in baseine (or pharmaceutical formulation thereof) as described either unit dose or multi-dose form) is provided for treatment herein to the over a period of about 1 day, about 1 Week, about 2 Weeks, In some embodiments of each of the methods of using the about 3 Weeks, about 4 Weeks, about 1 month, about 2 compounds described herein, step (a) is performed once per 55 months, about 3 months, about 4 months, about 6 months, day, tWice per day, three times per day, four times per day, about 9 months, or about 1 year. In particular embodiments, once every other day, once per Week, or tWice per Week. In suf?cient 3-arylidene-anabaseine compound(s) or pharma particular embodiments, step (a) is performed once per day or ceutical formulation(s) thereof is provided for about 3 tWice per day. months. In other embodiments, su?icient compound or for In some embodiments the methods further include a step 60 mulation is provided for about 1 or 2 months. (b), Where step (b) includes administering to the individual a In some embodiments, the kits include more than one pharmaceutical agent (e.g., an anabaseine compound not 3-arylidene-anabaseine compound or pharmaceutical formu described herein as a 3-arylidene-anabaseine or a pharmaceu lation thereof (e.g., tWo, three, four or more 3-arylidene tical agent unrelated to anabaseines (e.g., a pro-angiogenic anabaseine compounds). compound (e.g., nicotine, etc.); anti-angiogenic compound 65 Unless otherWise noted, the 3-arylidene-anabaseines (e.g., mecamylamine, etc.); cancer chemotherapeutic com described herein, and pharmaceutical formulations contain pound (e.g., taxanes (e. g., paclitaxel, etc.), alkylating agents, ing one or more 3-arylidene-anabaseines as described herein, US 8,592,458 B2 15 16 are intended for use in the methods of treatment and/ or pre neuronal pathWays. These benZylidene- and cinnamylidene vention as described herein and may be incorporated in the anabaseine compounds are not selective-binding ligands for kits described herein. The 3-arylidene-anabaseines and phar the ACh-binding site on the alpha7 nAChR; rather, they are maceutical formulations described herein may, unless clearly selectively stimulatory to the alpha7 subtype. Since trans dictated otherWise by the context in Which they appear, be genic mice lacking alpha4beta2 receptors experience dis made as described herein and, additionally using techniques torted learning and enhanced neurodegeneration during aging knoWn in the ?eld in light of the teaching provided herein. (Picciotto et al., 1995, 1998), alpha7 nAChR-targeted drugs In a further aspect of the invention is provided use of the should avoid blocking this receptor Whenever possible to 3-arylidene-anabaseines and pharmaceutical formulations as avoid cognitive dysfunction. described herein in the manufacture of a medicament, par Because inhibition of alpha4beta2 Would be counterpro ticularly the manufacture of a medicament for use in the ductive therapeutically, the identi?cation of 3-arylidene-ana treatment and/or prevention of conditions as described baseine compounds that also selectively bind to the alpha7 herein. Further, the 3-arylidene-anabaseine compounds and receptor provides a neW opportunity to simultaneously pharmaceutical formulations thereof, variously described achieve greater enhancement of co gnition and reduce adverse herein, are also intended for use in the manufacture of a effects mediated through other, non-alpha7 nicotinic recep medicament for use in treatment and/or prevention of the tors. The unexpected selectivity of the disclosed compounds conditions and, in accordance With the methods, described toWard the apha7 receptor strongly suggests the utility of herein, unless clearly dictated otherWise by context or spe these compounds for development of agents for treatment of ci?cally noted. several conditions noW knoWn to involve either the alpha7 20 nicotinic receptors in the central nervous system, or alpha7 DETAILED DESCRIPTION OF THE INVENTION receptors occurring peripherally. Abbreviations and de?nitions used herein include: An important aspect of the invention is the development DMXBA (sometimes referred to as GTS-2l or DMXB) and identi?cation of novel selective alpha7 subtype nicotinic Which is (E)-3-(2,4-dimethoxybenZylidene)-3,4,5,6-tetrahy acetylcholine receptor (nAChR) ligands that can either be 25 dro-2,3'-bipyridine (also knoWn as 3-(2,4-dimethoxyben receptor agonists (including partial agonists and full agonists) Zylidene)-anabaseine. Similarly, 4-methyl-DMXBA may be or antagonists. These compounds have potential therapeutic used herein to refer to 3-(2,4-dimethoxybenZylidene)-(4-me applications for the treatment of a variety of human and thyl)-3,4,5,6-tetrahydro-2,3'-bipyridine (also knoWn as 3-(2, animal diseases. Because of their selectivity for animal 4 -dimethoxyb enZylidene)-4 -methyl -anabaseine); 5 -methyl - nAChRs that are homologous to the mammalian alpha7 30 DMXBA may be used herein to refer to 3-(2,4 nAChR, these compositions may also be active as selective dimethoxybenZylidene)- (5 -methyl) -3 ,4 , 5 ,6 -tetrahydro -2 , 3' - anti-parasitic drugs and pesticides. bipyridine (also known as 3-(2,4-dimethoxybenZylidene)-5 The invention also encompasses the rational development methyl-anabaseine); 6-methyl-DMXBA may be used herein of neW compounds structurally related to arylidene-ana to refer to 3-(2,4-dimethoxybenZylidene)-(6-methyl)-3,4,5, baseines, but Which exhibit signi?cantly enhanced alpha7 35 6-tetrahydro-2,3'-bipyridine (also knoWn as 3-(2,4 nAChR selectivity, relative to these basic structures. While dimethoxybenZylidene)-6-methyl-anabaseine); etc. previously described arylidene-anabaseines are selectively As used herein, the terms “3-arylidene-anabaseine com agonistic to alpha7 receptors, they also non-selectively bind pounds,” “3-arylidene-anabaseines,” including cognates of to other nAChRs and prevent them from being stimulated by the foregoing, refer collectively to the 3-arylidene-ana their natural transmitter acetylcholine. Since at least one of 40 baseine compounds described herein, including the these other nAChRs (alpha4 beta2) also is important for nor 3-arylidene compounds encompassed by the formulae dis mal CNS function, antagonism of this receptor Would be closed herein (explicitly including the 3-benZylidene-ana counterproductive therapeutically and could cause adverse baseines, 3-cinnamylidene-anabaseines, benZofuran-2-ylm effects on mental function. Because of their greatly enhanced ethylene-anabaseine, 3-(lH-indol-2-ylmethylene) selectivity toWard alpha7 receptors, these neW structures, and 45 anabaseines, and 3-benZylidene-glucuronide-anabaseines, compounds containing the important elements of these struc described herein, unless otherWise noted). It is intended that tures, Will provide a panel of useful therapeutic agents that this term also collectively refers to pharmaceutically accept can be targeted not only to speci?c diseases, but also to able salts, solvates, clathrates, stereoisomers, enantiomers, particular areas of the body. For example, these agents can be and prodrugs of the 3-arylidene-anabaseine compounds targeted to the CNS for neurodegenerative conditions, or to 50 described herein, including Where a sample of a 3-arylidene peripheral areas in cases of systemic in?ammation. anabaseine compound is enriched in a particular enantiomer The present invention shoWs that selection of appropriate compared to the racemic mixture (e. g., a sample enriched in substituents on the arylidene, tetrahydropyridyl and pyridyl the (S)-isomer, or a sample enriched in the (R)-isomer, When ring portions of anabaseine compounds determines alpha7 compared to the racemic mixture), as is also described in selectivity, either When done separately or in combinations. 55 greater detail herein. It is not intended that these terms or the Certain substituents also determine alpha7 receptor e?icacy; formulae described herein encompass any of the anabaseine some substituents increase ef?cacy over benZylidene-ana compounds disclosed in US. Pat. Nos. 5,977,144 and 5,741, baseines such as DMXBA, While other reduce ef?cacy to 802. essentially Zero, thereby creating a neW group of alpha7 The term “acyl” refers to the radical iC(O)R, Where R can nAChR antagonists. 60 be H or a Cl-C6 alkyl group (as described herein), including The invention is in broad terms the development of a series straight-chain alkyl groups, and branched-chain alkyl groups. of 3-arylidene-anabaseine compounds that display signi? In some embodiments, R is a Cl-C4 alkyl,C1-C5 alkyl, Cl-C3 cantly enhanced alpha7 receptor binding selectivity relative alkyl. Acyl groups include formyl, acetyl, etc.) to other benZylidene- and cinnamylidene-anabaseine com The term “alkyl” refers to the radical of saturated aliphatic pounds that selectively stimulate alpha7 nicotinic receptors 65 groups, including straight-chain alkyl groups, and branched but are inhibitory at other nAChRs, particularly the neuronal chain alkyl groups. The term alkyl further includes alkyl alpha4beta2 subtype also involved in cognition-enhancing groups, Which can further include oxygen, nitrogen, sulfur or US 8,592,458 B2 17 18 phosphorous atoms replacing one or more carbons of the lamino, diarylamino, and alkylarylamino), acylamino (in hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or cluding alkylcarbonylamino, arylcarbonylamino, carbamoyl phosphorous atoms. In preferred embodiments, a straight and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, chain or branched chain alkyl has 6 or feWer carbon atoms in thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, its backbone (e.g., Cl-C6 for straight chain, C3-C6 for nitro, halogenated alkyl (including tri?uoromethyl, di?uo branched chain), preferably 6 or feWer, and more preferably 4 romethyl and ?uroromethyl), halogenated alkoxy (including or feWer, and still more preferably 3 or feWer. tri?uoromethoxy, di?uoromethoxy and ?uroromethoxy), Moreover, the term alkyl as used throughout the speci?ca cyano, aZido, heterocyclyl, alkylaryl, arylalkyl or an aromatic tion and claims is intended to include both “unsubstituted or heteroaromatic moiety. Aryl groups can also be fused or alkyls” and “substituted alkyls,” the latter of Which refers to bridged With alicyclic or heterocyclic rings, Which are not alkyl moieties having substituents replacing a hydrogen on aromatic so as to form a polycycle (e.g., tetralin). one or more carbons of the hydrocarbon backbone. Such The term “cyclyl” refers to a hydrocarbon 3-8 membered substituents can include, for example, halogen, hydroxy, monocyclic or 7-14 membered bicyclic ring system having at alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, ary least one non-aromatic ring, Wherein the non-aromatic ring loxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbo has some degree of unsaturation. Cyclyl groups may be nyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, optionally substituted With one or more substituents. In one phosphonato, phosphinato, cyano, amino (including alkyl embodiment, 0, l, 2, 3, or 4 atoms of each ring of a cyclyl amino, dialkylamino, acylamino, diarylamino, and alkylary group may be substituted by a substituent. The term lamino), acylamino (including alkylcarbonylamino, arylcar “cycloalkyl” refers to a hydrocarbon 3-8 membered monocy bonylamino, carbamoyl and ureido), amidino, imino, sulfhy 20 clic or 7-14 membered bicyclic ring system having at least dryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, one saturated ring. Cycloalkyl groups may be optionally sub sulfamoyl, sulfonamido, nitro, tri?uoromethyl, cyano, aZido, stituted With one or more substituents. In one embodiment, 0, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic l, 2, 3, or 4 atoms of each ring of a cycloalkyl group may be moiety. It Will be understood by those skilled in the art that the substituted by a substituent. Cycloalkyls can be further sub moieties substituted on the hydrocarbon chain can them 25 stituted, e.g., With the substituents described above. Preferred selves be substituted, if appropriate. cyclyls and cycloalkyls have from 3-10 carbon atoms in their The term “alkyl” also includes unsaturated aliphatic ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons groups analogous in length and possible substitution to the in the ring structure. Those cyclic groups having heteroatoms alkyls described above, but that contain at least one double or in the ring structure may also be referred to as “heterocyclyl,” triple bond respectively. An “alkylaryl” moiety is an alkyl 30 “heterocycloalkyl” or “heteroaralkyl.” The aromatic ring can substituted With an aryl (e.g., phenyl methyl (benZyl)). An be substituted at one or more ring positions With such sub “alkylhydroxy” is an alkyl substituted With a hydroxy group stituents as described above. (e. g., C l-C3 alkylhydroxy includes iCHzOH, i(CH2)2OH, The terms “cyclyl” or “cycloalkyl” refer to the radical of 4(CH2)3OH) tWo or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, The terms “alkoxy, amino alkyl” and “thioalkoxy” refer 35 cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls). In to alkyl groups, as described above, Which further include some cases, tWo or more carbons are common to tWo adjoin oxygen, nitrogen or sulfur atoms replacing one or more car ing rings, e.g., the rings are “fused rings”. Rings that are bons of the hydrocarbon backbone, e.g., oxygen, nitrogen or joined through non-adjacent atoms are termed “bridged” sulfur atoms. rings. Each of the rings of the polycycle can be substituted The terms “alkenyl” and “alkynyl” refer to unsaturated 40 With such substituents as described above, as for example, aliphatic groups analogous in length and possible substitution halogen, hydroxy, alkylcarbonyloxy, arylcarbonyloxy, to the alkyls described above, but that contain at least one alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkyl double or triple bond, respectively. For example, the inven carbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbo tion contemplates cyano and propargyl groups. nyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, The term “aralkyl” means an aryl group that is attached to 45 amino (including alkyl amino, dialkylamino, arylamino, dia another group by a (Cl-C6)alkylene group. Aralkyl groups rylamino, and alkylarylamino), acylamino (including alkyl may be optionally substituted, either on the aryl portion of the carbonylamino, arylcarbonylamino, carbamoyl and ureido), aralkyl group or on the alkylene portion of the aralkyl group, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy With one or more substituents. late, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, halo The term “aryl” as used herein, refers to the radical of aryl 50 genated alkyl (including tri?uoromethyl, di?uoromethyl and groups, including 5- and 6-membered single-ring aromatic ?uroromethyl), halogenated alkoxy (including tri?uo groups that may include from Zero to four heteroatoms (het romethoxy, di?uoromethoxy and ?uroromethoxy), cyano, eroaryl), for example, phenyl, pyrrolyl, furyl, thiophen-yl, aZido, heterocyclyl, alkyl, alkylaryl, or an aromatic or het imidaZolyl, benZoxaZolyl, benZothiaZolyl, triaZolyl, tetra eroaromatic moiety. Zolyl, pyraZolyl, pyridyl, pyraZinyl, pyridaZinyl and pyrim 55 The term “carbamoyl” refers to the radical iC(O)iNH2, idinyl, and the like. Aryl groups also include polycyclic fused Where one or both hydrogens bound to the nitrogen atom may aromatic groups such as naphthyl, quinolyl, indolyl, and the optionally be independently replaced With a C l-C4 alkyl (e. g., like. 4C(O)iNH(Cl-C4 alkyl), 4C(O)iN(Cl-C4 alkyl)2 or an Those aryl groups having heteroatoms in the ring structure aromatic moiety (e. g., phenyl (either substituted or unsubsti may also be referred to as “heteroaryls” or “heteroaromatics.” 60 tuted) or heteroaryl moiety (e. g., pyridyl (either substituted or The aromatic ring can be substituted at one or more ring unsubstituted), etc.). In certain embodiments, the carbamoyl positions With such substituents as described above, as for may be, for example, dimethylcarbamoyl, methylcarbamoyl, example, halogen, hydroxy, alkoxy, alkylcarbonyloxy, aryl ethylcarbomoyl, diethylcarbamoyl, methyl-phenylcarbam carbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, car oyl, methyl-pyridylcarbamoyl, etc. boxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, 65 The term “haloalkyl” is intended to include alkyl groups as alkylthiocarbonyl, phosphate, phosphonato, phosphinato, de?ned above that are mono-, di- or polysub stituted by halo cyano, amino (including alkyl amino, dialkylamino, ary gen, e. g., ?uoromethyl and tri?uoromethyl. US 8,592,458 B2 19 20 The term “halogen” or “halo” designates iF, 4C1, iBr Another aspect is an isotopologue compound of any of the or *1. formulae delineated herein. Such compounds have one or The term “hydroxy” means ‘OH. more isotopic atoms (e.g., 3H, 2H, 14C, 13C, 35S, 32P, 1251, The term “heteroatom” as used herein means an atom of 131I) introduced into the compound. Such compounds are any element other than carbon or hydrogen. Preferred het useful for drug metabolism studies and diagnostics, as Well as eroatoms are nitrogen, oxygen, sulfur and phosphorus. therapeutic applications. The term “mercapto” refers to a iSH group. The term “obtaining” as used in obtaining the benZylidene The term “sulfhydryl” or “thiol” means iSH. anabaseine or cinnamylidene-3-arylidene-anabaseine com The compounds of the invention encompass various iso pound as used herein is intended to include purchasing, syn meric forms. Such isomers include, e.g., stereoisomers, e.g., thesiZing or otherWise acquiring the benZylidene-anabaseine chiral compounds, e.g., diastereomers and enantiomers. or cinnamylidene-3 -arylidene-anabaseine compound. The term “chiral” refers to molecules, Which have the The term “prodrug” includes compounds With moieties, property of non-superimposability of the mirror image part Which can be metaboliZed in vivo. Generally, the prodrugs are ner, While the term “achiral” refers to molecules, Which are metaboliZed in vivo by esterases or by other mechanisms to superimposable on their mirror image partner. active drugs. Examples of prodrugs and their uses are Well The term “diastereomers” refers to stereoisomers With tWo knoWn in the art (See, e.g., Berge et al. (1977) “Pharmaceu or more centers of dissymmetry and Whose molecules are not tical Salts”, J. Pharm. Sci. 66:1-19; Silverman (2004) The mirror images of one another. Organic Chemistry ofDrug Design andDrugAcZion, Second The term “enantiomers” refers to tWo stereoisomers of a 20 Ed., Elsevier Press, Chapter 8, pp. 497-549). The prodrugs compound, Which are non-superimposable mirror images of can be prepared in situ during the ?nal isolation and puri? one another. An equimolar mixture of tWo enantiomers is cation of the compounds, or by separately reacting the puri called a “racemic mixture” or a “racemate.” ?ed compound in its free acid form or hydroxyl With a suit When a 3 -arylidene-anabaseine compound (or pharmaceu able esterifying agent. Hydroxyl groups can be converted into esters via treatment With a carboxylic acid. Examples of tical formulation thereof) is referred to as “enriched” in a 25 particular enantiomer, it is intended that more of one particu prodrug moieties include substituted and unsubstituted, lar enantiomer is present than the other enantiomer. For branched or unbranched loWer alkyl ester moieties, (e.g., example, Where a sample is said to be enriched in the (S) propionoic acid esters), loWer alkenyl esters, di-loWer alkyl enantiomer, it is to be understood that more of the (S)-enan amino loWer-alkyl esters (e.g., dimethylaminoethyl ester), tiomer is present in the sample of compound than the (R) 30 acylamino loWer alkyl esters (e.g., acetyloxymethyl ester), isomer. Samples enriched in a particular isomer can include acyloxy loWer alkyl esters (e.g., pivaloyloxymethyl ester), samples in Which greater than about 50%, greater than about aryl esters (phenyl ester), aryl-loWer alkyl esters (e. g., benZyl 60%, greater than about 70%, greater than about 80%, greater ester), substituted (e.g., With methyl, halogen, or methoxy than about 90%, and about 100% of that particular isomer. substituents) aryl and aryl-loWer alkyl esters, amides, loWer Particular enantiomers may also be characterized by (includ 35 alkyl amides, di-loWer alkyl amides, and hydroxy amides. ing differentiated from each other and/or the racemic mix Preferred prodrug moieties are propionoic and succinic acid ture) and/or referred to by their relative retention times on a esters, acyl esters and substituted carbamates. Prodrugs, given chiral chromatography column compared to each other Which are converted to active forms through other mecha or compared to the racemic mixture of the same compound. nisms in vivo, are also included. Similarly, particular enantiomers can also be characterized 40 3 -Arylidene-Anabaseine Compounds (including differentiated from each other and/or the racemic The compounds of the invention are generally selective mixture) by their optical rotation, Which can be determined ligands (agonists or antagonists) of alpha7 nicotinic recep readily by the skilled artisan. tors, Which have little or no activity With respect to other The term “isomers” or “stereoisomers” refers to com nACh receptor subtypes, particularly (x462 receptors. Exem pounds, Which have identical chemical constitution, but differ 45 plary 3-arylidene-anabaseine compounds include com With regard to the arrangement of the atoms or groups in pounds With substituents on one or more of the three ring space. systems present; i.e., pyridyl, tetrahydropyridyl and Furthermore the indication of con?guration across a car 3-arylidene. It has been discovered that selection of a particu bon-carbon double bond can be “Z” referring to What is often lar substituent to be placed on one of these rings can improve referred to as a “cis” (same side) conformation Whereas “E” 50 selectivity of binding for the alpha7 receptor and can also refers to What is often referred to as a “trans” (opposite side) conformation. Regardless, both con?gurations, cis/trans and/ determine Whether the occupied receptor Will be activated or or Z/E are contemplated for the compounds for use in the inhibited (i.e., Whether the 3-arylidene-anabaseines present invention. described herein are agonists or antagonists of the alpha7 With respect to the nomenclature of a chiral center, the 55 nicotinic receptor). For example, arylidenes at the 3-position terms “d” and “l” con?guration are as de?ned by the IUPAC of the tetrahydropyridyl ring expected to provide these prop Recommendations. As to the use of the terms, diastereomer, erties include 3-benZylidene-anabaseines, cinnamylidene racemate, epimer and enantiomer, these Will be used in their anabaseines, benZofuran-2-ylmethylene-anabaseine, (lH-in normal context to describe the stereochemistry of prepara dol-2-ylmethylene)-anabaseines, and 3-benZylidene tions. 60 glucuronide-anabaseines, as described in greater detail Natural amino acids represented by the compounds uti herein. These arylidenes may be further substituted on the liZed in the present invention are in the “L” con?guration, unless otherWise designated. Unnatural or synthetic amino phenyl ring of the 3-arylidene (R1 in the formulae described acids represented by the compounds utiliZed in the present herein) With 0-5 substituents, such as acetoxy, acetamido, invention may be in either the “D” or “L” con?gurations. 65 amino, dimethylcarbamoyl, diethylcarbamoyl, methylcar Similarly, glycosidic bonds may be in either alpha- or beta bamoyl, ethylcarbamoyl, di?uoromethoxy, dimethylamino con?guration. propoxy, hydroxy, Cl-C3 alkoxy, tri?uoromethoxy, methy US 8,592,458 B2 21 lamino or thiomethoxy. Surprisingly, substitution, particularly by C l-C3 alkyl at the alpha- or beta-oriented sites H3COOC at positions 4, 5 and 6 of the tetrahydropyridyl ring form A00 chiral products that display improved alpha7 receptor selec A00 tivity in comparison With non-alkylated versions of the same anabaseine. In addition, When the anabaseine compounds are enriched With a particular enantiomer, the enriched ana baseine shoWs surprisingly enhanced selectivity for the alpha7 nicotinic receptor When compared to the selectivity of 10 the corresponding racemic substituted compounds, as described, for example, in Table l. Combinations of substitu ents on tWo or all three different ring portions of these 3-arylidene-anabaseine compounds are expected to provide even greater selectivity than When they are made individually on just one of the three ring structures. From a comparison of the eight possible carbon-methy Particular 3-benZylidene-anabaseine compounds include: lated anabaseines synthesiZed in our laboratory, it Was 3-(4 -thiomethoxybenZylidene) -anabaseine 20 observed that tWisting of the tWo anabaseine rings (as mea sured by NMR in aqueous solution) With respect to each other 3-(4-(3-trimethylammoniumpropoxy)benZylidene)-ana simultaneously reduces a?inity and e?icacy at the alpha7 baseine receptor. Since coplanar orientation of unsubstituted ana 3-(4-acetoxybenZylidene)-anabaseine baseine appears to be optimal for selective stimulation of the alpha7 receptor, it is believed that addition of an additional 3-(2-acetoxybenZylidene)-anabaseine 25 connection or bridge betWeen one of the anabaseine rings and 3-(2,4-diacetoxybenZylidene)-anabaseine the 3-arylidene group Would improve coplanarity of the 3-(2-(3-pentoxy-4-methoxybenZylidene)-anabaseine bridged rings and also permanently place the tWo anabaseine nitrogen atoms into the most optimal, cisoid orientation for 3-(4-acetamidobenZylidene)-anabaseine receptor binding. The 4'C on the pyridyl ring can be con 3-(2-acetamidobenZylidene)-anabaseine 30 nected through an added methylene, ether 0, S or other group, 3-(2,4-diacetamidobenZylidene)-anabaseine With the vinyl-bond forming methylene C linking the ben Zylidene group to the 3-position C on the tetrahydropyridyl 3(4-hydroxybenZylidene)-4-methyl-anabaseine ring; this forms a structure Where the tWo N atoms on the 3(4-hydroxybenZylidene) -4'-methyl-anabaseine anabaseine portion Will be cisoid With respect to each other, 35 and is expected to be the correct conformation for ef?cient 3(4-hydroxybenZylidene)-5'-methyl-anabaseine receptor binding. 3(4-hydroxybenZylidene)-6'-methyl-anabaseine Accordingly, in another embodiment of the invention are 3-(4 -anthranoylbenZylidene)-anabaseine provided bridged benZylidene-anabaseines of the structure 3-(4-pivaloylbenZylidene)-anabaseine shoWn beloW. 3-(2-pivaloylbenZylidene)-anabaseine 40 3-(2,4-dipivaloylbenZylidene)-anabaseine Particular cinnamylidene-3-arylidene-anabaseine com pounds include 3-(2,4-dimethoxycinnamylidene)-4-methyl-anabaseine 45 3-(2,4-dimethoxycinnamylidene)-5-methyl-anabaseine 3-(2,4-dimethoxycinnamylidene)-6-methyl-anabaseine 3-(2,4-dimethoxycinnamylidene)-4'-methyl-anabaseine 50 3-(2,4-diacetamidocinnamylidene)-6-methyl-anabaseine 3-(2,4-dihydroxycinnamylidene)-6-methyl-anabaseine Particular 3-(benZofuran-2-ylmethylene)-3-arylidene anabaseine compounds include: 3-(BenZofuran-2-ylmethyl 55 where R1 is, independently, acetoxy, acetamido, amino, dim ene)-anabaseine. ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl Particular 3-(lH-lndol-2-ylmethylene)-3 -arylidene-ana carbamoyl, di?uoromethoxy, dimethylaminopropoxy, trim baseine compounds include: 3-(lndol-2-ylmethylene)-ana ethylammoniumpropoxy, trimethylammoniumpentoxy, baseine. Cl-C3 alkyl, Cl-C3 alkylhydroxy, hydroxyl, Cl-C3 alkoxy, A particular embodiment of the invention includes modi 60 tri?uoromethoxy, methylamino or thiomethoxy and n is 0-5; ?ed glucuronide metabolites of 3-arylidene-anabaseines; in R2 is independently Cl-C3 alkyl and n' is 0-3, R3 is indepen particular Where hydroxy functions at the para-position (as dently Cl-C3 alkyl, Cl-C3 alkylhydroxy, Cl-C3 alkoxy, shoWn beloW) and/or ortho-position or on the carbohydrate cyano, halo, phenoxy, phenyl, pyridyl or benZyl and n" is 0-3; unit are modi?ed With a protecting group such as acetoxy X is CH2, 0, S, NH or NR8, Wherein R8 is Cl-C5 alkyl or (shoWn beloW) or methyl-esteri?ed carboxyl group. A par 65 Cl-C5 alkylhydroxy, or a pharrnaceutically acceptable salt, ticular compound is 3-[4-(2,3,4-Triacetyl-6-methyl-B-glucu solvate, clathrate, stereoisomer, enantiomer, prodrug or com ronidinyl)-2-methoxybenZylidene]-anabaseine: bination thereof. US 8,592,458 B2 23 24 In some embodiments of the 3-bridged-benZylidene-ana where R1 is thiomethoxy and n is n is 2 or 3, or more; etc.). In baseines, n' is I-3 and an R2 is present at position 4, 5, or 6. certain of these embodiments, n is 0, l, 2, 3, or 4. In some Although a benZylidene ring is shoWn in the structure embodiments, n is 0, l, 2 or 3. In particular embodiments, n is above, the bridged structure could also lack the benZylidene, l, 2, or 3. In some embodiments, n is 1. In some embodiments, or have another arylmethylene substituent (cinnamylidene, n is 2. In other embodiments, n is 3. In certain embodiments, etc.). the 3-arylidene-anabaseine is a 3-benZylidene-anabaseine. In In particular embodiments, the 3-arylidene-anabaseine is certain embodiments, the 3-arylidene-anabaseine is a 3-ben an agonist of the alpha7 nicotinic receptor. In certain embodi Zylidene-anabaseine substituted by a C l-C3 alkyl on the tet ments, the 3-arylidene-anabaseine is a partial agonist of the rahydropyridyl ring. In certain embodiments, the alpha7 nicotinic receptor. In certain embodiments, the 3-arylidene-anabaseine is a 3-benZylidene-glucuronide-ana 3-arylidene-anabaseine is a full agonist of the alpha7 nico tinic receptor. In certain of these embodiments, the baseine. In certain embodiments, the 3-arylidene-anabaseine 3-arylidene-anabaseine is a 3-benZylidene. In certain of these is a 3-benZylidene-glucuronide-anabaseine substituted by a embodiments, the 3-arylidene-anabaseine is a 3-cin C l-C3 alkyl on the tetrahydropyridyl ring. namylidene. In others, the 3-arylidene-anabaseine is a In particular embodiments, at least one R1 is, indepen 3-(benZofuran-2-ylmethylene)-anabaseine. In still others, the dently, C l-C3 alkoxy, thiomethoxy, or dimethylcarabamoyl. 3-arylidene-anabaseine is a 3-(1H-indol-2-ylmethylene) In particular embodiments, at least one R1 is, indepen anabaseine. In yet others, the 3-arylidene-anabaseine is a dently, Cl-C3 alkoxy (e.g., methoxy, ethoxy, or propoxy (in 3-benZylidene-glucuronide-anabaseine. cluding e.g., isopropoxy)). In particular embodiments, at In certain of these embodiments, the agonist is 3-(3,4 least one R1 is methoxy or isopropoxy. In some embodiments, (ethylenedioxy)benZylidene)-anabaseine, 3 -(3 ,4- (methyl 20 at least one R1 is methoxy. In still other embodiments, at least enedioXy)benZylidene)-anabaseine, 3-((6-Methoxynaphth one R1 is isopropoxy. In some embodiments, at least one R1 is 2-yl)methylene)-anabaseine, or 3-((benZofuran-2-yl) thiomethoxy. In some embodiments, at least one R1 is dim methylene)-anabaseine. In certain embodiments, ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, or eth combinations of tWo or more of the foregoing may be used in ylcarbamoyl. In certain of these embodiments, n is l, 2, 3, 4, the methods of treatment. In some embodiments, the ana 25 or 5. In particular embodiments, n is l-3. In certain embodi baseine is 3-((benZofuran-2-yl)methylene)-anabaseine. In ments n is 2. other embodiments, the anabaseine is 3-(3,4-(ethylenedioxy) In certain embodiments, the 3-arylidene-anabaseine is a benZylidene)-anabaseine or 3-(3,4-(methylenedioxy)ben 3-benZylidene. In certain of these embodiments, the Zylidene)-anabaseine. In particular embodiments, the ana 3-arylidene-anabaseine is a 3-cinnamylidene. In others, the baseine is 3-(4-thiomethoXybenZylidene)-anabaseine. 30 3-arylidene-anabaseine is a 3-(benZofuran-2-ylmethylene) In certain embodiments, the 3-arylidene is an antagonist of anabaseine. In still others, the 3-arylidene-anabaseine is a the alpha7 nicotinic receptor. In certain of these embodi 3-(lH-indol-2-ylmethylene)-anabaseine. In yet others, the ments, the 3-arylidene-anabaseine is a 3-benZylidene. In cer 3-arylidene-anabaseine is a glucuronide-benZylidene-ana tain of these embodiments, the 3-arylidene-anabaseine is a baseine. In some of these embodiments, Rl may be indepen 3-cinnamylidene-anabaseine. In others, the 3-arylidene-ana 35 dently, hydroxy, amino, methylamino, thiomethoxy, or meth baseine is a 3-(benZofuran-2-ylmethylene)-anabaseine. In oxy, including combinations of the foregoing (Where n is 2 or still others, the 3-arylidene-anabaseine is a 3-(lH-indol-2 more), and including where R1 may be the same or different ylmethylene)-anabaseine. In yet others, the 3-arylidene-ana (e.g., R1 is methoxy and n is 2 or 3, etc.; where R1 is methoxy baseine is a 3-benZylidene-glucuronide-anabaseine. and hydroxy and n is 2 or 3, or more; where R1 is thiomethoxy In particular embodiments, the phenyl ring of the 40 and n is n is 2 or 3, or more; etc.). In particular embodiments, 3-arylidene is substituted, Valence permitting, by 0-5 Rl (e.g., R1 is thiomethoxy and n is l, 2, or 3. In particular embodi n is 0-5 for benZylidene-anabaseines and cinnamylidene-ana ments, at least one R1 is thiomethoxy and n is l, 2, or 3. In baseines, n is 0-4 for 3-(benZofuran-2-ylmethylene)-ana particular embodiments, at least one R1 is thiomethoxy and a baseines, n is 0-4 for 3-(1H-indol-2-ylmethylene)-ana different R1 is methylamino, and n is l, 2, or 3. baseines, and n is 0-4 for 3-benZylidene-glucuronide 45 In particular embodiments, R1 is, independently, hydroxy, anabaseines, as previously described herein). In other amino, methylamino, thiomethoxy, or C l-C3 alkoxy, includ embodiments, n is 0, l, 2, 3, 4, or 5 (benZylidene/cin ing combinations of the foregoing (Where n is 2 or more), and namylidene-anabaseines only). In certain embodiments, n is including where R1 may be the same of different (e.g., R1 is 0-4, 0-3, 0-2, or O-l. In still other embodiments, n is 1-5 methoxy and n is 2 or 3, etc.). (benZylidene/cinnamylidene-anabaseines only), l-4, l-3 or 50 In certain of embodiments, n is l or 2 and R1 is Cl-C3 l-2. In some embodiments, n is 0, l, 2 or 3. In particular alkoxy. In certain embodiments, n is l or 2 and R1 is, inde embodiments, n is l, 2, or 3. In some embodiments, n is 1. In pendently, methoxy or isopropoxy. In certain embodiments, n some embodiments, n is 2. In other embodiments, n is 3. is 2 and R1 is, independently, methoxy or isopropoxy (e.g., In certain embodiments of the 3-arylidenes, is R1 is, inde both R1 are methoxy, both R1 are isopropoxy, or one R1 is pendently, acetoxy, acetamido, Cl-C3 alkyl, amino, dimeth 55 methoxy and the other is isopropoxy). In certain embodi ylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcar ments, Rl includes hydroxy. In particular embodiments, n is bamoyl, di?uoromethoxy, dimethylaminopropoxy, one and R1 is hydroxy. trimethylammoniumpropoxy, trimethylammoniumpentoxy, In particular embodiments of the 3-arylidene-anabaseines, Cl-C3 alkylhydroxy (e.g., 4CH2OH, i(CH2)2OH, n is 2 and R1 may be, independently, acetoxy, acetamido, i(CH2)3 OH), hydroxy, C l-C3 alkoxy, tri?uoromethoxy, 60 amino, methylamino, dimethylamino, dimethylcarbamoyl, methylamino or thiomethoxy. In some embodiments, Rl may diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, dif be independently, hydroxy, amino, methylamino, thi luoromethoxy, dimethylaminopropoxy, hydroxyl, C l-C5 omethoxy, or Cl-C3 alkoxy, including combinations of the alkoxy (e.g., methoxy, isopropoxy, etc. and including C3-C5 foregoing (Where n is 2 or more), and including where R1 may isoalkoxy), tri?uoromethoxy, methylamino or thiomethoxy, be the same or different (e.g., R1 is methoxy and n is 2 or 3, 65 Wherein at least one R1 is methylamino or dimethylcarbam etc.; where R1 is methoxy and hydroxy and n is 2 or 3, or oyl. In particular embodiments, the 3-arylidene is a ben more; Zylidene. In certain embodiments, the tWo R1 are at positions US 8,592,458 B2 25 26 2" and 4" on the benZylidene ring. In particular embodiments, In certain embodiments, the anabaseine compound is a both R1 are methylamino. In other embodiments, both R1 are 3-((benZofuran-2-yl)methylene)-anabaseine as described dimethylcarbamoyl. In some embodiments, one R1 is methy herein. lamino and the other R1 is acetoxy, acetamido, amino, dim In other embodiments, the anabaseine compound is a ethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethyl 3 -((l J-indol-2 -yl)methylene)anabaseine as described herein. carbamoyl, di?uoromethoxy, dimethylaminopropoxy, In some embodiments, the anabaseine compound is 6-me hydroxy, Cl-C3 alkoxy (e.g., methoxy, isopropoxy, etc.), tri thyl-anabaseine; dimethoxy)-benZylidene)-4-methyl-ana ?uoromethoxy, or thiomethoxy. In other embodiments, one baseine, 3-(4-HydroxybenZylidene) -4 -methyl-anabaseine; R1 is dimethylcarbamoyl and the other R1 is acetoxy, aceta 3 -(2,4-dimethoxy)-benZylidene)-5-methyl-anabaseine, or mido, amino, methylamino, dimethylaminopropoxy, 3 -(2,4-dimethoxy)-benZylidene)-6-methyl-anabaseine. In hydroxy, Cl-C3 alkoxy (e.g., methoxy, isopropoxy, etc.), tri certain embodiments, the anabaseine compound is 3-(2,4 ?uoromethoxy, or thiomethoxy. In certain embodiments, one R1 is dimethylcarbamoyl and the other R1 is methoxy or dimethoxy)-benZylidene)-4-methyl-anabaseine, 3-(4-Hy ispopropoxy. In certain embodiments, one R1 is methylamino droxybenZylidene)-4-methyl-anabaseine; dimethoxy)-ben and the other R1 is methoxy or ispopropoxy. In certain of Zylidene)-5-methyl-anabaseine, or 3-(2,4-dimethoxy) these embodiments, the dimethylcarbamoyl is at the 2" posi benZylidene)-6-methyl-anabaseine. tion. In certain of these embodiments, the dimethylcarbamoyl The folloWing neW 3-(di-substituted benZylidene)-ana is at the 4" position. In certain of these embodiments, the baseines are expected to have improved e?icacy compared dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, or With GTS-2 l, considering that at least tWo polar benZylidene ethylcarbamoyl is at the 4" position. In certain of these 20 substituents improve e?icacy. embodiments, the methoxy is at the 2" position. In certain of these embodiments, the methoxy is at the 4" position. In particular embodiments, the pyridyl ring of the 3-arylidene-anabaseine is substituted, by 0-3 R3 (e.g., n" is 0-3). In other embodiments, n" is 0, l, 2, or 3. In certain 25 embodiments, n" is 0-3, 0-2, or 0-1. In still other embodi ments, n" is 1-3 or l-2. In some embodiments, n" is 0, l, 2 or 3. In particular embodiments, n" is l, or 2. In some embodi ments, n" is 1. In some embodiments, n" is 2. In other embodi ments, n" is 3. 30 In some embodiments, R3 is, independently, Cl-C3 alkyl, Cl-C3 alkylhydroxy, Cl-C3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benZyl. In certain embodiments, n" is 3 and R3 are present at the 4', 5' and 6' positions of the pyridyl ring. In other embodiments, 35 n" is l and R2 is present at the 4', 5' or 6' position. In still other embodiments, n" is 2 and R3 are present at the 4' and 5', 4' and 6', or 5' and 6' positions. In certain embodiments, n" is l and R1 R2 R3 is present at the 4' position. In certain embodiments, n" is Bis-compounds l and R3 is present at the 5' position. In certain embodiments, 40 n" is l and R3 is present at the 6' position. In certain of these l methylamino methylamino embodiments, n is l or 2 and R1 is, independently, Cl-C3 2 amino amino 3 acetoxy acetoxy alkoxy. In certain embodiments, n is l or 2 and R1 is, inde 4 isopropoxy isopropoxy pendently, methoxy or isopropoxy. In certain embodiments, n 5 acetamido acetamido is 2 and R1 is, independently, methoxy or isopropoxy (e.g., 45 6 dimethylcarbalnate dimethylcarbalnate both R1 are methoxy, both R1 are isopropoxy, or one R1 is Mixed-compounds methoxy and the other is isopropoxy). In certain embodi 7 methoxy methylamino ments, Rl includes hydroxy. In particular embodiments, n is 8 isopropoxy methylamino one and R1 is hydroxy. In certain embodiments, R1 is, inde 9 methoxy amino pendently, hydroxy, amino, methylamino, thiomethoxy, or 50 l0 isopropoxy amino 1 l methoxy pivaloyloxy C l-C3 alkoxy. l2 isopropoxy pivaloyloxy In particular embodiments of the 3-(1 H-Indol-2-ylmethyl l3 methoxy dimethylcarbalnate ene)-anabaseine compounds, R7 is hydrogen, Cl-C5 alkyl l4 isopropoxy dimethylcarbalnate (e.g., methyl, ethyl, pentyl, etc.), Cl-C5 dialkoxy, or Cl-C5 l5 methoxy acetamido l6 isopropoxy acetamido alkoxy. In some embodiments, R7 is hydrogen or C l-C5 alkyl. 55 In some embodiments, R7 is hydrogen. In other embodi ments, R7 is methyl, ethyl, propyl or pentyl. In certain It is expected that removal of certain metabolically labile embodiments, the Cl-C5 alkoxy is optionally further substi groups on some of these compounds Will expose other active tuted by halo, Cl-C5 alkyl, etc. substituents and that some of these compounds may also In certain embodiments, the anabaseine compound is a 60 possess good pharmacological activity. Synthesis of the com 3-cinnamylidene-anabaseine as described herein. pounds is expected to involve routine procedures Well-known In certain embodiments, the anabaseine compound is a to those skilled in the art. In general, the appropriate benZal 3-benZylidene-anabaseine as described herein (e.g., tetrahy dehyde Will be prepared by routine alkylation, esteri?cation dropyridyl-alkylated-benZylidene-anabaseine, bridged ben or amidation reaction methods. Zylidene-anabaseine, disubstituted (at phenyl of ben 65 Cinnamylidene-anabaseine compounds With expected Zylidene)-benZylidene-anabaseine or modi?ed benZylidene improved activities Will also be prepared. 3-(Dimethylami glucuronide-anabaseine as described herein). nocinnamylidene)-anabaseine (DMACA) displays higher US 8,592,458 B2 27 28 alpha7 a?inity and ef?cacy than 3-(Dimethylaminoben groups at the 3-position, this leads to compounds With unpre Zylidene)-anabaseine (DMABA) and DMABA. New com dicted improvements, including alpha7 receptor a?inity and pounds based on DMAC-anabaseine Would also be expected selectivity of binding relative to DMXB-anabaseine and to have the same lack of toxicity as the benZylidene-ana related arylidene-anabaseine compounds in Which the tet baseines. The following shoWs the structure of the neW com rahydropyridyl and pyridyl anabaseine rings are otherWise pounds, the synthesis of Which requires only routine skill in unsubstituted. the art. For example, While 4'-methyl-anabaseine displayed sig ni?cantly diminished nAChR agonistic or binding activity, relative to anabaseine or DMXBA, a signi?cant improvement (>l0-fold) in alpha7 selectivity Was observed relative to DMXBA When the DMXB group Was attached to the 3-po sition of the methylated-anabaseine (e.g., 4-methyl DMXBA, S-methyI-DMXBA, 6-methyl-DMXBA). Improvements in selectivity, binding af?nity, etc. of the neW anabaseine compounds in comparison to DMXBA represent a signi?cant step forWard in the possible development of therapeutic products, because DMXBA, as is knoWn to those of skill in the ?eld, is a promising anabaseine compound under development in the ?elds of cognition enhancement 20 and the treatment of neurodegenerative conditions. Although alkylation (e.g., methylation, etc.) of individual carbons in the tetrahydropyridyl and pyridyl rings of the anabaseine compounds did not lead to an enhancement of agonist activity at central nicotinic receptors including alpha7 25 and alpha4beta2 types involved in various mental processes, some methylations at the available carbon atoms on the tet rahydropyridyl ring of the anabaseine structure lead to com Cpd R1 R2 M R4 pounds With unpredicted improvements in alpha7 receptor 17 methoxy methoxy hydro gen hydrogen a?inity and selectivity of binding relative to GTS-2l and 1 8 methoxy methoxy methyl methyl 30 related compounds. Particularly, alkylation at positions 4', 4, 19 hydrogen dimethylamino hydro gen hydrogen 5 and/or 6, When coupled With addition of 2,4-dimethoxyben 20 hydrogen dimethylamino methyl methyl 2 1 hydroxyl hydroxyl hydro gen hydrogen Zylidene, para-hydroxy-benzylidene or para-amino-ben 22 hydroxyl hydroxyl methyl methyl Zylidene groups at the 3-position provided unexpected increases in alpha7 receptor a?inity and selectivity, as dem 35 onstrated by the data provided in Table 1. 3-Arylidene-Anabaseines With Alkyl Substitution Additionally, potency (ECSO), and receptor selectivity are Contrary to What Was initially expected from analogous both affected by the THP (tetrahydropyridyl) ring substitu substitution experiments With nicotine, it Was observed that ents at positions 4, 5 and 6. The anticipated therapeutic advan alkylation of individual carbons in otherWise unsubstituted tage of applying a single high a?inity (for alpha7) enantiomer anabaseines sometimes caused remarkable losses in a?inity 40 is that adverse side effects of the relatively loW a?inity enan for the alpha7 and alpha4beta2 receptors. This Was particu tiomer at other nAChR subtypes, including alpha4beta2 and larly the case for methyl substitutions at the 3-position of the other sites, on the alpha 7 receptor Will be minimized. Regard tetrahydropyridyl ring, and the 2' and 4'-positions on the ing the latter site of action, We have recently shoWn that many pyridyl ring of anabaseine. Thus, it Was surprising that methy benZylidene-anabaseines also enter the nAChR ion channel to lations at available carbon atoms on the tetrahydropyridyl 45 cause block of ion ?ux through the channel, usually at higher ring of the substituted anabaseine structure on the available concentrations than cause channel opening (Arias et al., sub ring carbons (particularly at the 4, 5 and 6 positions), Would mitted). Since both DMXB-methylanabaseine enantiomers lead to compounds With unpredicted improvements, includ bind equally Well Within the ion channel, it can be predicted ing alpha7 receptor a?inity and selectivity of binding. Addi that application of the enantiomer displaying high a?inity for tion of a methyl substituent at the 6-position of the THP ring 50 the ACh binding site on the alpha7 receptor, rather than the preferentially reduces alpha4beta2 receptor a?inity, Whereas racemic compound, shouldproduce a greater activating effect substituting a methyl at the 6' position on the pyridyl ring on this receptor and less adverse effect. Since channel block preferentially reduces alpha7 nAChR af?nity and also pro ers generally shoW little structural speci?city and block a duces a >90% loss of ef?cacy in activating the alpha7 receptor variety of related ion channels (other ligand-gated channels (the alpha4beta2 receptor ef?cacy is unchanged by this sub 55 including GABA and glycine receptors), alpha7 agonists stitution). Methyl substitutions at the 2', 4', and 3 positions Which display less channel blocking activity at otherWise cause very drastic decreases in alpha7 and alpha4beta2 recep effective concentrations are expected to be safer drugs. tor a?inity and e?icacy due to at least tWo different factors: For example, in some embodiments of the 3-benZylidene altering stability of the active cyclic iminium forms of the anabaseines, the anabaseine is 4-methyl-DMXBA. In certain anabaseine compound, and second, interfering With close 60 embodiments the 4-methyl-DMXBA is enriched in the one contacts Within the binding site of the nAChR. enantiomer that has a shorter retention time on a Chiracel When alkylation of the tetrahydropyridyl ring carbons is OJ-H column than the other enantiomer. This enantiomer coupled With substitution of the tetrahydropyridyl ring at displayed a relative alpha7 nAChR (versus alpha4beta2) position 3 With an arylidene (including Where the arylidene receptor binding selectivity that Was 6.5-fold higher than that ring itself may be additionally substituted), for example, as in 65 of the other enantiomer (See Table 1). In other embodiments, 2, 4-dimethoxybenZylidene, p-hydroxy-benZylidene, 4-methyl-DMXBA is enriched in the one enantiomer, Which p-amino-benZylidene, or (benZofuran-2-yl)methylene had a longer retention time on a Chiracel OJ-H column than US 8,592,458 B2 29 30 the other enantiomer. The relative alpha7 nAChR binding thyl-DMXBA, or 6-methyl-DMXBA, the anabaseine com selectivity of this enantiomer Was similar (1.28) to unmethy pound is enriched in the most selective enantiomer, Which has lated DMXBA (1.00). The ?rst, enantiomer, on the basis of its a shorter retention time on a Chiracel OJ-H column, in par binding properties to rat brain nAChR, Would be predicted to ticular When measured as described herein. be tWice as potent as the racemic compound. Also, because of In certain embodiments are provided 3-arylidene-ana the greater nAChR selectivity of this faster eluting species, it baseines, as described herein, Which are substituted With Would also be predicted to be less likely to produce adverse C l-C3 alkyl at the 4, 5, or 6 position of the tetrahydropyridyl side effects related to alpha4beta2 nAChR ring (corresponding to (R2)n,). In particular embodiments, In some embodiments, the relative alpha7 receptor/ there is one alkyl group at position 4 (i.e., n':l). In other alpha4beta2 receptor selectivity of the enantiomerically embodiments, there is one alkyl group at position 5. In still enriched 3-arylidene-anabaseine compound is about 2 times other embodiments there is one alkyl group at position 6. In (i.e., about 2><), about 5><, about 6><, about 7x, about 8><, about particular embodiments, n' is 2 or n' is 3. In some of these 9x, about 10x, about l2><, about l4><, about l5><, about l8><, embodiments, the alkyl group is methyl. In other embodi about 20x, about 25x, about 30x, about 40x, about 50x, about ments, the alkyl group is ethyl. In still other embodiments, the 60x, about 70x, about 80x, about 90x, about 100x, or about alkyl group is propyl. In particular of these embodiments, the 150x more selective than the relative alpha7 receptor/ phenyl ring of the arylidene is substituted, valence permitting, alpha4beta2 receptor selectivity of DMXBA measured under by 0-5 Rl (e.g., n is 0-5 for benZylidene-anabaseines/cin the same conditions. In particular embodiments, relative namylidene-anabaseines; n is 0-4 for 3-(benZofuran-2-ylm selectivity is as described in Example 1 herein. In certain of ethylene)-anabaseines, n is 0-4 for 3-(lH-indol-2-ylmethyl these embodiments, the enantiomerically enriched 20 ene)-anabaseines, and n is 0-4 for 3-benZylidene 3-arylidene-anabaseine compound is enriched in the S-iso glucuronide-anabaseines (as previously described herein)). mer. In others, the enantiomerically enriched 3-arylidene In other embodiments, n is 0, l, 2, 3, 4, or 5 (benZylidene/ anabaseine compound is enriched in the R-isomer. In certain cinnamylidene-anabaseines only). In certain embodiments, n of these embodiments of 4-methyl-DMXBA, 5-methyl is 0-4, 0-3, 0-2, or O-l. In still other embodiments, n is 1-5 DMXBA, or 6-methyl-DMXBA, the anabaseine compound 25 (benZylidene/cinnamylidene-anabaseines only), l-4, l-3 or is enriched in the most selective enantiomer, Which has a l-2. In particular embodiments, R1 is, independently, shorter retention time on a Chiracel OJ-H column, in particu hydroxy, amino, methylamino, thiomethoxy, or methoxy, lar When measured as described herein. including combinations of the foregoing (Where n is 2 or In some embodiments, the relative alpha7 receptor/ more), and including where R1 may be the same of different alpha4beta2 receptor selectivity of the enantiomerically 30 (e.g., R1 is methoxy and n is 2 or 3, etc.). In certain of these enriched 3-arylidene-anabaseine compound, Which is the embodiments, n is l or 2 and R1 is Cl-C3 alkoxy. In certain more selective enantiomer, is about 2 times (i.e., about 2><), embodiments, n is l or 2 and R1 is, independently, methoxy or about 5><, about 6x, about 7x, about 8x, about 9x, about l0><, isopropoxy. In certain embodiments, n is 2 and R1 is, inde about l2><, about l4><, about 15x, about 18x, about 20x, about pendently, methoxy or isopropoxy (e.g., both R1 are methoxy, 25x, about 30x, about 40x, about 50x, about 60x, about 70x, 35 both R1 are isopropoxy, or one R1 is methoxy and the other is about 80x, about 90x, about 100x, or about l50>< more selec isopropoxy). In certain embodiments, Rl includes hydroxy. tive than the relative alpha7 receptor/alpha4beta2 receptor In particular embodiments, n is l and R1 is hydroxy. In certain selectivity of the racemic mixture of the same anabaseine of these embodiments, the 3-arylidene-anabaseine is compound, measured under the same conditions. In particular enriched in the R-isomer. In other embodiments the embodiments, relative selectivity is as described in Example 40 3-arylidene-anabaseine is enriched in the S-isomer. 1 herein. In certain of these embodiments, the enantiomeri In certain embodiments are provided 3-benZylidene-ana cally enriched 3-arylidene-anabaseine compound is enriched baseines, as described herein, Which are substituted With in the S-isomer. In others, the enantiomerically enriched C l-C3 alkyl at the 4, 5, or 6 position of the tetrahydropyridyl 3-arylidene-anabaseine compound is enriched in the R-iso ring (corresponding to (R2)n,). In particular embodiments, mer. In certain embodiments of 4-methyl-DMXBA, 5-me 45 there is one alkyl group at position 4 (i.e., n':l). In other thyl-DMXBA, or 6-methyl-DMXBA, the anabaseine com embodiments, there is one alkyl group at position 5. In still pound is enriched in the most selective enantiomer, Which has other embodiments there is one alkyl group at position 6. In a shorter retention time on a Chiracel OJ-H column, in par particular embodiments, n' is 2 or n' is 3. In some of these ticular When measured as described herein. embodiments, the alkyl group is methyl. In other embodi In some embodiments, the relative alpha7 receptor/ 50 ments, the alkyl group is ethyl. In still other embodiments, the alpha4beta2 receptor selectivity of the enantiomerically alkyl group is propyl. In certain of these embodiments, the enriched 3-arylidene-anabaseine compound, Which is the benZylidene ring is substituted by 0-5 Rl (i.e., n:0-5). In other more selective enantiomer, is about 2 times (L e., about 2><), embodiments, n is 0, l, 2, 3, 4, or 5. In certain embodiments, about 5><, about 6x, about 7x, about 8x, about 9x, about l0><, n is 0-4, 0-3, 0-2, or O-l. In still other embodiments, n is l-5, about l2><, about l4><, about 15x, about 18x, about 20x, about 55 l-4, l-3 or l-2. In particular embodiments, R1 is, indepen 25x, about 30x, about 40x, about 50x, about 60x, about 70x, dently, hydroxy, amino, methylamino, thiomethoxy, or meth about 80x, about 90x, about 100x, or about l50>< more selec oxy, including combinations of the foregoing (Where n is 2 or tive than the relative alpha7 receptor/alpha4beta2 receptor more), and including where R1 may be the same of different selectivity of the opposite enantiomer (less selective enanti (e.g., R1 is methoxy and n is 2 or 3, etc.). In certain of these omer) of the same anabaseine compound, measured under the 60 embodiments, n is l or 2 and R1 is Cl-C3 alkoxy. In certain same conditions. In particular embodiments, relative selec embodiments, n is l or 2 and R1 is, independently, methoxy or tivity is as described in Example 1 herein. In certain of these isopropoxy. In certain embodiments, n is 2 and R1 is, inde embodiments, the enantiomerically enriched more selective pendently, methoxy or isopropoxy (e.g., both R1 are methoxy, 3-arylidene-anabaseine compound is enriched in the S-iso both R1 are isopropoxy, or one R1 is methoxy and the other is mer. In others, the enantiomerically enriched more selective 65 isopropoxy). In certain embodiments, Rl includes hydroxy. 3-arylidene-anabaseine compound is enriched in the R-iso In particular embodiments, n is one and R1 is hydroxy. In mer. In certain embodiments of 4-methyl-DMXBA, 5-me certain embodiments, the 3-benZylidene-anabaseine is US 8,592,458 B2 31 32 enriched in the R-isomer. In other embodiments the 3-ben enantiomerically enriched compounds obtained by chiral Zylidene-anabaseine is enriched in the S-isomer. chromatography of the racemic 4, 5, or 6-methyl-DMXBA In some embodiments of the 3-arylidene-anabaseines, R1 compounds. is methoxy, n is 2, R2 is methyl, n' is l, n" is 0 and R4 is H. In Thus, in certain embodiments are provided 3-arylidene certain of these embodiments, the 3-arylidene-anabaseine is anabaseines as described herein, Where the anabaseine enriched in the R-isomer. In other embodiments the includes a Cl-C3 alkyl substituent on the tetrahydropyridyl 3-arylidene-anabaseine is enriched in the S-isomer. ring. In particular of these embodiments, the 3-arylidene In certain embodiments, the 3-arylidene-anabaseine is a anabaseines is enriched in the R-isomer. In other embodi 3-benZylidene-anabaseine and R1 is methoxy, n is 2, R2 is ments, the 3-arylidene-anabaseine is enriched in the S-iso methyl, n' is l, n" is 0 and R4 is H. In certain ofthese embodi mer. In certain of these embodiments, the arylidene is a ments, the 3-benZylidene-anabaseine is 4-methyl-DMXBA. benZylidene-anabaseine, a 3-cinnamylidene-anabaseine a In other embodiments, the 3-benZylidene-anabaseine is 3-(benZofuran-2-ylmethylene)-anabaseine, a 3-(lH-indol-2 S-methyI-DMXBA. In still other embodiments, the 3-ben ylmethylene)-anabaseine, or a glucuronide-benZylidene-ana Zylidene-anabaseine is 6-methyl-DMXBA. In certain of these baseine, as described herein. In certain embodiments, the embodiments, the 4-methyl-DMXBA is enriched in the 3-arylidene-anabaseine is a benZylidene. In certain of these R-isomer. In others, the 4-methyl-DMXBA is enriched in the embodiments, the 3-arylidene-anabaseine is a 3-cin S-isomer. In other embodiments, the S-methyI-DMXBA is namylidene. In others, the 3-arylidene-anabaseine is a enriched in the R-isomer. In others, the S-methyI-DMXBA is 3-(benZofuran-2-ylmethylene)-anabaseine. In still others, the enriched in the S-isomer. In still other embodiments, the 3-arylidene-anabaseine is a 3-(lH-indol-2-ylmethylene) 6-methyl-DMXBA is enriched in the R-isomer. In others, the 20 anabaseine. In yet others, the 3-arylidene-anabaseine is a 6-methyl-DMXBA is enriched in the S-isomer. 3-benZylidene-glucuronide-anabaseine. In some of these In some embodiments of the 3-arylidene-anabaseines, R1 embodiments, Rl may be independently, hydroxy, amino, is hydroxy, n is l, R2 is methyl, n' is l, n" is 0 and R4 is H. In methylamino, thiomethoxy, or methoxy, including combina certain of these embodiments, the 3-arylidene-anabaseine is tions of the foregoing (Where n is 2 or more), and including enriched in the R-isomer. In other embodiments the 25 where R1 may be the same or different (e.g., R1 is methoxy 3-arylidene-anabaseine is enriched in the S-isomer. and n is 2 or 3, etc.; where R1 is methoxy and hydroxy and n In certain embodiments, the 3-arylidene-anabaseine is a is 2 or 3, or more; where R1 is thiomethoxy and n is n is 2 or benZylidene-anabaseine and R1 is hydroxy, n is l, R2 is 3, or more; etc.). In particular embodiments, R1 is thi methyl, n' is l, n" is 0 and R4 is H. In certain ofthese embodi omethoxy and n is l, 2, or 3. In other embodiments, at least ments, the 3-benZylidene-anabaseine is 3-(4-hydroxyben 30 one R1 is thiomethoxy and n is 1,2, or 3. In particular embodi Zylidene)-4-methylanabaseine. In certain of these embodi ments, at least one R1 is thiomethoxy and a different R1 is ments, the 3-benZylidene-anabaseine is 3-(4 methylamino, and n is l, 2, or 3. In certain of these embodi hydroxybenZylidene)-6-methylanabaseine. In certain of ments, n is l or 2 and R1 is Cl-C3 alkoxy. In certain embodi these embodiments, the 3-benZylidene-anabaseine is ments, n is l or 2 and R1 is, independently, methoxy or enriched in the R-isomer. In other embodiments the 3-ben 35 isopropoxy. In certain embodiments, n is 2 and R1 is, inde Zylidene-anabaseine is enriched in the S-isomer. pendently, methoxy or isopropoxy (e.g., both R1 are methoxy, Replacement of a hydrogen With an alkyl (methyl, ethyl or both R1 are isopropoxy, or one R1 is methoxy and the other is propyl) group at the methylene C, Which links the ben isopropoxy). In certain embodiments, Rl includes hydroxy. Zylidene group to the 3-position C on the tetrahydropyridyl In particular embodiments, n is one and R1 is hydroxy. ring, also is expected to effect alpha7 binding selectivity. 40 In addition to the use of chiral chromatography, separation Thus in certain embodiments are provided 3-arylidenes of enantiomers can be achieved by methods Well knoWn to the Where R4 is Cl-C3 alkyl or Cl-C3 alkylhydroxy. In some skilled artisan, such as, for example, fractional crystallization embodiments are provided 3-arylidenes Where R5 is Cl-C3 With optically active salts. alkyl. In some embodiments are provided 3-arylidenes Where Separation by chiral chromatography is Well understood in R6 is C l-C3 alkyl. In certain embodiments, R4, R5 , and R6 are 45 the ?eld, particular in light of the teaching provided herein. hydrogen. In certain embodiments R4 is hydrogen. In other The use of chiral chromatography for the separation of race embodiments R4 is methyl. In certain embodiments R5 is mic mixtures or 3-arylidene-anabaseines is described in more hydrogen. In other embodiments R5 is methyl. In certain detail herein. embodiments R6 is hydrogen. In other embodiments R6 is The 3-arylidene-anabaseine enantiomers can also be syn methyl. In certain embodiments, R4 is hydrogen and, Where 50 thesiZed by methods Well knoWn to those skilled in the art, present, R5 and/or R6 are hydrogen. In certain embodiments including preparation of the appropriate chiral methyl-piperi R4 is methylhydroxy, ethylhydroxy, or propylhydroxy. In cer done precursor of the tetrahydropyridyl ring. Both traditional tain embodiments R4 is hydrogen, methylhydroxy, ethylhy asymmetric synthesis and biocatalysis approaches Will yield droxy, or propylhydroxy. the required chiral precursors for synthesis of a large variety In particular embodiments of the 3-(1 H-Indol-2-ylmethyl 55 of substituted benZylidene-anabaseine, benZofuran-2-yl-me ene)-anabaseine compounds, R7 is hydrogen, Cl-C5 alkyl thylene-anabaseine, and cinnamylidene-anabaseines dis (e.g., methyl, ethyl, pentyl, etc.), Cl-C5 dialkoxy, or Cl-C4 playing signi?cantly enhanced alpha7 selectivity. Further alkoxy. In some embodiments, R7 is hydrogen or C l-C5 alkyl. more, other chiral substituents at the 4, 5, or 6 positions are In some embodiments, R7 is hydrogen. In other embodi expected to also display different Alpha7 nAChr selectivities ments, R7 is methyl, ethyl, propyl or pentyl. In certain 60 and e?icacies. Besides asymmetric synthesis, the individual embodiments, the Cl-C4 alkoxy is optionally further substi enantiomers may also be obtained by fractional crystalliza tuted. tion of a chiral salt or by chiral chromatography. As is clearly demonstrated by the data in Table l, the 3-Arylidene-Anabaseine Metabolites orientation (chirality) of the alkyl group at positions 4, 5 or 6 The metabolism of DMXBA has been studied in the rat, of the tetrahydropyridyl ring is also important for alpha7 65 dog, and human. The primary metabolites are O-demethy versus alpha4beta2 selectivity. The data in Table 1 Was lated products that are excreted as glucuronic acid conjugates. obtained by resolution and subsequent characterization of the The three main metabolites in rat urine are the 4-hydroxy US 8,592,458 B2 33 34 DMXBA and 2-hydroxy-DMXBA glucuronides and to a anabaseine compound as described herein is a (X7 nicotinic lesser extent unconjugated 4-hydroxy-DMXBA. DMXBA is receptor full agonist or partial agonist, the pharmaceutical rapidly absorbed and distributed to the brain and other organs formulation or method of treatment as described herein may after oral administration. Most of the administered DMXBA include additional pharmaceutical agents knoWn to be ef?ca is excreted in the feces as the above-mentioned metabolites. cious for treatment of the particular condition (e.g., pro As demonstrated herein, these glucuronides are even more angiogenic compounds for use in Wound healing (e.g., nico selective (>10-fold relative to DMXBA) and ef?cacious par tine, etc.), including those described in Us. Pat. Nos. 6,417, tial agonists on the human alpha7 receptor than the parent 205; and 6,720,340, incorporated by reference in their compound. Lipophilic derivatives of these polar drug entirety. metabolites should enter the brain and permit selective alpha7 Exemplary nicotine receptor agonists include, but are not nAChR stimulation. Altemately, conjugation of the polar necessarily limited to, naturally occurring plant alkaloids metabolite to small organic moieties (such as aromatic car (e.g., lobeline, lobeline derivatives, and the like), Which plant boxylic acids), peptides or proteins that have carrier-medi derived compounds can be provided in a herbal preparation ated passage across the blood-brain barrier should facilitate (e.g., in the form of dried tobacco leaves, in a poultice, in a their entry into the brain. Thus a variety of analogs of botanical preparation, etc.), in isolated form (e.g., separated arylidene-anabaseine polar metabolites may be useful drugs. or partially separated from the materials that naturally accom Polar metabolites of DMXBA and related arylidene-ana pany it), or in a substantially puri?ed form. Other nicotine baseines that do not pass across the blood-brain barrier could receptor agonists include choline esterase inhibitors (e.g., also be used to target peripherally-distributed alpha7 recep that increase local concentration of acetylcholine), deriva tors such as are found on macrophages, vascular endothelium 20 tives of epibatidine that speci?cally bind the neuronal type of and bronchial epithelium. nicotinic receptors (With reduced binding to the muscarinic Methods of Preparation of 3-Arylidene-Anabaseines receptor) and having reduced deleterious side effects (e.g., Generally, the 3-arylidene-anabaseines may be prepared Epidoxidine, ABT-154, ABT-418, ABT-594, Abbott Labora using synthetic methods knoWn to the skilled artisan, particu tories; and Damaj et al. (1998) .1. Pharmacol Exp. Ther. 284: lar in vieW of the teaching provided herein, for example, as 25 1058-65, describing several analogs of epibatidine of equal described in Us. Pat. Nos. 5,581,785; 5,741,802; 5,977,144; potency but With high speci?city to the neuronal type of 5,602,257; 5,840,906, 5,734,059 and 6,630,491 and in the nicotinic receptors). Further nicotine receptor agonists of scienti?c literature (Kern et al., 1971; Kern, 1973; ZolteWicZ interest include, but are not necessarily limited to, N-methyl et al., 1989; Kern et al., 2004.), Which are incorporated herein carbamyl and N-methylthi-O-carbamyl esters of choline e. g., by reference in their entirety. Basically, a slight excess of the 30 trimethylaminoethanol (Abood et al. (1988)Pharmac0l. Bio selected aryl aldehyde is dissolved in a Weakly acidic ethan chem. Behay. 30:403-8); acetylcholine (an endogenous olic solution of the appropriate anabaseine and then re?uxed ligand for the nicotine receptor); and the like. for several hours depending on the reactivity of the aldehyde. Additionally, Where a 3-arylidene-anabaseine compound The resulting product can be precipitated With a less polar as described herein is a (X7 nicotinic receptor antagonist, the solvent such as ether and then recrystallized, or otherWise 35 pharmaceutical formulation or method of treatment as puri?ed by silica gel or reversed-phase loW pressure or high described herein may include additional pharmaceutical pressure chromatography. Particular synthetic methods are agents knoWn to be ef?cacious for treatment of the particular also set forth in the Examples. condition to be treated. For example, anti-angiogenic com Pharmaceutical Compositions pounds (e. g., nicotine receptor antagonists) e. g., for the treat In another aspect, the present invention provides pharma 40 ment of proliferative retinopathies, for treatment of cancer ceutical formulations for treatment of individuals in need (e.g., cancer chemotherapeutics, etc.), include, but are not thereof, comprising the 3-arylidene-anabaseine compounds limited to, mecamylamine; hexamethonium (Wotring et al., (including pharmaceutically acceptable salt, solvate, clath 1995 Neuroscience 67: 293-300); dihydro-beta-erythroidine rate, stereoisomer, enantiomers, prodrug or combination (Stolerman et al., 1997 Psychopharrnacology 129: 390-397); thereof) as described herein and one or more pharmaceuti 45 d-tubocurarine (Wotring et al., 1995); pempidine (Rapier et cally acceptable carriers, excipients, diluents, stabiliZers, pre al., 1990.]. Neurochem. 54: 937-945); chlorisondamine (Cag servatives, or other inactive ingredients, including combina giula et al., 1995 Psychopharmacology 122: 301-306); ery tions of the foregoing, knoWn to skilled artisans and described sodine (Decker et al., 1995 Eur: JPharmacol. 280: 79-80); further herein. trimethaphan camsylate (Hisayama et al., 1988 B1: .1. Phar Pharmaceutical compositions and dosage forms of the 50 macol. 95:465-472); pentolinium; bungarotoxin; succinyl invention comprise one or more active ingredients in relative choline; tetraethylammonium; trimethaphan; chlorison amounts and formulated so that a given pharmaceutical com damine; and trimethidinium. position or dosage form is in a therapeutically effective Preferred pharmaceutical compositions and dosage forms amount. comprise a compound of formula I or a pharmaceutically Pharmaceutical compositions and dosage forms of the 55 acceptable prodrug, salt, solvate or clathrate thereof, option invention include formulations that comprise one or more ally in combination With one or more additional active agents. active ingredients (including at least one 3-arylidene-ana Uses of the 3-Arylidene Compounds baseine compound as described herein) in relative amounts As noted previously, in one aspect are provided methods of and formulated so that a given pharmaceutical composition or treating and/or preventing the conditions described herein dosage form inhibits cancer cell proliferation. 60 using the 3-arylidene-anabaseine compounds and pharrna Additional pharmaceutical agents (Which do not include ceutical formulations thereof as described herein. Unless the 3-arylidene-anabaseine compounds described herein), clearly indicated otherWise by the context, the 3-arylidene can include, but are not limited to, anabaseine-related com anabaseine compounds (and pharmaceutical formulations pounds knoWn to those of skill in the art (e.g., as described in thereof) described herein may be used Without limitation in Us. Pat. Nos. 5,977,144 and 5,741,802, incorporated by 65 the methods herein described. reference in their entirety) as Well as additional non-ana The methods may be practiced as a therapeutic approach baseine active agents. For example, Where a 3-arylidene toWards the treatment and/or prevention of the conditions US 8,592,458 B2 35 36 described herein. Thus, in certain embodiments, the tinic receptors are stimulated by an agonist, the inWard cur 3-arylidene-anabaseine compounds and pharmaceutical for rent needed to clamp the membrane potential at —60 mV is mulations thereof may be used to treat and/or prevent the recorded as a function of time and either the peak current or conditions described herein in individuals in need thereof, the integrated current over several hundred milliseconds is including humans. used as a measure of nAChR activation. Current responses In some embodiments, the individual is a mammal, includ Were alWays measured relative to the response to a standard ing, but not limited to, bovine, equine, feline, rabbit, canine, concentration of acetylcholine, usually 100 micromolar for rodent, or primate. In particular embodiments, the mammal is the alpha7 receptor. A series of concentrations Was tested on a primate. In certain embodiments, the primate is a human. In a minimum of three oocytes per concentration to construct a certain embodiments, the individual is human, including concentration-response curve. The concentration of com adults, children and premature infants. pound required to produce 50% of the maximal normaliZed In certain embodiments, the individual has been identi?ed current that could be produced by that compound Was mea as having one or more of the conditions described herein. sured by curve-?tting With a modi?ed Hill equation. This Identi?cation of the conditions as described herein by a EC5O is a measure of agonist potency. If a compound Was not skilled physician is routine in the art and may also be sus stimulatory, its ability to be an antagonist Was measured by pected by the individual. As for example, in proliferative coapplying different concentrations With the standard ACh retinopathies, When an individual notices to loss of vision or calibrating pulse. The median inhibitory concentration (ICSO) visual acuity (e.g., reduction in the ?eld of vision, blurriness, Was thus measured. The loWer the IC5O concentration, the etc.). more potent the compound’s inhibitory potency. In some embodiments, the individual has been identi?ed as 20 As Will be understood by the skilled artisan, the susceptible to one or more of the conditions as described 3-arylidene-anabaseine compounds described herein, When herein. The susceptibility of an individual may be based on identi?ed as agonists (including partial agonists and full ago any one or more of a number of risk factors and/ or diagnostic nists) or antagonists of the (X7 nicotinic receptor can be used approaches appreciated by the skilled artisan, including, but in the treatment and/ or prevention of conditions that are medi not limited to, genetic pro?ling, family history, medical his 25 ated by agonism or antagonism of the (X7 nicotinic receptor, tory (e. g., appearance of related conditions (e.g., diabetes for such as the conditions described herein. For example, antago diabetic ulcers, proliferative retinopathies, etc.), lifestyle or nists can be used in the treatment of conditions Where a habits). reduction in angiogenesis is desirable (e.g., macular degen The terms, “pharmaceutically effective amount” or “thera eration and related conditions (e.g., age-related macular peutically effective amount,” and cognates of these terms, as 30 degeneration and other conditions characterized by abnormal used herein refer to an amount of a formulation su?icient to neovasculariZation of the retina and/or choroid, or prolifera treat a speci?ed condition (e.g., disease, disorder, etc.) or one tive retinopathies); cancer or other conditions related to or more of its symptoms and/ or to prevent the occurrence of abnormal proliferation, etc. Additional conditions amenable the condition. In reference to cancers, a pharmaceutically or to treatment With (X7 nicotinic receptor antagonists are knoWn therapeutically effective amount comprises an amount sul? 35 in the ?eld and described, for example, in WO 03/068208, the cient to, among other things, cause a tumor to shrink, or to disclosure of Which is herein incorporated by reference in its decrease the groWth rate of the tumor. entirety. While many of the 3-arylidene-anabaseine compounds As used herein, the terms “alpha7 nicotinic acetyl choline described herein are full agonists or partial agonists of the (X7 receptor agonist,” “alpha7 nicotinic agonist,” and “alpha7 nicotinic receptor, some 3-arylidene-anabaseine compounds 40 nicotinergic receptor agonist,” and cognates thereof, refer to are (X7 nicotinic receptor antagonists. Determination of ago compounds that bind to the alpha7 nicotinic acetylcholine nist/ antagonist activity can be accomplished using techniques receptor (nAChR) and stimulate the alpha7 nicotinic receptor knoWn to those of skill in the art, particularly in vieW of the (e.g., provide a pharmacological effect, for example, stimu teaching provided herein. The most direct method of deter lation of angiogenesis). The agonist effect of a compound mining Whether a compound is a nicotinic agonist or antago 45 may be determined using methods routine in the ?eld, for nist is to measure the ion ?ux caused by activation of the example, by measuring electrophysiologically or radioiso nAChR ion channel as a result of exposure to that compound. topically the ion ?ux or change in intracellular calcium con A number of cell lines expressing a particular mammalian centration as described herein. A “partial agonist” is a com nAChR are available for such use. The ion ?ux or change in pound that stimulates the alpha7 receptor, but Whose maximal intracellular calcium concentration can be measured With 50 response is less than that of acetylcholine When measured radioisotopically labeled ions or in some cases by calcium ion under the same conditions. A “full agonist” is a compound imaging (nAChRs are permeable to calcium ions as Well as Whose maximal response is the same or greater than that of sodium and potassium ions). Additionally, the net ?ux of all acetylcholine When measured under the same conditions. ions can be measured electrophysiologically, probably the Relatedly, chronic administration of alpha7 nicotinic agonists customary method for assessing the functional properties of 55 can stimulate or upregulate the concentration of alpha7 nAChR compounds. As described herein, in the present appli nAChRs. cation We transiently transfected messenger RNAs of the Similarly, 3-arylidene-anabaseine compounds that are (X7 particular nAChR in marine frog (Xenopus laevis) oocytes, nicotinic receptor agonists can be used in conditions Where Which readily express the subunits for Which mRNA are stimulation of (X7 nicotinic receptor function is desired. For injected over a period of several days. The response of a 60 example, Where stimulation of angiogenesis is indicated for perfused oocyte to a rapid application of compound Was therapeutic effect (e.g., Wound healing, e.g., of diabetic measured With a standard tWo microelectrode voltage-clamp ulcers, non-healing Wounds, etc.) and Where nicotinic recep method Where one intracellular electrode measures the inter tor de?cits have been implicated in neurodegenerative condi nal potential relative to a large external electrode and the other tions and cognitive disorders (such as, e.g., AD and schiZo intracellular microelectrode is used to pass a current needed 65 phrenia). Additional conditions amenable to treatment With to maintain the cell membrane potential at a predetermined (X7 nicotinic receptor full agonists or partial agonists are intracellular voltage (usually —60 millivolts). When the nico knoWn in the ?eld and described, for example, in Us. Pat. US 8,592,458 B2 37 38 Nos. 6,417,205; 6,720,340, 5,977,144; 5,741,802; and Us. administration of alpha4beta2 agonists is more likely to cause Pat. App. Pub. No. 2005/004550, the disclosures of Which are tolerance. An up-regulation in responsiveness is expected incorporated by reference in their entirety. With the compounds of the invention, either alone or in com In certain embodiments, the pharmaceutically effective bination, in appropriate pharmaceutically acceptable forms. amount is suf?cient to prevent the condition, as in being Possible applications of these neW alpha7 agonists and administered to an individual prophylactically. antagonists based on the anabaseine structure include thera The 3-arylidene-anabaseine compounds and pharmaceuti peutic treatments for neurodegenerative diseases and addic cal formulations thereof and methods described herein may tions involving nicotinic receptors, as Well as potential devel be used alone or in conjunction With (e.g., prior to, concur opment as antiproliferation drugs. In particular, it is shoWn rently With, or after) other modes of treatment (e.g., adjunc that altering anabaseine compound polarity and ioniZation tive therapy With additional agents used to treat or prevent the can permit drug application and localiZation to the peripheral condition being treated and/ or administration of an additional (blood and interstitial ?uid) compartments Without signi? treatment modality, or combinations thereof). For example, cant entry into the central nervous system. the compounds may be used in combination With one or more The nAChR population in the AD brain at death is greatly additional pharmaceutical agents (also referred to as thera reduced relative to a normal aging brain. Neurodegeneration peutic agents) as described herein and knoWn to those of skill is most obvious in the neocortex and the hippocampus regions in the art and/ or currently available as treatment modalities. associated With higher mental functions. The tWo most abun As used herein, the term “additional treatment modality” dant nAChR subtypes can be separately measured using the refers to treatment of the conditions described herein Without radiolabeled snake toxin alpha-bungarotoxin for the (X7 sub the use of a pharmaceutical agent (e.g., for proliferative ret 20 type and radiolabeled (S)-nicotine or cytisine for the (x462 inopathies, one or more of thermal laser photocoagulation, nAChR subtype. Recent studies in AD brains shoWed that in photodynamic therapy, etc.; for cancer, one or more of sur the neocortex the major loss of binding sites With nicotine gery, radiation therapy, etc). Where combinations of pharma agonists is associated With a marked reduction in the (x462 ceutical agent(s) and/ or additional treatment modality(ies) nAChRs and a much smaller reduction in (X7 nAChRs. Using are used, they may be, independently, administered prior to, 25 either in situ hybridization or monoclonal antibodies, there is concurrently With, or after administration of the 3-arylidene a decrease in both the alpha4 (40%) and the alpha7 (17%) anabaseine compounds or pharmaceutical formulations subunit protein expression in AD cortices compared to age thereof, as described herein. matched controls. Since there is less signi?cant reduction in The 3-arylidene-anabaseine compounds or pharmaceutical the (X7 nAChR subtype in AlZheimer’s disease patients, it is formulations thereof described herein can be administered in 30 an attractive target for therapeutic drugs that can stimulate the conjunction With one or more of the pharmaceutical agents as function of the remaining receptors. described herein and, as known in the art, one or more addi Harmful peptides such as [3-amyloidl_42 formed through tional agents to further reduce the occurrence and/or severity the abnormal cleavage of amyloid precursor protein (APP) of side effects reactions and/or clinical manifestations may be responsible for AD. APP is a transmembrane protein thereof, or in conjunction With (e.g., prior to, concurrently 35 located on the surface of cells in many tissues and organs. The With, or after) adjunctive therapies as described herein. The exact function of this protein is not knoWn; hoWever, it has 3-arylidene-anabaseine compounds or pharmaceutical for been implicated in nerve cell groWth and movement and as a mulations thereof as described herein may be administered gene sWitch. [3-amyloidl_4O is present in the brain and cere before, concurrently With, or after the administration of one brospinal ?uid of normal subjects in picomolar concentra or more of the pharmaceutical agents described herein. The 40 tions. In AD patients, there is evidence of an elevated level of formulations thereof described herein may also be adminis [3-amyloidl_42, Which exhibits toxic effects on neurons. The tered in conjunction With (e. g., prior to, concurrently With, or [3-amyloidl_42 peptide may lose its helical shape and form after) agents to alleviate the symptoms associated With either ?brils With other proteins, making them less soluble. As these the condition or the treatment regimen. ?brils bind With other ?brils, amyloid plaques are ultimately The optimal combination of one or more of surgery and/or 45 formed; neuronal degeneration associated With AD seems to additional agents in conjunction With administration of the be related to some as yet unidenti?ed, insolubiliZed form of 3-arylidene-anabaseine compounds or pharmaceutical for [3-amyloid. mulations thereof described herein can be determined by an Evidence for a more direct involvement of the (X7 nAChR attending physician based on the individual and taking into in AlZheimer’s disease is the ability of [3-amyloidl_42 to bind consideration the various factors effecting the particular indi 50 to the (X7 receptor, as suggested by the co-immunoprecipita vidual, including those described herein. tion of [3-Amyloidl_42 With the (X7 receptor in samples from Conditions to be Treated postmortem AD hippocampus. Additionally, (X7 antagonists The invention is expected to be useful in a number of and [3-amyloid competitively bind to heterologously applications, particularly in treatment of diseases or condi expressed (X7 receptors. If the (X7 receptor is a receptor for tions Where it is advantageous to upregulate alpha7 nicotinic 55 [3-amyloidl_42 neurotoxicity, selective (X7 nAChR full ago receptor activity. Loss of alpha7 receptors occurs in the pro nists, partial agonists, or antagonists Which prevent [3-amy gression of AD and there is de?cient expression of this recep loid from binding to this receptor may also inhibit the devel tor subtype in schizophrenia. It has been shoWn that chronic opment of AD. administration of alpha7 agonists like DMXBA can lead to an In addition to CNS applications, this invention is expected increased expression of functional alpha7 receptors on cell 60 to provide therapeutic agents that selectively stimulate surfaces. Thus, chronic administration of an alpha7-selective peripheral alpha7 receptors expressed on non-neuronal cells drug may have an even greater effect than before up-regula such as macrophages, vascular endothelium and bronchial tion in alpha7 number and responsiveness has occurred. In epithelium, Which are peripheral cells knoWn to express func contrast to alpha7 selective ligands, alpha4beta2 receptor tional alpha7 nAChRs. When macrophage alpha7 receptors ligands generally cause a doWn-regulation of overall respon 65 are stimulated, the secretion of in?ammatory cytokines such siveness of a cell While at the same time there may be an as TNF is inhibited. These cytokines are knoWn to exacerbate increase in alpha4beta2 receptor number. Thus, chronic an immune response When overproduced and not e?iciently