US20080167286A1 - Pharmaceutical compositions and their methods of use - Google Patents

Pharmaceutical compositions and their methods of use Download PDF

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Publication number
US20080167286A1
US20080167286A1 US11/953,625 US95362507A US2008167286A1 US 20080167286 A1 US20080167286 A1 US 20080167286A1 US 95362507 A US95362507 A US 95362507A US 2008167286 A1 US2008167286 A1 US 2008167286A1
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United States
Prior art keywords
pyridin
oxadiazole
oxadiazol
phenyl
substituted
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Abandoned
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US11/953,625
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English (en)
Inventor
Murali Gopalakrishnan
Marie P. Honore
Chih-Hung Lee
John Malysz
Jianguo Ji
Tao Li
Michael R. Schrimpf
Kevin B. Sippy
David J. Anderson
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Abbott Laboratories
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Abbott Laboratories
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Priority to US11/953,625 priority Critical patent/US20080167286A1/en
Priority to PCT/US2007/087090 priority patent/WO2008073942A2/en
Priority to BRPI0720124-9A2A priority patent/BRPI0720124A2/pt
Priority to ES07869109T priority patent/ES2389116T3/es
Priority to EP10163998.7A priority patent/EP2226074B1/de
Priority to CA002671683A priority patent/CA2671683A1/en
Priority to JP2009541533A priority patent/JP2010512419A/ja
Priority to EP15180552.0A priority patent/EP2974727A1/de
Priority to AU2007333129A priority patent/AU2007333129A1/en
Priority to ES10163998.7T priority patent/ES2558054T3/es
Priority to TW096147575A priority patent/TW200901995A/zh
Priority to MX2009006235A priority patent/MX2009006235A/es
Priority to EP07869109A priority patent/EP2101763B1/de
Priority to KR1020097014515A priority patent/KR20090098884A/ko
Assigned to ABBOTT LABORATORIES reassignment ABBOTT LABORATORIES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SIPPY, KEVIN B., GOPALAKRISHNAN, MURALI, ANDERSON, DAVID J., HONORE, MARIE P., LEE, CHIH-HUNG, MALYSZ, JOHN, JI, JIANGUO, LI, TAO, SCHRIMPF, MICHAEL R.
Priority to US12/134,678 priority patent/US8486979B2/en
Publication of US20080167286A1 publication Critical patent/US20080167286A1/en
Priority to DO2009000137A priority patent/DOP2009000137A/es
Priority to CR10873A priority patent/CR10873A/es
Priority to CO09066751A priority patent/CO6210820A2/es
Priority to EC2009009495A priority patent/ECSP099495A/es
Priority to NO20092584A priority patent/NO20092584L/no
Priority to US13/080,071 priority patent/US9186407B2/en
Priority to US14/877,783 priority patent/US20160022658A1/en
Abandoned legal-status Critical Current

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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2333/70571—Assays involving receptors, cell surface antigens or cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor

Definitions

  • the invention relates to a composition comprising a neuronal nicotinic receptor ligand and an ⁇ 4 ⁇ 2 allosteric modulator, a method of using the same, and a related article of manufacture.
  • Neuronal nicotinic receptors especially ⁇ 4 ⁇ 2 neuronal nicotinic acetylcholine receptors (nAChRs) have been targeted for pain and various central nervous system diseases.
  • Antisense knockdown of the ⁇ 4 subunit was found to decrease the analgesic effect of agonists (Bitner R S, Nikkel A L, Curzon P, Donnelly-Roberts D L, Puttfarcken P S, Namovic M, Jacobs I C, Meyer M D, and Decker M W (2000) Brain Res. 871:66-74).
  • Antinociceptive effects through ⁇ 4 ⁇ 2 nAChRs are generally attributed to stimulation of brainstem monoaminergic transmission, particularly in the raphe (Cucchiaro G, Chaijale N, and Commons K G (2005) J Pharmacol Exp Ther. 313:389-394).
  • ⁇ 4 ⁇ 2 stimulation of GABAergic and glycinergic inhibitory transmission in the spinal cord also may contribute (Rashid M H, Furue H, Yoshimura M, and Ueda H (2006) Pain 125:125-135).
  • Central ⁇ 3* nAChRs may contribute to nicotinic analgesia (Khan I M, Wennerholm M, Singletary E, Polston K, Zhang L, Deerinck T, Yaksh T L, and Taylor P (2004) J Neurocytol. 33:543-556), but ⁇ 3 ⁇ 4 ligands are of little interest because of likely autonomic side effects. Indeed, the goal has been to avoid ⁇ 3* neuronal nicotinic receptor (NNR), as the dose-limiting emetic liability of nonselective compounds has been attributed to activation of ⁇ 3 containing nAChRs.
  • NNR neuronal nicotinic receptor
  • ⁇ 3* nAChRs are expressed in the enteric nervous system as well as in other components of the peripheral and central nervous systems. Area postrema and nucleus tractus solitarius are brainstem nuclei thought to be involved in nausea and emesis. ⁇ 3* nAChRs in the dorsal motor nucleus of the vagus and in nucleus tractus solitarius have been implicated in gastric and blood pressure responses to nicotine injected locally (Ferreira M, Singh A, Dretchen K L, Kellar K J, and Gillis R A (2000) J. Pharmacol. Exp. Ther. 294:230-238).
  • Compounds with varying degrees of selectivity for ⁇ 4 ⁇ 2 nAChRs over other nicotinic subtypes have been discovered over the years.
  • ABT-594 (referred to as Compound A in this application) was efficacious across a number of rodent models of nociception including acute thermal, chemogenic, neuropathic, and visceral pain (Decker M W, Meyer M D, and Sullivan J P (2001) Expert Opinion on Investigational Drugs 10:1819-1830).
  • Available data suggest that ligands with selectivity for the ⁇ 4 ⁇ 2 nAChRs over ⁇ 3 ⁇ 4 efficacy is preferred for low adverse event profiles.
  • the therapeutic index could be expanded by (a) reducing ⁇ 3 ⁇ 4 activity or (b) increasing ⁇ 4 ⁇ 2 efficacy without increasing ⁇ 3 ⁇ 4 activity.
  • the latter may be achieved by an ⁇ 4 ⁇ 2 selective positive allosteric modulator (PAM) either alone or in combination with exogenous ⁇ 4 ⁇ 2 agonist.
  • PAM selective positive allosteric modulator
  • Positive allosteric modulators can potentiate effects by enhancing the efficacy and or potency of agonists.
  • an ⁇ 4 ⁇ 2 selective positive allosteric modulator can selectively enhance effects at the preferred ⁇ 4 ⁇ 2 nAChRs over other nAChR subtypes.
  • nAChR nicotinic
  • compositions that are useful for treatment of diseases or disorders related to the nicotinic acetylcholine receptor (nAChR) with enhanced efficacy and less side effects than nicotinic agents alone.
  • the invention relates to a composition wherein the efficacy of a nicotinic (nAChR) agent is enhanced by co-dosing a nicotinic ligand with a positive allosteric modulator (PAM) of nAChR subtype ⁇ 4 ⁇ 2.
  • PAM positive allosteric modulator
  • the invention relates to compositions for treatment of individuals with nAChR-mediated diseases or disorders, and particularly for pain or CNS disorders, which involves a combination of a nicotinic ligand with an ⁇ 4 ⁇ 2 positive allosteric modulator.
  • the invention provides a synergistic combination of a nicotinic agonist or partial agonist with a ⁇ 4 ⁇ 2 positive allosteric modulator.
  • the invention further provides for the treatment or prevention of nAChR-mediated diseases and disorders, particularly pain and central nervous system disorders, in mammals, and particularly in humans. Such combination enhances the efficacy of ⁇ 4 ⁇ 2 ligand and can provide a beneficial alternative to current treatments.
  • the invention relates to a composition
  • a composition comprising (i) a nicotinic acetylcholine receptor ligand; and (ii) a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 selective positive allosteric modulator, in admixture with at least one pharmaceutically acceptable excipient.
  • the preferred nicotinic acetylcholine receptor ligand is a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 ligand.
  • the invention is most beneficial wherein the amounts of (i) and (ii) together are effective in treating nAChR-mediated disease states, for example pain.
  • Other CNS diseases where ⁇ 4 ⁇ 2 nAChRs are involved, such as cognition and attention disorders, may also benefit.
  • the invention in another embodiment, relates to method for use in treating or preventing pain, including neuropathic pain, and cognitive disorders in a patient, comprising: (i) administering an amount of a nicotinic acetylcholine receptor ligand to the patient; and (ii) administering an amount of a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 allosteric modulator to the patient; wherein the amounts of (i) and (ii) together are more effective in treating pain or cognitive disorders.
  • the preferred nicotinic acetylcholine receptor ligand is a neuronal nicotinic receptor subtype ⁇ 4 ⁇ 2 ligand.
  • the invention also relates to use of a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 allosteric modulator in combination of a pharmaceutical active agent that improves cholinergic function to treat attention or cognitive dysfunction.
  • a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 allosteric modulator in combination with a pharmaceutical active agent used to treat neuropsychological dysfunction also is described.
  • Yet another embodiment of the invention relates to an article of manufacture, comprising: (i) a first pharmaceutical dosage form comprising at least one nicotinic acetylcholine receptor ligand; (ii) a second pharmaceutical dosage form comprising at least one nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 positive allosteric modulator, wherein the article contains first and second pharmaceutical dosage forms.
  • Radiolabelled compounds useful for evaluating the binding affinity of nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 positive allosteric modulators also are described herein. Radiolabelled ⁇ 4 ⁇ 2 positive allosteric modulators also are disclosed.
  • FIGS. 1A and 1B depict responses of a representative nicotinic acetylcholine receptor ligand, 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) in the absence and presence of a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 positive allosteric modulator, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (PAM, Compound 1), at human ⁇ 4 ⁇ 2 or ⁇ 3 ⁇ 4 nicotinic acetylcholine receptor subtypes expressed in HEK-293 cells.
  • the data demonstrate a leftward shift in potency (EC 50 value) at ⁇ 4 ⁇ 2, but not ⁇ 3 ⁇ 4, nAChRs.
  • FIGS. 2A and 2B depict responses of another representative nicotinic acetylcholine receptor ligand, (3R)-1-pyridin-3-ylpyrrolidin-3-amine (Compound B), in the absence and presence of an ⁇ 4 ⁇ 2 positive allosteric modulator, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (PAM, Compound 1), at human ⁇ 4 ⁇ 2 or ⁇ 3 ⁇ 4 nicotinic receptor subtypes expressed in HEK-293 cells.
  • PAM 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile
  • FIGS. 3A and 3B graphically represents the effect of ⁇ 4 ⁇ 2 positive allosteric modulator in enhancing the effect of a nAChR partial agonist, such as 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (Compound C, also known as ABT-089; Reuter, L. E., Anderson, D. J., Briggs, C. A., Donnelly-Roberts et al., CNS Drug Rev., 10 (2), 167-182, 2004).
  • a nAChR partial agonist such as 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine
  • Compound C alone does not evoke a calcium response, but when co-applied with the PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), evoked robust responses at ⁇ 4 ⁇ 2 nAChRs ( FIG. 3A ), but not at ⁇ 3 ⁇ 4 nAChRs ( FIG. 3B ).
  • Compound C is a representative of other nicotinic partial agonists.
  • Compound D alone does not evoke a response, but when co-applied with the PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), evoked robust responses at ⁇ 4 ⁇ 2 nAChRs ( FIG. 4A ), but not at ⁇ 3 ⁇ 4 nAChRs ( FIG. 4B ).
  • Compound D is a representative of other nicotinic partial agonists.
  • FIG. 5 shows correlation of potencies for activation of ⁇ 4 ⁇ 2 nAChRs by various nicotinic acetycholine receptor ligands in the presence and absence of an ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1).
  • these nicotinic ligands are found to be more potent in activating ⁇ 4 ⁇ 2 nAChRs in the presence of ⁇ 4 ⁇ 2 PAM (Compound 1).
  • FIG. 6A graphically represents the effect of an ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), on enhancing the efficacy by 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) in reversing neuropathic pain.
  • FIG. 6B graphically represents the dose dependent effect of an ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), on enhancing the neuropathic pain efficacy of 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A).
  • An ineffective dose of Compound A (1 nmol/kg) demonstrates effect when combined with various doses of ⁇ 4 ⁇ 2 PAM (Compound 1).
  • FIG. 7A shows dose-dependent effects in neuropathic pain of 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), alone and a combination of Compound 1 (3.5 ⁇ mol/kg) with various doses of Compound A.
  • An ⁇ 4 ⁇ 2 PAM (Compound 1) alone is ineffective.
  • the dose response curve of Compound A in the Chung model of neuropathic pain shifts to the left.
  • FIG. 7B shows the effects on emesis in ferrets.
  • the effects of 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1), alone and a combination of Compound 1 (3.5 ⁇ mol/kg) with various doses of Compound A are shown.
  • An ⁇ 4 ⁇ 2 PAM (Compound 1) alone does not cause emesis, and does not shift the dose response curve of Compound A in the ferret model of emesis.
  • FIGS. 8A and 8B show plasma level analysis in models of neuropathic pain and emesis.
  • the efficacy of Compound A is shifted left-ward as shown in FIG. 8A , but no shift in effects on emesis are shown in FIG. 8B .
  • the maximal efficacy of Compound A can be realized in neuropathic pain without incidence of emesis, in presence of ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1).
  • the data demonstrates that the therapeutic window of ⁇ 4 ⁇ 2 nAChR agonists is wider in the presence of ⁇ 4 ⁇ 2 PAM.
  • FIG. 9 shows the efficacy of a partial agonist, Compound D, in the presence and absence of ⁇ 4 ⁇ 2 PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1).
  • Compound D when administered alone is ineffective in relieving pain.
  • Compound D When co-dosed with ⁇ 4 ⁇ 2 PAM (Compound 1), Compound D demonstrates effect, and the data demonstrate that Compound D provides significant relief of neuropathic pain in rats.
  • FIG. 10 is a graphical representation of specific binding to receptor sites in human brain membranes (fmoles per mg protein) as a function of the concentration of a radioligand [ 3 H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile ([ 3 H]-POB, nM).
  • Compounds suitable for the composition, method, and article of manufacture for the invention are any chemical compounds for which ⁇ 4 ⁇ 2 nicotinic receptor activity can be identified.
  • ⁇ 4 ⁇ 2* indicates a receptor that contains the ⁇ 4 and ⁇ 2 subunits proteins in combination with other subunits.
  • nicotinic receptor ligands surprisingly can be improved by combining a nicotinic acetylcholine receptor ligand, particularly an ⁇ 4 ⁇ 2 receptor ligand (agonist, partial agonist), with a nicotinic acetylcholine receptor ⁇ 4 ⁇ 2 subtype selective positive allosteric modulator (PAM).
  • PAM nicotinic acetylcholine receptor ⁇ 4 ⁇ 2 subtype selective positive allosteric modulator
  • Nicotinic acetylcholine subtype ⁇ 4 ⁇ 2 receptor ligands modulate the function by altering the activity of the receptor. Suitable compounds also can be partial agonists that partially block or partially activate the ⁇ 4 ⁇ 2 receptor or agonists that activate the receptor. Nicotinic acetylcholine receptor ⁇ 4 ⁇ 2 receptor ligands suitable for the invention can include full agonists or partial agonists. Compounds modulating activity of nicotinic acetylcholine receptor ⁇ 4 ⁇ 2 subtype are suitable for the invention regardless of the manner in which they interact with the receptor.
  • [ 3 H]-Cytisine binding values (“K i Cyt”) of compounds of the invention ranged from about 0.001 nanomolar to greater than 100 micromolar.
  • Preferred compounds for the composition demonstrate binding values of from about 0.001 nanomolar to 10 micromolar.
  • the [ 3 H]-cytisine binding assays have been well reported; however, further details for carrying out the assays can be obtained in International Publication No. WO 99/32480; U.S. Pat. Nos. 5,948,793 and 5,914,328; WO 2004/018607; U.S. Pat. No. 6,809,105; WO 00/71534; and U.S. Pat. No. 6,833,370.
  • ⁇ 4 ⁇ 2 receptor ligands suitable for the invention can be compounds of various chemical classes.
  • some examples of ⁇ 4 ⁇ 2 receptor ligands suitable for the invention include, but are not limited to heterocyclic ether derivatives, for example as described in International Publication No. WO 99/32480, published Jul. 1, 1999 and further described and claimed in U.S. Pat. Nos. 5,948,793, issued Sep. 7, 1999, and 5,914,328, issued Jun. 22, 1999; N-substituted diazabicyclic derivatives, for example as described in International Publication No. WO 2004/0186107, published Sep. 23, 2004, and further described and claimed in U.S. Pat. No. 6,809,105, issued Oct.
  • ⁇ 4 ⁇ 2 receptor ligands suitable for the invention include, but are not limited to aryl-fused azapolycyclic compounds, for example as described in International Publication No. WO 2001062736, published Aug. 30, 2001; aryl-substituted olefinic amine compounds, for example as described in International Publication Nos. WO 9965876, published Dec. 23, 1999, and WO 00/75110, published Dec. 14, 2000; pyridopyranoazepine derivatives, for example as described in U.S. Pat. No. 6,538,003, published Mar. 25, 2003; benzylidene- and cinnamylidene-anabaseines, for examples as described in International Publication No.
  • TC-1734 ispronicline
  • GTS-21 4-hydroxy-GTS-21
  • TC-5619 TC-2696
  • dianicline varenicline
  • Positive allosteric modulators are compounds that potentiate receptor responses to acetylcholine without themselves triggering receptor activation or desensitization, or either, of the receptor.
  • ⁇ 4 ⁇ 2 positive allosteric modulator activity is by characterization in human HEK cells expressing the human nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2, particularly by use of Fluorescent Image Plate Reader technology. Such assay has been reported and further details for carrying out the assays can be obtained in International Publication Nos. WO 2006/114400, published Nov. 2, 2006.
  • Another method to identify and characterize allosteric modulator activity is by expressing the ⁇ 4 ⁇ 2 subunits in Xenopus oocytes or cell lines, and by measuring effects on ligand-evoked current responses as previously described (Curtis L, Buisson B, Bertrand S and Bertrand, D., 2002; Molecular Pharmacology, 61: 127-135).
  • Steroid hormones represent a family of molecules with varying modulatory effects on nAChRs as well as other members of the LGIC superfamily.
  • positive allosteric modulation of human ⁇ 4 ⁇ 2 nAChRs expressed either in Xenopus oocytes or in human embryonic kidney cells was reported with 17 ⁇ -estradiol (Curtis L, Buisson B, Bertrand S, and Bertrand D, 2002; Molecular Pharmacology, 61: 127-135).
  • Examples of compounds reported as selective ⁇ 4 ⁇ 2 positive allosteric modulators are oxadiazole derivatives, for example as described in WO 2006/114400.
  • Another suitable ⁇ 4 ⁇ 2 positive allosteric modulator is 3,5-diphenylisoxazole, which is commercially available from Sigma Aldrich, St. Louis, Mo., USA.
  • ⁇ 4 ⁇ 2 positive allosteric modulators include, but are not limited to, oxadiazole derivatives.
  • Suitable oxadiazole derivatives can include 1,2,4-oxadiazole derivatives and 1,3,4-oxadiazole derivatives. Examples of 1,3,4-oxadiazole derivatives are described in co-pending U.S. Patent Application No. 61/000,295, filed on Apr. 12, 2007, wherein the methods of preparation disclosed are incorporated by reference herein. Such compounds have the formula (I):
  • X is a bond, O, NR 1 , S, or C 1 -C 3 alkylene
  • Y represents a monocyclic aryl, cycloalkyl, heterocycle, or heteroaryl group
  • Ar 1 represents a monocyclic aryl or a heteroaryl group
  • R 1 is hydrogen, alkyl, haloalkyl or arylalkyl.
  • X is selected from a bond, O, NR 1 , S, or C 1 -C 3 alkylene, wherein R 1 is selected from hydrogen, alkyl, haloalkyl, and arylalkyl.
  • R 1 is selected from hydrogen, alkyl, haloalkyl, and arylalkyl.
  • X is a bond.
  • R 1 is hydrogen or alkyl.
  • Y represents a monocyclic aryl, cycloalkyl, heterocycle, or heteroaryl group, which can be substituted or unsubstituted with substituents.
  • suitable heterocycle groups can include, but are not limited to, pyrrolidine, piperidine, and the like.
  • suitable heteroaryl groups can include, but are not limited to, thienyl, furanyl, pyridinyl, pyrazinyl, and the like.
  • a preferred monocyclic aryl group is substituted or unsubstituted phenyl.
  • Suitable substituents for the monocyclic aryl, heterocycle, or heteroaryl group are, for example, alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, nitro, and cyano.
  • Ar 1 represents a monocyclic aryl, such as substituted or unsubstituted phenyl, or heteroaryl group.
  • suitable heteroaryl groups include, but are not limited, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, and pyridinyl, each of which can be unsubstituted or substituted with one, two, or three substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, nitro, cyano, and amino.
  • suitable 2,5-disubstituted-1,3,4-oxadiazole derivatives can have the formula (I) wherein X is a bond; Y is aryl, cycloalkyl, heterocycle, or heteroaryl; and Ar 1 is monocyclic aryl or heteroaryl.
  • suitable 2,5-disubstituted-1,3,4-oxadiazole derivatives can have the formula (I) wherein X is a bond; Y is monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridinyl, pyrazinyl, pyrrolidinyl, or piperidinyl optionally substituted with one or more of the substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro and cyano; and Ar 1 is phenyl, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl, pyrimidinyl, pyrazinyl, or pyridinyl optionally substituted with one or more of the substituents selected from the group consisting of alkyl, alkylcarbonyl, alkyl
  • the suitable 2,5-disubstituted-1,3,4-oxadiazole derivatives can have the formula (I) wherein X is a bond; Y is pyridyl; and Ar 1 is phenyl, pyrimidinyl, pyrazinyl, or pyridinyl optionally substituted with one or more of the substituents selected from the group consisting of alkyl, halogen, haloalkyl, hydroxy, alkoxy, haloalkoxy, nitro, cyano, and NZ 1 Z 2 , wherein Z 1 and Z 2 are hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, and formyl.
  • ⁇ 4 ⁇ 2 positive allosteric modulators include oxadiazole derivatives, for example as described in WO 2006/114400, published Nov. 2, 2006. Further examples of oxadiazole compounds that are suitable as ⁇ 4 ⁇ 2 positive allosteric modulators are also provided in WO 02/100826, published Dec. 19, 2002. Yet other suitable examples of ⁇ 4 ⁇ 2 positive allosteric modulators include, but are not limited to, compounds of the formula (II):
  • Ar 2 is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with 1, 2, 3, or 4 substituents selected from halo, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 5 -C 10 heteroaryl, C 4 -C 10 heterocycle, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)NHC(O)O—(C 1 -C 6 alkyl), C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylcarbonyl, amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO 2 —, alkyl-SO 2 —,
  • Ar 3 is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with a substituent selected from halo, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 5 -C 10 heteroaryl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, amino, hydroxyl, haloalkyl-SO 2 —, cyano, nitro, C 1 -C 6 acylamino, C 1 -C 6 alkoxy, —N(C 1 -C 6 alkyl) 2 , and carboxy.
  • a substituent selected from halo, C 1 -C 6 haloalkyl, C 6 -
  • suitable 3,5-disubstituted-1,2,4-oxadiazole derivatives can have the formula (I) wherein Ar 2 is substituted monocyclic aryl or monocyclic heteroaryl, which can be substituted or unsubstituted, and Ar 3 is substituted monocyclic aryl or heteroaryl, which can be substituted or unsubstituted.
  • the substituent is selected from halo, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 5 -C 10 heteroaryl, C 4 -C 10 heterocycle, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)NHC(O)O—(C 1 -C 6 alkyl), C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylcarbonyl, amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO 2 —, alkyl-SO 2 —, —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 ,
  • the substituent is selected from halo, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 5 -C 10 heteroaryl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, amino, hydroxyl, haloalkyl-SO 2 —, cyano, nitro, C 1 -C 6 acylamino, C 1 -C 6 alkoxy, —N(C 1 -C 6 alkyl) 2 , and carboxy.
  • Preferred for monocyclic heteroaryl are pyridine-3-yl, pyridine-4-yl, and pyridine-2(1H)-one.
  • suitable 3,5-disubstituted-1,2,4-oxadiazole derivatives can have the formula (I) wherein Ar 2 is pyridinyl, which can be substituted or unsubstituted, or substituted phenyl; and Ar 3 is pyridinyl, which can be substituted or unsubstituted, or substituted phenyl.
  • the pyridinyl group when substituted, is substituted with fluoro.
  • the phenyl group is substituted with cyano or halo. It is preferred that the pyridinyl group for Ar 2 or Ar 3 is pyridin-3-yl.
  • the preferred phenyl group is substitute with fluoro, sulfonamide or cyano, and preferably cyano.
  • ⁇ 4 ⁇ 2 positive allosteric modulators are, for example,
  • ⁇ 4 ⁇ 2 positive allosteric modulators are, for example, 2,5-disubstituted-1,3,4-oxadiazole derivatives, such as:
  • C x -C y wherein x and y are integers from 1 to 10 refer to a range of carbon atoms in the hydrocarbon portion of the group which it modifies, for example, the designation “C 1 -C 6 haloalkyl” refers to at least one halogen appended to the parent molecular moiety through an alkyl group having from 1 to 6 carbon atoms.
  • the following terms have the following meanings:
  • acyl hydrazide means a —C(O)NHNH 2 group.
  • alkenyl means a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
  • alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkoxy means an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein.
  • Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, and methoxymethoxy.
  • alkoxyalkoxyalkyl means an alkoxyalkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkoxyalkyl include, but are not limited to, tert-butoxymethoxymethyl, ethoxymethoxymethyl, (2-methoxyethoxy)methyl, and 2-(2-methoxyethoxy)ethyl.
  • alkoxyalkyl means an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.
  • alkoxycarbonyl means an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • alkoxycarbonylalkyl means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxycarbonylalkyl include, but are not limited to, 3-methoxycarbonylpropyl, 4-ethoxycarbonylbutyl, and 2-tert-butoxycarbonylethyl.
  • alkoxysulfonyl means an alkoxy group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkoxysulfonyl include, but are not limited to, methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl.
  • alkyl means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylcarbonyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkylcarbonylalkyl means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl, and 3-oxopentyl.
  • alkylcarbonyloxy means an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy.
  • alkylcarbonyloxylalkyl means an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group.
  • alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, and —CH 2 CH(CH 3 )CH 2 —.
  • alkylsulfinyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein.
  • Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
  • alkylsulfinylalkyl means an alkylsulfinyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylsulfinylalkyl include, but are not limited to, methylsulfinylmethyl and ethylsulfinylmethyl.
  • alkylsulfonyl means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkylsulfonylalkyl means an alkylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylsulfonylalkyl include, but are not limited to, methylsulfonylmethyl and ethylsulfonylmethyl.
  • alkylthio means an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • alkylthioalkyl means an alkylthio group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkylthioalkyl include, but are not limited, methylthiomethyl and 2-(ethylthio)ethyl.
  • alkynyl means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
  • amino means a —NH 2 group.
  • aryl means phenyl, a bicyclic aryl or a tricyclic aryl.
  • the bicyclic aryl is naphthyl, a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl.
  • Representative examples of the bicyclic aryl include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl.
  • the tricyclic aryl is anthracene or phenanthrene, or a bicyclic aryl fused to a cycloalkyl, or a bicyclic aryl fused to a cycloalkenyl, or a bicyclic aryl fused to a phenyl.
  • Representative examples of tricyclic aryl ring include, but are not limited to, azulenyl, dihydroanthracenyl, fluorenyl, and tetrahydrophenanthrenyl.
  • aryl groups of this invention can be substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl, alkylsulfinylalkyl, alkylsulfonyl, alkylsulfonylalkyl, alkylthio, alkylthioalkyl, alkynyl, arylalkyl, arylalkoxy, aryloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, formylalkyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxy
  • arylalkoxy means an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
  • arylalkyl means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
  • aryloxy means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy, and 3,5-dimethoxyphenoxy.
  • carbonyl as used herein, means a —C(O)— group.
  • carboxyalkyl means a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl.
  • cyano as used herein, means a —CN group.
  • cyanoalkyl means a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.
  • cycloalkenyl means a cyclic hydrocarbon containing from 3 to 8 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of cycloalkenyl include, but are not limited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yl and 3-cyclopenten-1-yl.
  • cycloalkyl means a monocyclic, bicyclic, or tricyclic ring system.
  • Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems are exemplified by a bridged monocyclic ring system in which two adjacent or non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • Tricyclic ring systems are exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3,7 ]nonane and tricyclo[3.3.1.1 3,7 ]decane (adamantane).
  • the cycloalkyl groups of the invention are optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, oxo, —NZ 1 Z 2 , and (NZ 3 Z 4 )carbonyl.
  • substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbony
  • cycloalkylalkyl means a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.
  • formylalkyl means a formyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of formylalkyl include, but are not limited to, formylmethyl and 2-formylethyl.
  • halo or “halogen”, as used herein, means —Cl, —Br, —I or —F.
  • haloalkoxy means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl means a monocyclic heteroaryl or a bicyclic heteroaryl.
  • the monocyclic heteroaryl is a 5 or 6 membered ring that contains at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • the 5 membered ring contains two double bonds and the 6 membered ring contains three double bonds.
  • the 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the heteroaryl, provided that proper valance is maintained.
  • monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
  • the bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a cycloalkyl, or a monocyclic heteroaryl fused to a cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl.
  • the bicyclic heteroaryl is connected to the parent molecular moiety through any carbon atom or any substitutable nitrogen atom contained within the bicyclic heteroaryl, provided that proper valance is maintained.
  • bicyclic heteroaryl include, but are not limited to, azaindolyl, benzimidazolyl, benzofuranyl, benzoxadiazolyl, benzoisoxazole, benzoisothiazole, benzooxazole, 1,3-benzothiazolyl, benzothiophenyl, cinnolinyl, furopyridine, indolyl, indazolyl, isobenzofuran, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, quinoxalinyl and thienopyridinyl.
  • heteroaryl groups of the invention are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, —NZ 1 Z 2 and (NZ 3 Z 4 )carbonyl.
  • Heteroaryl groups of the invention that are substituted with a hydroxyl group may be present as tautomers.
  • the heteroaryl groups of the invention encompass all tauto
  • heterocycle or “heterocyclic”, as used herein, means a monocyclic heterocycle, a bicyclic heterocycle or a tricyclic heterocycle.
  • the monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S.
  • the 5 membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle.
  • Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyr
  • the bicyclic heterocycle is a 5 or 6 membered monocyclic heterocycle fused to a phenyl group, or a 5 or 6 membered monocyclic heterocycle fused to a cycloalkyl, or a 5 or 6 membered monocyclic heterocycle fused to a cycloalkenyl, or a 5 or 6 membered monocyclic heterocycle fused to a monocyclic heterocycle.
  • the bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the bicyclic heterocycle.
  • bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, benzodioxolyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, chromenyl and 1,2,3,4-tetrahydroquinolinyl.
  • the tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl, or a bicyclic heterocycle fused to a cycloalkyl, or a bicyclic heterocycle fused to a cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle.
  • the tricyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the tricyclic heterocycle.
  • tricyclic heterocycle include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.
  • heterocycles of this invention are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, mercapto, oxo, —NZ 1 Z 2 and (NZ 3 Z 4 )carbonyl.
  • substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl
  • hydroxy means an —OH group.
  • hydroxyalkyl means at least one hydroxy group, as defined herein, is appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and 2-ethyl-4-hydroxyheptyl.
  • hydroxy-protecting group or “O-protecting group” means a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures.
  • hydroxy-protecting groups include, but are not limited to, substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl, benzyl, and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclic acetals and ketals, for example, methylene acetal, acetonide and benzylidene acetal; cyclic ortho esters, for example, methoxymethylene; cyclo
  • lower alkenyl is a subset of alkenyl, as defined herein, and means an alkenyl group containing from 2 to 4 carbon atoms. Examples of lower alkenyl are ethenyl, propenyl, and butenyl.
  • lower alkoxy is a subset of alkoxy, as defined herein, and means a lower alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom, as defined herein.
  • Representative examples of lower alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.
  • lower alkyl is a subset of alkyl, as defined herein, and means a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
  • Examples of lower alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.
  • lower haloalkoxy is a subset of haloalkoxy, as defined herein, and means a straight or branched chain haloalkoxy group containing from 1 to 4 carbon atoms.
  • Representative examples of lower haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, dichloromethoxy, fluoromethoxy, and pentafluoroethoxy.
  • lower haloalkyl is a subset of haloalkyl, as defined herein, and means a straight or branched chain haloalkyl group containing from 1 to 4 carbon atoms.
  • Representative examples of lower haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, dichloromethyl, fluoromethyl, and pentafluoroethyl.
  • methylenedioxy means a —OCH 2 O— group wherein the oxygen atoms of the methylenedioxy are attached to the parent molecular moiety through two adjacent carbon atoms.
  • nitrogen protecting group means those groups intended to protect an amino group against undesirable reactions during synthetic procedures.
  • Preferred nitrogen protecting groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), tert-butylacetyl, trifluoroacetyl, and triphenylmethyl (trityl).
  • mercapto means a —SH group.
  • nitro means a —NO 2 group.
  • NZ 1 Z 2 means two groups, Z 1 and Z 2 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z 1 and Z 2 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, aryl, arylalkyl, and formyl. In certain instances within the invention, Z 1 and Z 2 taken together with the nitrogen atom to which they are attached form a heterocyclic ring.
  • NZ 1 Z 2 include, but are not limited to, amino, methylamino, acetylamino, acetylmethylamino, phenylamino, benzylamino, azetidinyl, pyrrolidinyl and piperidinyl.
  • NZ 3 Z 4 means two groups, Z 3 and Z 4 , which are appended to the parent molecular moiety through a nitrogen atom.
  • Z 3 and Z 4 are each independently selected from the group consisting of hydrogen, alkyl, aryl and arylalkyl.
  • Representative examples of NZ 3 Z 4 include, but are not limited to, amino, methylamino, phenylamino and benzylamino.
  • oxo means a ⁇ O moiety
  • sulfinyl as used herein, means a —S(O)— group.
  • sulfonyl means a —SO 2 — group.
  • tautomer means a proton shift from one atom of a compound to another atom of the same compound wherein two or more structurally distinct compounds are in equilibrium with each other.
  • radioactive atom refers to a compound in which at least one of the atoms is a radioactive atom or radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons.
  • radioactive atoms include, but are not limited to, 3 H (tritium), 14 C, 11 C, 15 O, 18 F, 35 S, 123 I, and 125 I.
  • Preparation of Compounds Suitable for the Composition of the Invention can be understood in connection with the following synthetic schemes and examples, which illustrate a means by which the compounds can be prepared.
  • Methods for preparing suitable nicotinic acetylcholine receptor ligands and suitable nicotinic acetylcholine subtype ⁇ 4 ⁇ 2 allosteric modulators are readily available in the literature.
  • Suitable compounds can be prepared by conventional methods for chemical synthesis with readily available starting materials. Nicotinic acetylcholine receptor ligands and nicotinic acetylcholine subtype ⁇ 4 ⁇ 2 allosteric modulators also may be commercially available.
  • Oxadiazole derivatives suitable for the composition of the invention can be prepared according to conventional methods. Some suitable methods for preparing such oxadiazole derivatives are provided in the Schemes and Examples below. However, such further illustration is intended only for reference and is not intended in any way to limit the scope of the invention.
  • compounds of formula (4) can be reacted with compounds of formula (5) in POCl 3 at temperatures from 40-100° C. over 1-24 hours to provide compounds of formula (6); wherein R 3 is Ar 1 and R 4 is Y, or R 3 is Y and R 4 is Ar 1 .
  • compounds of formula (4) can be reacted with compounds of formula (5) in the presence of triphenylphosphine, which may optionally be polymer bound, and trichloroacetonitrile in acetonitrile.
  • the mixture may be heated in a microwave oven at 100-175° C. for 5-30 minutes as described by Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron. Lett.
  • Another alternative includes combining compounds of formula (4) and compounds of formula (5) in a solvent such as methylene chloride in the presence of 2-chloro-1,3-dimethylimidazolinium chloride and a base such as triethylamine at 15-35° C. for 10-120 hours as described by Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989-6992.
  • compounds of formula (1) can be reacted with urea (7) in a solvent such as dichloromethane in the presence of a base such as triethylamine at 25-40° C. for 1-12 hours to provide compounds of formula (8) as described in Sobol, E.; Bialer, M.; Yagen, B. J. Med. Chem. 2004, 47, 4316-4326.
  • compounds of formula (1) and (7) may be combined in pyridine at 20-110° C. for 1-24 hours to provide compounds of formula (8).
  • Compounds of formula (8) can be treated with POCl 3 at 25-100° C. for 1-24 hours to provide compounds of formula (9).
  • Compounds of formula (9) can be reacted with H—X—Y in the presence of a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, cesium or carbonate in a solvent such as tetrahydrofuran, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide, or acetonitrile at temperatures from ⁇ 20° C. to 150° C. over 1-48 hours to provide compounds of formula (I).
  • a base such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, cesium or carbonate in a solvent such as tetrahydrofuran, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide, or ace
  • compounds of formula (II), wherein Ar 2 and Ar 3 , are as defined in formula (II), can be prepared as described in Scheme 4.
  • Aryl or heteroaryl compounds of general formula (10) can be treated with compounds of formula (2) in the presence of a coupling agent such as N-(3-methylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole with heat in a solvent including, but not limited to dimethylformamide, to provide compounds of general formula (II).
  • the compounds and intermediates of the invention may be isolated and purified by methods well-known to those skilled in the art of organic synthesis.
  • Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described for instance in “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.
  • Suitable 2,5-disubstituted-1,3,4-oxadiazole derivatives were prepared using readily available starting materials.
  • International Publication WO 02/100826 published Dec. 19, 2002, describes the preparation of some oxadiazole derivatives.
  • Compounds of formula (I) also can be prepared according to the following general methods.
  • Method B A Smith Process vial (0.5-2 ml) was charged with a stir bar. To the vessel were added a carboxylic acid (0.1 mmol), nicotinic hydrazide (Aldrich, 13.7 mg, 0.1 mmol), PS-PPh 3 (Fluka, 2.2 mmol/g, 136 mg, 0.3 mmol) and MeCN (anhydrous, Aldrich, 2 mL), followed by CCl 3 CN (Aldrich, 28.8 mg, 0.20 mmol). The reaction vessel was sealed and heated to 150° C. for 15 minutes using an EmrysTM Optimizer Microwave (Personal Chemistry, www.personalchemistry.com).
  • EmrysTM Optimizer Microwave Personal Chemistry, www.personalchemistry.com.
  • reaction vessel was uncapped and the resin was removed by filtration.
  • the mixture was purified by preparative HPLC [Waters, column: Nova-Pak® HR C18 6 ⁇ m 60 ⁇ Prep-Pak® (25 mm ⁇ 100 mm), solvent: MeCN/water (v. 1% TFA), 5/95 to 95/5, flow rate of 40 mL/min. Fractions were collected based upon UV signal threshold, and selected fractions were subsequently analyzed by flow injection analysis mass spectrometry using positive APCI ionization on a Finnigan LCQ using 70:30 MeOH:10 mM NH 4 OH(aq) at a flow rate of 0.8 mL/min.].
  • Suitable Oxadiazole Derivatives are of Particular Interest. Many oxadiazole derivatives are suitable nicotinic acetylcholine subtype ⁇ 4 ⁇ 2 positive allosteric modulators for the composition. Preparation of oxadiazole derivatives has been described in the literature. For example, WO 2006/114400, published Nov. 2, 2006, discloses that oxadiazole derivatives can be readily prepared. International Publication WO 02/100826, published Dec. 19, 2002, also describes the preparation of other oxadiazole derivatives.
  • 3-Pyridylamideoxime (Aldrich, 5.5 g, 40 mmol) was dissolved in 60 mL of pyridine and 3-cyanobenzoyl chloride (Aldrich, 6.6 g, 40 mmol) was added. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. The solution was poured into water (500 mL), filtered, and the solid were collected and dried under vacuum.
  • 3-Pyridylamideoxime (5.5 g, 40 mmol) was dissolved in 60 mL of pyridine and nicotinoyl chloride hydrochloride (7.2 g, 40 mmol) was added. The reaction mixture was heated to reflux for 4 hours and then cooled to room temperature. The solution was poured into water (500 mL), basified, filtered, and the solid was collected and dried under vacuum.
  • N′-Hydroxynicotinimidamide (137 mg, 1.0 mmol) was added and the mixture was stirred for 6-10 hours, and then warmed to 140° C. for 2-4 hours. The reaction was cooled to ambient temperature and triturated with water (10 mL). The precipitate was filtered and dried under vacuum to give the titled compound.
  • Example 32A A solution of the product of Example 32A (320 mg, 1.23 mmol) in ethyl acetate (5 mL) was stirred with hydrochloric acid (Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol) at ambient temperature for 4 hours. The titled compound was collected by filtration and dried under vacuum.
  • hydrochloric acid Aldrich, 4 M in dioxane, 0.5 mL, 2.0 mmol
  • N′-Hydroxynicotinimidamide (274 mg, 2.00 mmol) was coupled with 3-(tert-butoxycarbonyl)benzoic acid (Aldrich) according to the procedure described in Example 8.
  • 1 H NMR 300 MHz, CD 3 OD
  • 7.65 (ddd, J 7.9, 4.8, 0.8 Hz, 1H)
  • 7.71-7.77 m, 1H
  • MS DCI/NH 3 ) m/z 324 (M+H) + .
  • the free base of the title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-((dimethylamino)methyl)benzoic acid (Aldrich).
  • a solution of this free base in ethyl acetate (5 mL) was treated with hydrochloric acid (Aldrich, 0.5 mL, 4M in dioxane) at ambient temperature for 2 hours.
  • the title compound was collected by filtration and dried under vacuum.
  • Zinc chloride (Aldrich, 1 M in diethyl ether, 2.0 mL, 2.0 mmol) was then added slowly and the resultant solution was stirred at ⁇ 78° C. for additional 30 minutes and then warmed up to ambient temperature, stirred for another 30 minutes at room temperature before the addition of a solution of the product of the Example 63 (0.30 g, 1.0 mmol) in tetrahydrofuran (anhydrous, 5.0 mL) and bis(tri-t-butylphosphine)palladium(0) (Strem, 10.2 mg, 0.02 mmol). The mixture was stirred at ambient temperature for 15 hours and quenched with ammonium hydroxide (5 mL).
  • Example 68 A solution of the product of Example 68 (265 mg, 1.0 mmol) in ethanol (5 mL) was stirred with sodium borohydride (Aldrich, 83 mg, 2.2 mmol) at room temperature for 16 hours.
  • Example 4B The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 6-chloronicotinoyl chloride (Aldrich).
  • Example 4B The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 2-fluoronicotinoyl chloride (Aldrich).
  • 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ 7.87 (m, 1H), 7.95 (m, 1H), 8.17 (m, 1H), 8.17 (m, 1H), 8.43 (m, 1H), 8.6 (m, 1H), 8.8 (m, 1H) ppm; MS (DCI/NH 3 ) m/z 267 (M+H) + .
  • Example 4B The title compound was prepared according to the procedure of Example 4B using 3-cyano-5-fluoro-N′-hydroxybenzimidamide (Prepared from 5-fluoroisophthalonitrile using the procedure described in Example 4A.) and nicotinoyl chloride (Aldrich).
  • 1 H NMR 300 MHz, DMSO-d 6 ) ⁇ 7.77 (m, 1H), 8.2 (m, 2H), 8.4 (m, 1H), 8.6 (m, 1H), 8.9 (m, 1H), 9.4 (m, 1H) ppm; MS (DCI/NH 3 ) m/z 267 (M+H) + .
  • Suitable pharmaceutically acceptable basic addition salts include, but are not limited to cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • esters include pharmaceutically acceptable amides and esters.
  • “Pharmaceutically acceptable ester” refers to those esters, which retain, upon hydrolysis of the ester bond, the biological effectiveness and properties of the carboxylic acid and are not biologically or otherwise undesirable.
  • esters are typically formed from the corresponding carboxylic acid and an alcohol.
  • ester formation can be accomplished via conventional synthetic techniques. (See, e.g., March Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York p.
  • the alcohol component of the ester will generally comprise (i) a C2-C12 aliphatic alcohol that can or can not contain one or more double bonds and can or can not contain branched carbons or (ii) a C7-C12 aromatic or heteroaromatic alcohols.
  • This invention also contemplates the use of those compositions, which are both esters as described herein, and at the same time are the pharmaceutically acceptable salts thereof.
  • “Pharmaceutically acceptable amide” refers to those amides, which retain, upon hydrolysis of the amide bond, the biological effectiveness and properties of the carboxylic acid and are not biologically or otherwise undesirable.
  • pharmaceutically acceptable amides as prodrugs, see Bundgaard, H., Ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam. These amides are typically formed from the corresponding carboxylic acid and an amine. Generally, amide formation can be accomplished via conventional synthetic techniques. (See, e.g., March Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New York, p. 1152 (1985) and Mark et al.
  • compositions which are amides, as described herein, and at the same time are the pharmaceutically acceptable salts thereof.
  • the compounds can be generated in vivo by administration of a drug precursor which, following administration, releases the drug in vivo via a chemical or physiological process (e.g., a parent compound on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
  • a chemical or physiological process e.g., a parent compound on being brought to the physiological pH or through enzyme action is converted to the desired drug form.
  • pain can be treated by concurrently administering to a patient (e.g., a mammal, such as a human) in need thereof, an ⁇ 4 ⁇ 2 PAM and an ⁇ 4 ⁇ 2 receptor ligand.
  • a patient e.g., a mammal, such as a human
  • an ⁇ 4 ⁇ 2 PAM and an ⁇ 4 ⁇ 2 receptor ligand may be especially useful in expanding the dosage range for obtaining therapeutically beneficial effects.
  • the term “concurrent administration” refers to administering the ⁇ 4 ⁇ 2 receptor ligand to a patient, who has been prescribed (or has consumed) at least one an ⁇ 4 ⁇ 2 PAM, at an appropriate time so that the patient's symptoms may subside. This may mean simultaneous administration of an ⁇ 4 ⁇ 2 PAM and an ⁇ 4 ⁇ 2 receptor ligand, or administration of the medications at different, but appropriate times. Establishing such a proper dosing schedule will be readily apparent to one skilled in the art, such as a physician treating various pain states.
  • the dosage range at which the ⁇ 4 ⁇ 2 PAM and an ⁇ 4 ⁇ 2 receptor ligand will be administered concurrently can vary widely.
  • the specific dosage will be chosen by the patient's physician taking into account the particular compounds chosen, the severity of the patient's illness, any other medical conditions or diseases the patient is suffering from, other drugs the patient is taking and their potential to cause an interaction or adverse event, the patient's previous response to medication, and other factors.
  • Suitable dosage ranges for the ⁇ 4 ⁇ 2 PAM are from about 0.0001 mg/kg to 100 mg/kg of body weight.
  • Suitable dosage ranges for the ⁇ 4 ⁇ 2 receptor ligand are from about 0.0001 mg/kg to 100 mg/kg of body weight.
  • the ⁇ 4 ⁇ 2 PAM and an ⁇ 4 ⁇ 2 receptor ligand should be administered concurrently in amounts that are effective to treat the patient's pain, cognitive disorder, or related condition.
  • the invention also is carried out by administering an ⁇ 4 ⁇ 2 PAM together with an ⁇ 4 ⁇ 2 receptor ligand in any manner which provides effective levels of the compounds in the body at the same time. Typically, the combination will be administered orally.
  • the invention is not limited to oral administration.
  • the invention should be construed to cover any route of administration that is appropriate for the medications involved and for the patient.
  • transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine. Injections may be appropriate for patients refusing their medication.
  • One of the drugs may be administered by one route, such as oral, and the others may be administered by the transdermal, percutaneous, intravenous, intramuscular, intranasal, or intrarectal route, in particular circumstances.
  • the route of administration may be varied in any way, limited by the physical properties of the drugs and the convenience of the patient and the caregiver.
  • Analgesics can be broadly categorized as non-opioid analgesics (acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs)), opioid analgesics (morphine) and adjuvant analgesics or co-analgesics (antiepileptic drugs and antidepressants).
  • NSAIDs non-opioid analgesics
  • opioid analgesics morphine
  • adjuvant analgesics or co-analgesics antiepileptic drugs and antidepressants
  • non-opioid analgesics are mostly used to relieve mild to moderate nociceptive pain
  • adjuvant analgesics (gabapentin, pregabalin) are used to relieve neuropathic pain
  • opioid analgesics are used to treat severe pain of all origins, depending on the dose prescribed.
  • Nicotinic acetylcholine receptor ligands act at multiple locations throughout the pain pathway to relieve pain. Nicotinic acetylcholine receptor ligands are found on primary sensory neurons (periphery) where nociceptive information is initiated, in the cell body regions of these neurons (i.e. the dorsal root ganglion or DRG), the dorsal spinal cord where the first pain synapse is located, in the brainstem cell body regions that control descending innervation, as well as in the higher brain regions that integrate and perceive sensory information such as the thalamus and the cortex.
  • nAChR ligands are mediated by activation of brain stem nuclei with descending inhibitory inputs to the spinal cord. Additional pathways may also mediate analgesic effects of nAChR agonists in persistent or neuropathic pain.
  • Another aspect of the invention is the potential to enhance efficacy of other medications used for treating pain when combined with an ⁇ 4 ⁇ 2 PAM.
  • examples of currently used drugs include opioids, gabapentin, pregabalin, duloxetine and others. Novel mechanisms such as cannabinoids, vanilloid receptor antagonists, calcium channel blockers and sodium channel blockers are also being developed for the treatment of pain. For many of these mechanisms, it is emerging that a component of efficacy may be driven by activation of descending inhibitory inputs.
  • opioid analgesics can block pain transmission, in part by increasing descending inhibitory pathways to modulate pain transmission at the spinal level (Pasternack, G. W., Clin Neuropaharmcol. 16: 1, 1993; Lauretti, G.
  • nAChR-mediated diseases or disorders also can benefit from such concurrent administration.
  • the combination of ⁇ 4 ⁇ 2 nAChR ligands and ⁇ 4 ⁇ 2 selective PAMs can be used for treatment of diseases or disorders related to the cholinergic system of the central nervous system, the peripheral nervous system, diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, and withdrawal symptoms caused by the termination of abuse of chemical substances, in for example nicotine, as well as pain.
  • the combination is useful for conditions and disorders related to attention deficit disorder, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD), schizophrenia, mild cognitive impairment, age-associated memory impairment (AAMI), senile dementia, AIDS dementia, Pick's Disease, dementia associated with Lewy bodies, dementia associated with Down's syndrome, schizophrenia, smoking cessation, substance abuse, amyotrophic lateral sclerosis, Huntington's disease, diminished CNS function associated with traumatic brain injury, acute pain, post-surgical pain, chronic pain, inflammatory pain, neuropathic pain, infertility, lack of circulation, need for new blood vessel growth associated with wound healing, more particularly circulation around a vascular occlusion, need for new blood vessel growth associated with vascularization of skin grafts, ischemia, inflammation, sepsis, wound healing, and other complications associated with diabetes, among other systemic and neuroimmunomodulatory activities.
  • the method is useful for conditions and disorders related to conditions and disorders characterized by neuropsychological and cognitive dysfunction, for example in Alzheimer'
  • one embodiment relates to a method of use for treating or preventing a condition or disorder characterized by attention or cognitive dysfunction, such as Alzheimer's disease and ADHD, among other condition and disorders.
  • the method comprises the step of administering a therapeutically effective amount of a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 positive allosteric modulator to a subject in need thereof in combination with a drug that improves cholinergic function.
  • a drug that improves cholinergic function are examples of such drugs.
  • Another method of use relates to treating or preventing a condition or disorder characterized by neuropsychological dysfunction, for example schizophrenia, wherein the method comprises the step of administering a therapeutically effective amount of a nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 positive allosteric modulator to a subject in need thereof in combination with an antipsychotic agent.
  • HEK 293 cells stably expressing human ⁇ 4 ⁇ 2 or ⁇ 3 ⁇ 4 combinations are grown to confluency in 162 cm 2 tissue culture flasks in DMEM media supplemented with 10% FBS and 25 ⁇ g/ml zeocin and 200 ⁇ g/ml hygromycin B.
  • IMR-32 neuroblastoma cells are grown to confluency in 162 cm 2 tissue culture flasks in minimum essential media supplemented with 10% FBS and 1 mM sodium pyruvate, 1% non-essential amino acids and 1% antibiotic-antimycotic.
  • the cells are then dissociated using cell dissociation buffer and 100-150 ⁇ l per well of 3.5 ⁇ 10 5 cells/ml cell suspension ( ⁇ 50,000-100,000 cells/well) was plated into 96-well black plates (poly-D-lysine precoated) with clear bottom and maintained for 24-48 hrs in a tissue culture incubator at 37° C. under an atmosphere of 5% CO 2 : 95% air.
  • Other clonal cell lines or primary cell cultures that express endogenous ⁇ 4* nicotinic receptors may also be used in this assay.
  • Calcium flux was measured using calcium-3 assay kit (Molecular Devices, Sunnyvale, Calif.) or fluo-4 (Invitrogen).
  • a stock solution of the dye was prepared by dissolving each vial supplied by the vendor in Hank's balanced salt solution buffer (HBSS) or 150 mM NMDG, 20 mM CaCl 2 containing 10 mM HEPES, The stock solution was diluted 1:20 using the same buffer before use.
  • the growth media was removed from the cells.
  • the cells were loaded with 100 ⁇ l of the dye per well and incubated at room temperature for up to one hour for HEK 293 clonal stable cell lines or 30 min-45 min at 37° C. for IMR-32 cells Fluorescence measurements were read simultaneously from all the wells by a Fluorometic Imaging Plate Reader (FLIPR) at an excitation wavelength of 480 nm and an emission wavelength of 520 nm.
  • FLIPR Fluorometic Imaging Plate Reader
  • Baseline fluorescence was measured for the first 6 seconds at which 3 ⁇ concentrations of modulator/test compounds were added to the cell plate at 50 ⁇ l and incubated for five minutes. The fluorescence intensity was captured every second for the first 1 minute followed by every 5 seconds for an additional 4 minutes. This procedure was followed by 50 ⁇ l of 4 ⁇ concentration of agonist and readings were taken for a period of 3-5 minutes as described above. Data was normalized to maximal responses and plotted as a function of concentration. The concentration dependence of changes fluorescence responses was fitted by nonlinear regression analysis (GraphPad Prism, San Diego, Calif.) to obtain EC 50 values.
  • the positive allosteric modulator effects on ⁇ 4 ⁇ 2 nAChRs exemplified by 3-(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1) and 3,5-di(pyridin-3-yl)-1,2,4-oxadiazole (Compound 2) can be identified by measuring their potentiating effect to fluorescence changes in intracellular calcium using a fluorimetric plate reader.
  • the potentiating effect of an ⁇ 4 ⁇ 2 modulator on ⁇ 4 ⁇ 2 receptor can also be illustrated by concentration responses to ⁇ 4 ⁇ 2 agonists, for example 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) and (3R)-1-pyridin-3-ylpyrrolidin-3-amine (Compound B), in presence of a fixed concentration of PAM. As shown in FIGS.
  • ⁇ 4 ⁇ 2 PAM 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile
  • FIGS. 1B and 2B the PAM is unable to affect the concentration responses to the agonists.
  • PAMs can selective enhance potency of the compound selectively at ⁇ 4 ⁇ 2, but not other (e.g. ⁇ 3 ⁇ 4) subtypes. This could lead to preferential effects of the agonist at the desired subtype, viz., ⁇ 4 ⁇ 2, without effects at other nicotinic receptor subtypes and thus enhancing in vivo selectivity of the agonist.
  • Table 1 lists the results for the compounds of the present invention.
  • the activity allosteric effects—potentiation of fluorescence responses) ranges are defined as follows; “a” denotes as activity range from 200-400%, “b” denotes an activity range from 150-200%, “c” denotes an activity range from 120-150% and “d” denotes an activity range 90-120%.
  • HEK-293 cells stably expressing human ⁇ 4 ⁇ 2 or ⁇ 3 ⁇ 4 are to confluency in 162 cm 2 tissue culture flasks in DMEM media supplemented with 10% FBS and 25 ⁇ g/ml zeocin and 200 ⁇ g/ml hygromycin B.
  • IMR-32 neuroblastoma cells are grown to confluency in 162 cm 2 tissue culture flasks in minimum essential media supplemented with 10% FBS and 1 mM sodium pyruvate, 1% non-essential amino acids and 1% antibiotic-antimycotic.
  • the cells are then dissociated using cell dissociation buffer and 100-150 ⁇ l per well of 3.5 ⁇ 10 5 cells/ml cell suspension ( ⁇ 50,000-100,000 cells/well) was plated into 96-well black plates (poly-D-lysine precoated) with clear bottom and maintained for 24-48 hrs in a tissue culture incubator at 37° C. under an atmosphere of 5% CO 2 : 95% air.
  • Other clonal cell lines or dissociated primary cortical neurons that express endogenous ⁇ 4* nicotinic receptors may also be used in this assay.
  • Calcium flux was measured using calcium-3 assay kit (Molecular Devices, Sunnyvale, Calif.) or fluo-4 (Invitrogen).
  • a stock solution of the dye was prepared by dissolving each vial supplied by the vendor in Hank's balanced salt solution buffer (HBSS) or 150 mM NMDG, 20 mM CaCl 2 containing 10 mM HEPES. The stock solution was diluted 1:20 using the same buffer before use. The growth media was removed from the cells. The cells were loaded with 100 ⁇ l of the dye per well and incubated at room temperature for up to one hour for HEK 293 clonal stable cell lines or 30 min-45 min at 37° C. for IMR-32 cells. Fluorescence measurements were read simultaneously from all the wells by a Fluorometic Imaging Plate Reader (FLIPR) at an excitation wavelength of 480 nm and an emission wavelength of 520 nm.
  • FLIPR Fluorometic Imaging Plate Reader
  • Baseline fluorescence was measured for the first 6 seconds at which 3 ⁇ concentrations of modulator/test compounds were added to the cell plate at 50 ⁇ l and incubated for five minutes. The fluorescence intensity was captured every second for the first 1 minute followed by every 5 seconds for an additional 4 minutes. This procedure was followed by 50 ⁇ l of 4 ⁇ concentration of agonist and readings were taken for a period of 3-5 minutes as described above. Data was normalized to maximal responses and plotted as a function of concentration. The concentration dependence of changes fluorescence responses was fitted by nonlinear regression analysis (GraphPad Prism, San Diego, Calif.) to obtain EC 50 values.
  • ⁇ 4 ⁇ 2 PAMs can also enhance the efficacy of partial agonists (compounds that bind, but activate ⁇ 4 ⁇ 2 nAChRs with low intrinsic efficacy leading to otherwise barely detectable effects on calcium responses).
  • partial agonists compounds that bind, but activate ⁇ 4 ⁇ 2 nAChRs with low intrinsic efficacy leading to otherwise barely detectable effects on calcium responses.
  • FIG. 3 responses to 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (Compound C) in the presence and absence of PAM is shown in FIG. 3 .
  • FIG. 5 shows a comparison of EC 50 values from calcium fluorescence (FLIPR) assays using ⁇ 4 ⁇ 2 nAChRs of several nicotinic agonists including varenicline and ispronicline in the presence and absence of positive allosteric modulator.
  • the potency (EC 50 values) of the nicotinic agonists increase in the presence of the positive allosteric modulator.
  • mice Male Sprague-Dawley rats (Charles River, Wilmington, Mass.) weighing 120-150 grams at time of surgery were utilized. These animals were group housed in AAALAC approved facilities at Abbott Laboratories in a temperature-regulated environment with lights on between 0700 and 2000 hours. Food and water was available ad libitum except during testing. All animal handling and experimental protocols were approved by an institutional animal care and use committee (IACUC). All experiments were performed during the light cycle.
  • IACUC institutional animal care and use committee
  • Compound 1 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, was prepared in 30% hydroxybetacyclodextrin and injected in solution in a volume of 4 ml/kg body weight immediately before Compound A.
  • the doses tested ranged from 0.3-30 ⁇ mol/kg i.p.
  • Tactile allodynia was measured using calibrated (force; g) von Frey filaments (Stoelting, Wood Dale, Ill.). Briefly, rats were placed into individual plexiglass containers and allowed to acclimate for 15-20 minutes before testing. Withdrawal threshold was determined by increasing and decreasing stimulus intensity and estimated using a Dixon non-parametric test (Chaplan et al., 1994; Chaplan S R, Bach F W, Pogrel J W, Chung J M and Yaksh T L (1994) J Neurosci Methods 53:55-63). Only rats with threshold scores ⁇ 4.5 g were considered allodynic and utilized in further testing.
  • a percent of maximal possible effect (% M.P.E.) of the tested compounds was calculated according to the formula: ([post-drug threshold]-[baseline threshold])/([maximum threshold]-[baseline threshold]) ⁇ 100%, where maximum threshold was equal to 15 g.
  • Compound A (0.03 ⁇ mol/kg, i.p.) produced weak but significant reversal of mechanical allodynia (PWT: 5.6 ⁇ 0.3 g, P ⁇ 0.001 vs. vehicle group).
  • Compound A+3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (Compound 1, PAM) produced a pronounced reversal of nerve injury-induced mechanical allodynia (PWT: 12.1 ⁇ 0.5 g) that was significantly different from vehicle (P ⁇ 0.001), but also from Compound A alone (P ⁇ 0.001) and 3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1, alone (P ⁇ 0.001).
  • FIG. 6B shows that the effects of PAM (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1) are dose-dependent.
  • An ineffective dose of Compound A (1 nmol/kg) when combined with varying doses of PAM (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1) results in dose-dependent increase in efficacy, approaching at least that of gabapentin, a drug clinically used for the treatment of neuropathic pain.
  • FIG. 7A shows dose dependent effects in neuropathic pain of 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, ⁇ 4 ⁇ 2 PAM (3-(3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, Compound 1) alone and a combination of Compound 1 (3.5 ⁇ mol/kg) with various doses of Compound A. (4 ⁇ 2 PAM (Compound 1) alone is ineffective, but is capable of left-shifting the dose response curve of Compound A in the Chung model of neuropathic pain.
  • Fasted male ferrets (Marshall BioResources, North Rose, N.Y.) weighing between 1.0 and 1.7 kg are used to determine the emetic effects.
  • ⁇ 4 ⁇ 2 PAM Compound 1 was administered first and thirty minutes later, Compound A was administered at various doses. After dosing, the animals were observed for emesis and behaviors characteristic of nausea for a period of 90 minutes. The percentage of animals that experienced emesis at a given dose was recorded.
  • FIG. 7B shows effects on emesis. Shown are effects of 5-[(2R)-azetidin-2-ylmethoxy]-2-chloropyridine (Compound A) alone, ⁇ 4 ⁇ 2 PAM (Compound 1) alone and a combination of Compound 1 (3.5 ⁇ mol/kg) with various doses of compound A. ⁇ 4 ⁇ 2 PAM (Compound 1) alone does not cause emesis, and does not shift the dose response curve of Compound A in the ferret model of emesis.
  • FIGS. 8A and 8B show plasma level analysis in models of neuropathic pain and emesis. Note the left ward shift in efficacy of Compound A in FIG. 8A , but no shift in effects on emesis in FIG. 8B . In other words, maximal efficacy of Compound A can be realized in neuropathic pain without incidence of emesis, in presence of ⁇ 4 ⁇ 2 PAM (Compound 1), thus widening the therapeutic window of ⁇ 4 ⁇ 2 nAChR agonists
  • FIG. 9 shows the efficacy of partial agonist, Compound D in the presence and absence of ⁇ 4 ⁇ 2 PAM (Compound 1). Compound D when administered alone is ineffective in relieving pain.
  • ⁇ 4 ⁇ 2 PAM Compound 1
  • Compound D when administered alone is ineffective in relieving pain.
  • PAM Compound 1 alone is ineffective (P+V).
  • the receptor interactions of positive allosteric modulators at ⁇ 4 ⁇ 2 nAChRs also can be evaluated according to the [ 3 H]-POB binding assay, which was performed as described below.
  • [ 3 H]-POB [ 3 H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile binding to a ⁇ 4 ⁇ 2 nAChR modulator site was determined using membrane enriched fractions from human cortex (ABS Inc., Wilmington, Del.). Pellets were thawed at 4° C., washed and resuspended with a Polytron at a setting of 7 in 30 volumes of BSS-Tris buffer (120 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 2 mM MgCl 2 , and 50 mM Tris-Cl, pH 7.4, 4° C.).
  • test compounds containing 100-200 ⁇ g of protein were incubated in a final volume of 500 ⁇ L for 75 minutes at 4° C. in duplicate.
  • Non-specific binding was determined in the presence of 30 ⁇ M 3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile.
  • Example 79A The compound of Example 79A was dissolved in a mixture of dichloromethane, triethylamine, and 5% palladium on carbon. The reaction solution was then saturated with tritium gas (1.2 Ci). The reaction mixture was stirred at room temperature for 3.5 hours, the catalyst was removed by filtration, ant the filtrate was concentrated to yield crude tritiated product. Further purification of the crude material by reverse-phase HPLC using a 30 minute 40% isocratic acetonitrile run (column LunaC18, 254 nm) to provide a total of 200 mCi (1 mL, MeOH).
  • the radiochemical purity of [ 3 H]-POB was found to be 99% and the specific activity was determined to be 16.4 Ci/mmol.
  • Nicotinic acetylcholine receptor ligands suitable for the invention exhibit K i values ranging about 1 nanomolar to about 10 micromolar when tested by the [ 3 H]-POB assay, many having a K i of less than 5 micromolar.
  • Compounds that modulate the function of ⁇ 4 ⁇ 2 nAChRs by altering the activity of the receptor or signaling are suitable for the composition. More specifically, the compounds that function as allosteric modulators enhancing the efficacy and/or potency of acetylcholine or a nicotinic agonist are desired. Multiple binding sites at ⁇ 4 ⁇ 2 nAChRs may exist for such compounds, of which only one site may be defined by [ 3 H]POB binding.
  • Ar 2 is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with 1, 2, 3, or 4 substituents selected from halo, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 5 -C 10 heteroaryl, C 4 -C 10 heterocycle, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)NHC(O)O—(C 1 -C 6 alkyl), C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkylcarbonyl, amino, hydroxyl, haloalkyl-C(O)—, haloalkyl-SO 2 —, alkyl-SO 2 —,
  • Ar 3 is monocyclic aryl or monocyclic heteroaryl, wherein the aryl or heteroaryl is substituted or unsubstituted, and, when substituted, the aryl or heteroaryl is substituted with a substituent selected from halo, C 1 -C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 5 -C 10 heteroaryl, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, amino, hydroxyl, haloalkyl-SO 2 —, cyano, nitro, C 1 -C 6 acylamino, C 1 -C 6 alkoxy, —N(C 1 -C 6 alkyl) 2 , and carboxy;
  • a particular radiolabelled compound of formula (II*) is [ 3 H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazol-3-yl)benzonitrile.
  • Such compounds are suitable for use in determining the binding affinity of nicotinic acetylcholine receptor subtype ⁇ 4 ⁇ 2 positive allosteric modulators.
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