US20090325973A1 - Formulations containing pyridazine compounds - Google Patents

Formulations containing pyridazine compounds Download PDF

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US20090325973A1
US20090325973A1 US12/298,652 US29865207A US2009325973A1 US 20090325973 A1 US20090325973 A1 US 20090325973A1 US 29865207 A US29865207 A US 29865207A US 2009325973 A1 US2009325973 A1 US 2009325973A1
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compound
alkyl
aryl
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heteroaryl
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D. Martin Watterson
Linda Van Eldik
Wenhui Hu
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Northwestern University
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Assigned to NORTHWESTERN UNIVERSITY reassignment NORTHWESTERN UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HU, WENHUI, VAN ELDIK, LINDA, WATTERSON, D. MARTIN
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
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Definitions

  • the invention relates to chemical compounds, compositions and methods of making and using the same.
  • the invention provides selected pyridazine compounds, compositions comprising the compounds, and methods of using the compounds and compositions for modulation of cellular pathways, for treatment or prevention of inflammatory diseases, for treatment or prevention of neurological conditions, for research, drug screening, and therapeutic applications.
  • Neuroinflammation is recognized as a prominent feature in the pathology of many neurological conditions and diseases. Neuroinflammation is a process that results primarily from abnormally high or chronic activation of glia (microglia and astrocytes). This overactive state of glia results in increased levels of inflammatory and oxidative stress molecules, which can lead to neuron damage or death. Neuronal damage or death can also induce glial activation, facilitating the propagation of a localized, detrimental cycle of neuroinflammation (Griffin, W S T et al, Brain Pathol 8: 65-72, 1998).
  • the inflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to treat inflammatory disease.
  • most anti-inflammatory therapeutics developed to date are palliative and provide minimal, short-lived, symptomatic relief with limited effects on inflammatory disease progression.
  • the present invention provides certain pyridazine compounds, compositions comprising the compounds, and methods of using the compounds and compositions for modulation of cellular pathways (e.g., signal transduction pathways), for treatment or prevention of inflammatory diseases, for treatment or prevention of neurological diseases and conditions, for research, drug screening, and therapeutic applications.
  • the invention generally provides dosage forms, formulations and methods that provide lower risk of side effects and/or produce beneficial pharmacokinetic profiles, in particular in neuroinflammatory diseases.
  • compositions in particular a formulation or dosage form, effective to provide lower risk of side effects and/or a beneficial pharmacokinetic profile following treatment comprising a compound of the formula I:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfate, sulfenyl, sulfinyl, sulfonyl, sulfonate, sulfoxide, silyl, silyloxy, silylalky
  • a compound of the formula I wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ⁇ O, ⁇ S, phosphonate, carboxyl, carbonyl, carbamoyl, or carboxamide; and X is
  • composition, formulation or dosage form which is effective to provide lower risk of side effects and/or a beneficial pharmacokinetic profile following treatment comprising a compound of the formula II:
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfenyl, sulfinyl, sulfonyl, sulfonate, sulfate, sulfoxide, silyl, silyl
  • a compound of the formula II wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ⁇ O, ⁇ S, carboxyl, carbonyl, carbamoyl, or carboxamide;
  • R 1 in a compound of the formula I or II is substituted or unsubstituted alkyl, cyclohexyl, aryl, arylalkoxy, aroyl, or heteroaryl.
  • R 1 in a compound of the formula I or II is substituted or unsubstituted aryl, arylalkoxy, aroyl, or heteroaryl.
  • R 1 in a compound of the formula I or II is:
  • R 15 , R 16 and R 17 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfonate, silyl, silyloxy, silylalkyl, silylthio, ⁇ O, ⁇ S, phosphonate, ureido, carboxyl,
  • compositions in particular a formulation or dosage form, effective to provide lower risk of side effects and/or a beneficial pharmacokinetic profile following treatment comprising an amount of a compound of the formula III:
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfon
  • R 4 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 in a compound of the formula III cannot all be hydrogen.
  • the invention relates to compounds of the formula I, II or III disclosed herein, in particular pure or substantially pure compounds of the formula I, II or III.
  • the invention also contemplates utilizing in compositions and methods of the invention a compound in FIG. 1 , in particular MW01-4-179LKM, MW01-7-084WH, MW01-7-085WH, MW01-7-133WH, MW01-2-151SRM, MW01-5-188WH or MW01-7-057, or isomers, pharmaceutically acceptable salts or derivatives thereof.
  • a composition of the invention in particular a formulation or dosage form, may be further characterized by its ability to selectively reduce or block up-regulation of IL-1 ⁇ and S100B, and/or reduce or prevent loss of PSD-95 and/or synaptophysin.
  • composition of the invention in particular a formulation or dosage form, may provide a lower risk of QT-related side effects.
  • the invention further provides a composition, in particular a formulation or dosage form, comprising a compound of the formula I, II or III in a therapeutically effective amount to treat a disease disclosed herein while reducing inhibitory activity at hERG potassium channel.
  • the invention provides a composition, in particular a formulation or dosage form, comprising a compound of the formula I, II or III in a therapeutically effective amount to treat a disease disclosed herein while reducing hERG inhibition.
  • the invention provides a composition, in particular a formulation or dosage form, comprising a compound of the formula I, II or III in a therapeutically effective amount to treat a disease disclosed herein in a subject receiving a therapeutic or treatment that prolongs QT interval.
  • the invention contemplates a formulation for the treatment of a disease disclosed herein comprising a therapeutically effective amount of a compound of the formula I, II or III, to provide a beneficial pharmacokinetic profile, in particular a sustained pharmacokinetic profile, in a pharmaceutically acceptable carrier, excipient, or vehicle.
  • a formulation comprising a compound of the formula I, II or III is provided which is in a form or which has been adapted for administration to a subject to provide a beneficial pharmacokinetic profile to treat a disease disclosed herein.
  • a dosage form such that administration of the dosage form to a subject suffering from a disease disclosed herein provides a beneficial pharmacokinetic profile resulting in therapeutic effects including selectively reducing or blocking up-regulation of IL-1 ⁇ and S100B, and/or reducing or preventing loss of PSD-95 and/or synaptophysin over a dosing period.
  • the composition is in a form adapted to provide a beneficial pharmacokinetic profile that results in one or more of the following in a subject for a sustained time over a dosing period: selective reduction of up-regulation of IL-1 ⁇ and S100B, and/or reduction of loss of PSD-95 and/or synaptophysin.
  • the invention relates to a dosage form comprising amounts of a compound of the formula I, II or III suitable for administration to a subject to provide effective concentrations of the compound in an environment of use or an effective dose that results in therapeutic effects in the prevention, treatment, or control of symptoms of a disease disclosed herein, in particular a neuroinflammatory disease.
  • the environment of use is the brain or plasma.
  • the invention is directed to a formulation or dosage form suitable for once, twice- or three-times a day administration to treat a disease disclosed herein comprising one or more compound of the formula I, II or III in an amount effective to provide lower risk of side effects and/or a beneficial pharmacokinetic profile in a dosing period.
  • the invention contemplates a dosage form comprising one or more compound of the formula I, II or III in an amount effective to maintain the compound within an effective plasma and/or brain drug concentration that results in therapeutic effects in the subject.
  • the invention additionally relates to a method of preparing a stable formulation or dosage form of a compound of the formula I, II or III adapted to provide lower risks of side effects and/or beneficial pharmacokinetic profiles following treatment.
  • Formulations may be placed in an appropriate container and labelled for treatment of an indicated disease.
  • labelling would include amount, frequency, and method of administration.
  • the invention also provides methods to make commercially available formulations which contain a compound of the formula I, II or III that provides lower risk of side effects and/or a beneficial pharmacokinetic profile in the treatment of a disease disclosed herein.
  • the invention relates to the use of at least one compound of the formula I, II or III for the preparation of a medicament for providing lower risks of side effects and/or a beneficial pharmacokinetic profile in treating a disease disclosed herein.
  • the invention additionally relates to uses of a pharmaceutical composition of the invention in the preparation of medicaments for providing lower risks of side effects and/or a beneficial pharmacokinetic profile in the prevention and/or treatment of a disease disclosed herein.
  • formulations or medicaments may be pills, tablets, caplets, soft and hard gelatin capsules, lozenges, sachets, cachets, vegicaps, liquid drops, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) suppositories, sterile injectable solutions, and/or sterile packaged powders, which contain a compound of the formula I, II or III.
  • Compounds of the formula I, II or III and compositions of the invention may be administered therapeutically or prophylactically to treat a disease disclosed herein, in particular neuroinflammatory disease. Therefore the invention provides a method for treating a disease disclosed herein, in particular a neuroinflammatory disease, comprising administering a therapeutically effective amount or prophylactically effective amount of a compound of the formula I, II or III. In an aspect, the invention provides a method for treating a disease disclosed herein in particular a neuroinflammatory disease comprising administering a compound of the formula I, II or III in an amount effective to lower risks of side effects and/or provide a beneficial pharmacokinetic profile.
  • a method for treating a disease disclosed herein, in particular a neuroinflammatory disease comprising administering a compound of the formula I, II or III in an amount effective to selectively inhibit up-regulation of IL-1 ⁇ and S100B, reduce or prevent loss of PSD-95 and/or synaptophysin, and/or prevent behavioral deficit.
  • aspects of the invention provide methods for treating a disease disclosed herein, in particular a neuroinflammatory disease, comprising administering to a subject a compound of the formula I, II or III in an amount effective to lower risk of QT-related side effects in the subject. Certain aspects of the invention provide methods for treating a disease disclosed herein, in particular a neuroinflammatory disease, comprising administering to a subject a therapeutically effective amount of a compound of the formula I, II or III to treat the disease while reducing inhibitory activity at hERG potassium channel.
  • aspects of the invention provide methods for treating a disease disclosed herein, in particular a neuroinflammatory disease, comprising administering to a subject a therapeutically effective amount of a compound of the formula I, II or III to treat the disease while reducing hERG inhibition.
  • Further aspects of the invention provide methods for treating a disease disclosed herein in a subject suffering from a disease disclosed herein and receiving a therapeutic or treatment that prolongs QT interval comprising administering to the subject a therapeutically effective amount of a compound of the formula I to reduce the QT-related side effects.
  • the invention also provides a method for treating and/or preventing a disease disclosed herein in a subject comprising administering to the subject one or more, in particular two, three or four dosages of a formulation comprising one or more compound of the formula I, II or III in an amount effective to maintain the compound within the effective brain and/or plasma drug concentration that results in therapeutic effects in the subject.
  • a method for treating in a subject a disease involving or characterized by inflammation, in particular neuroinflammation comprising administering to the subject a compound of the formula I, II or III in a therapeutically effective amount that provides beneficial pharmacokinetic profiles, in a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the invention provides a method involving administering to a subject a therapeutic compound of the formula I, II or III or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of the formula I, II or III and a pharmaceutically acceptable carrier, excipient, or vehicle which inhibit or reduce neuroflammation, activation of glia, activation of astrocytes, activation of microglia, proimflammatory cytokines, oxidative stress-related enzymes, acute phase proteins and/or components of the complement cascade, and provide lower risk of QT-related side effects and/or a beneficial pharmacokinetic profile.
  • the invention also provides a kit comprising one or more compound of the formula I, II or III, or a composition of the invention adapted to provide lower risk of side effects and/or a beneficial pharmacokinetic profile.
  • the invention provides a kit for preventing and/or treating a disorder and/or disease disclosed herein, comprising a formulation or dosage form of the invention, a container, and instructions for use.
  • FIG. 1 shows the structures of MW01-2-151SRM, MW01-6-189WH, MW01-7-107WH, MW01-4-179LKM, MW01-7-084WH, MW01-7-085WH, MW01-7-133WH, and MW01-7-057.
  • FIG. 2 depicts a synthetic scheme for MW01-3-183WH.
  • FIG. 3 depicts a synthetic scheme for MW01-2-151SRM.
  • FIG. 4 depicts a synthetic scheme for MW01-2-151SRM.
  • FIG. 5 depicts a synthetic scheme for MW01-2-151SRM.
  • FIG. 6 depicts a synthetic scheme for MW01-2-151SRM.
  • FIG. 7 depicts a synthetic scheme for MW01-5-188WH.
  • FIG. 8 depicts a synthetic scheme for MW01-5-188WH.
  • FIG. 9 depicts a synthetic scheme for MW01-5-188WH.
  • FIGS. 10A and 10B depict synthetic schemes for MW01-6-189WH
  • FIG. 11 depicts a synthetic scheme for MW01-7-084WH.
  • FIG. 12 depicts a synthetic scheme for MW01-7-085WH.
  • FIG. 13 depicts a synthetic scheme for MW01-7-133WH.
  • FIG. 14 depicts a synthetic scheme for MW01-7-107WH.
  • FIG. 15 depicts a synthetic scheme for MW01-7-057.
  • FIG. 16 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-151SRM.
  • A Concentration dependent inhibition by MW01-5-151SRM of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-1151SRM at concentrations up to 33 ⁇ M.
  • C MW01-5-1151SRM does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 17 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-189WH.
  • A Concentration dependent inhibition by MW01-5-189WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-189WH at concentrations up to 33 ⁇ M.
  • C MW01-5-189WH does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 18 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-107WH.
  • A Concentration dependent inhibition by MW01-5-107WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was inhibited by MW01-5-107WH.
  • C MW01-5-107WH also inhibited LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 19 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-179WH.
  • A Concentration dependent inhibition by MW01-5-179WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-179WH at concentrations up to 33 ⁇ M.
  • C MW01-5-179WH does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 20 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-084WH.
  • A Concentration dependent inhibition by MW01-5-084WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-084WH at concentrations up to 33 ⁇ M.
  • C MW01-5-084WH does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 21 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-085WH.
  • A Concentration dependent inhibition by MW01-5-085WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-085WH at concentrations up to 33 ⁇ M.
  • C MW01-5-085WH does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 22 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-0133WH.
  • A Concentration dependent inhibition by MW01-5-133WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-133WH at concentrations up to 33 ⁇ M.
  • C MW01-5-133WH does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 23 show graphs and micrographs illustrating proinflammatory cytokine production by MW01-5-057WH.
  • A Concentration dependent inhibition by MW01-5-057WH of LPS-induced increases of IL-1 ⁇ in the BV2 microglial cell line.
  • B LPS-stimulated accumulation of the NO metabolite, nitrite, was not inhibited by MW01-5-057WH at concentrations up to 33 ⁇ M.
  • C MW01-5-057WH does not suppress LPS-induced production of iNOS or COX-2 in activated BV-2 cells.
  • FIG. 24 A-H shows graphs illustrating in vivo activity of MW01-2-151SRM in the A ⁇ infusion mouse model. Graphs are of MW01-2-151SRM suppression of A ⁇ -induced neuroinflammation and synaptic damage and activity in the Y-maze.
  • Hippocampal sections or extracts from vehicle-infused mice (control), A ⁇ -infused mice injected with solvent, and A ⁇ -infused mice injected with MW01-2-151SRM were evaluated for neuroinflammation by measurement of the levels of the pro-inflammatory cytokines IL-1 ⁇ (A), TNF ⁇ (B), and S100B (C), and the number of GFAP-positive astrocytes (D), F4/80 (E), the presynaptic marker, synaptophysin (F), and evaluated for synaptic damage by analysis of the levels of the post-synaptic density protein 95 (PSD-95) (G), and Y-maze (H).
  • Data are from one of two independent experiments, and are the mean ⁇ SEM for 4-5 mice per experimental group.
  • FIG. 25 A-E shows graphs illustrating in vivo activity of MW01-2-189SRM in the A ⁇ infusion mouse model. Graphs are of MW01-2-189SRM suppression of A ⁇ -induced neuroinflammation and synaptic damage and activity in the Y-maze.
  • Hippocampal sections or extracts from vehicle-infused mice (control), A ⁇ -infused mice injected with solvent, and A ⁇ -infused mice injected with MW01-2-189SRM were evaluated for neuroinflammation by measurement of the levels of the pro-inflammatory cytokines IL-1 ⁇ (A), and S100B (B), the presynaptic marker, synaptophysin (C), and evaluated for synaptic damage by analysis of the levels of the post-synaptic density protein 95 (PSD-95) (D), and Y-maze (E).
  • Data are from three samples in the MW01-2-189SRM were analyzed.
  • FIG. 26 A-E shows graphs illustrating in vivo activity of MW01-2-084SRM in the A ⁇ infusion mouse model. Graphs are of MW01-2-084SRM suppression of A ⁇ -induced neuroinflammation and synaptic damage and activity in the Y-maze.
  • Hippocampal sections or extracts from vehicle-infused mice (control), A ⁇ -infused mice injected with solvent, and A ⁇ -infused mice injected with MW01-2-084SRM were evaluated for neuroinflammation by measurement of the levels of the pro-inflammatory cytokines IL-1 ⁇ (A), and S100B (B), the presynaptic marker, synaptophysin (C), and evaluated for synaptic damage by analysis of the levels of the post-synaptic density protein 95 (PSD-95) (D), and Y-maze (E). Data are from five samples per group analyzed.
  • FIG. 27 A-E shows graphs illustrating in vivo activity of MW01-2-085SRM in the A ⁇ infusion mouse model. Graphs are of MW01-2-085SRM suppression of A ⁇ -induced neuroinflammation and synaptic damage and activity in the Y-maze.
  • Hippocampal sections or extracts from vehicle-infused mice (control), A ⁇ -infused mice injected with solvent, and A ⁇ -infused mice injected with MW01-2-085SRM were evaluated for neuroinflammation by measurement of the levels of the pro-inflammatory cytokines IL-1 ⁇ (A), and S100B (B), the presynaptic marker, synaptophysin (C), and evaluated for synaptic damage by analysis of the levels of the post-synaptic density protein 95 (PSD-95) (D), and Y-maze (E).
  • Data are from three samples in the MW01-2-085SRM were analyzed.
  • FIG. 28 A-E shows graphs illustrating in vivo activity of MW01-2-057WH in the A ⁇ infusion mouse model. Graphs are of MW01-2-057WH suppression of A ⁇ -induced neuroinflammation and synaptic damage and activity in the Y-maze.
  • Hippocampal sections or extracts from vehicle-infused mice (control), A ⁇ -infused mice injected with solvent, and A ⁇ -infused mice injected with MW01-2-057WH were evaluated for neuroinflammation by measurement of the levels of the pro-inflammatory cytokines IL-1 ⁇ (A), and S100B (B), the presynaptic marker, synaptophysin (C), and evaluated for synaptic damage by analysis of the levels of the post-synaptic density protein 95 (PSD-95) (D), and Y-maze (E).
  • PSD-95 post-synaptic density protein 95
  • E Y-maze
  • FIG. 29 is a graph showing QTc interval of MW01-2-151SRM (15 mg/10 ml/kg/po) (Bazett's). Changes in QTc following oral administration of MW01-2-151SRM at 15 mg/kg in guinea pigs. QT intervals were corrected for heart rate changes using Bazett's formula. The broken lines represent 95% confidence limits (mean ⁇ 2SD) for QTc changes in the vehicle (2% Tween 80 in Distilled Water)-treated control. The five treated animals are represented by individual symbols.
  • FIG. 30 is a graph showing QTc interval of Sotalol (0.3 mg/kg/iv) (Bazett's). Changes in QTc following intravenous administration of Sotalol at 0.3 mg/kg in guinea pigs. QT intervals were corrected for heart rate changes using Bazett's formula. The broken lines represent 95% confidence limits (mean ⁇ 2SD) for QTc changes in the vehicle (0.9% NaCl)-treated control. The five treated animals are represented by individual symbols.
  • FIG. 31 is a graph showing QTc interval of MW01-2-151SRM (15 mg/10 ml/kg/po) (Fredericia's). Changes in QTc following oral administration of MW01-2-151SRM at 15 mg/kg in guinea pigs. QT intervals were corrected for heart rate changes using Federicia's formula. The broken lines represent 95% confidence limits (mean ⁇ 2SD) for QTc changes in the vehicle (2% Tween 80 in Distilled Water)-treated control. The five treated animals are represented by individual symbols.
  • FIG. 32 is a graph showing QTc interval of Sotalol (0.3 mg/kg/iv) (Fredericia's). Changes in QTc following intravenous administration of Sotalol at 0.3 mg/kg ⁇ in guinea pigs. QT intervals were corrected for heart rate changes using Fredericia's formula. The broken lines represent 95% confidence limits (mean ⁇ 2SD) for QTc changes in the vehicle (0.9% NaCl)-treated control. The five treated animals are represented by individual symbols.
  • FIG. 33 is a graph showing QTc interval of oral administration of MW01-5-188WH (15 mg/kg p.o.) in guinea pig.
  • FIG. 34 are graphs of results of liver toxicity studies with MW01-5-188WH, MW01-2-151SRM, and MW01-6-189WH.
  • Compounds were administered to C57Bl/6 mice by oral gavage (2.5 mg/kg/day, once daily for 2 weeks). Histological liver toxicity was assessed by examination of tissue architecture, cell necrosis, and inflammatory infiltrate. The scoring scale ranges from 0 (best) to 9 (worst).
  • MW01-5-188WH, MW01-2-151SRM, and MW01-6-189 show no significant differences in liver toxicity score from the control mice receiving either no gavage or vehicle gavage.
  • FIG. 35 shows that MW01-5-188WH is readily detected in the plasma and the brain after a single oral dose administration and does not suppress peripheral tissue inflammatory responses or cause liver injury after chronic oral administration.
  • C57BL/6 mice were administered MW01-5-188WH (2.5 mg/kg) by oral gavage, blood and brain processed at different times after administration, and compound levels in plasma and brain determined as described herein.
  • MW01-5-188WH rapidly appears in plasma (A) and brain (B), reaches a peak at 15 min, and then slowly declines to basal levels by 120 min.
  • Data are the mean_SEM from three to six mice at each time point.
  • MW01-5-188WH does not inhibit increased production of IL-1 ⁇ (C) and TNF- ⁇ (D) in the serum but does suppress the cytokine response in the brains from the same mice (E, F).
  • FIG. 36 are graphs of stability data using human (A, B) and rat (C, D) microsomes with MW01-2-151SRM in two different amounts, for two time periods.
  • E and F show human (E) and (F) rat microsomes with MW01-2-151SRM stability for different time periods compared to minaprine.
  • FIG. 37 shows a synthetic scheme for synthesis of compounds of the formula I where R 11 is benzyl, 4-pyridyl, iso-butyl, or methyl.
  • Reagents and conditions a) PhCH 2 NH 2 NH 2 , CH 3 COONa, ethanol, reflux, 29 h; b) POCl 3 , PCL 5 , 120° C., 12 h; c) CH 3 COOH, reflux, 5 h; d) 1-(2-pyrimidyl)piperazine, 1-butanol, 130° C., 41 h; e) POCl 3 , 100° C., 3 h; f) boronic acid, Pd(0).
  • FIG. 38 shows a synthetic scheme for synthesis of compounds of the formula I where R 1 is methyl.
  • FIG. 39 shows a synthetic scheme for synthesis of pyrazine analogs of the invention. a) NaOH, ⁇ 41° C., MeOH; b) Tf 2 O, DMAP, Pyridine, rt; c) 1-(2-pyrimidyl)piperazine, DMSO, 60° C.
  • Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers and fractions thereof are presumed to be modified by the term “about.” The term “about” means plus or minus 0.1 to 50%, 5-50%, or 10-40%, preferably 10-20%, more preferably 10% or 15%, of the number to which reference is being made. Further, it is to be understood that “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a composition comprising “a compound” includes a mixture of two or more compounds.
  • administering and “administration” refer to a process by which a therapeutically effective amount of a compound of the formula I, II or III or composition contemplated herein is delivered to a subject for prevention and/or treatment purposes.
  • Compositions are administered in accordance with good medical practices taking into account the subject's clinical condition, the site and method of administration, dosage, patient age, sex, body weight, and other factors known to physicians.
  • co-administration refers to the administration of at least two compounds or agent(s) or therapies to a subject.
  • the co-administration of two or more agents/therapies is concurrent.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • each component may be administered separately, but sufficiently close in time to provide the desired effect, in particular a beneficial, additive, or synergistic effect.
  • formulations and/or routes of administration of the various agents/therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art.
  • agents/therapies when agents/therapies are co-administered, the respective agents/therapies are administered at lower dosages than appropriate for their administration alone.
  • co-administration is especially desirable in embodiments where the co-administration of the agents/therapies lowers the requisite dosage of a known potentially harmful (e.g., toxic) agent(s).
  • treating refers to reversing, alleviating, or inhibiting the progress of a disease, or one or more symptoms of such disease, to which such term applies.
  • the term also refers to preventing a disease, and includes preventing the onset of a disease, or preventing the symptoms associated with a disease.
  • a treatment may be either performed in an acute or chronic way.
  • the term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease.
  • Such prevention or reduction of the severity of a disease prior to affliction refers to administration of a compound or composition of the present invention to a subject that is not at the time of administration afflicted with the disease.
  • Preventing also refers to preventing the recurrence of a disease or of one or more symptoms associated with such disease.
  • Treatment and “therapeutically,” refer to the act of treating, as “treating” is defined above. The purpose of prevention and intervention is to combat the disease, condition, or disorder and includes the administration of an active compound to prevent or delay the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • subject refers to an animal preferably a warm-blooded animal such as a mammal.
  • Mammal includes without limitation any members of the Mammalia.
  • a mammal, as a subject or patient in the present disclosure, can be from the family of Primates, Carnivora, Proboscidea, Perissodactyla, Artiodactyla, Rodentia, and Lagomorpha.
  • a mammal of the present invention can be Canis familiaris (dog), Felis catus (cat), Elephas maximus (elephant), Equus caballus (horse), Sus domesticus (pig), Camelus dromedarious (camel), Cervus axis (deer), Giraffa camelopardalis (giraffe), Bos taurus (cattle/cows), Capra hircus (goat), Ovis aries (sheep), Mus musculus (mouse), Lepus brachyurus (rabbit), Mesocricetus auratus (hamster), Cavia porcellus (guinea pig), Meriones unguiculatus (gerbil), or Homo sapiens (human).
  • the mammal is a human.
  • animals can be treated; the animals can be vertebrates, including both birds and mammals.
  • the terms include domestic animals bred for food or as pets, including equines, bovines, sheep, poultry, fish, porcines, canines, felines, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice.
  • Typical subjects for treatment include persons afflicted with or suspected of having or being pre-disposed to a disease disclosed herein, or persons susceptible to, suffering from or that have suffered a disease disclosed herein.
  • a subject may or may not have a genetic predisposition for a disease disclosed herein.
  • the term “subject” generally refers to an individual who will receive or who has received treatment (e.g., administration of a compound of the formula I, II or III, and optionally one or more other agents) for a condition characterized by inflammation, the dysregulation of protein kinase activity, and/or dysregulation of apototic processes.
  • a subject may be a healthy subject.
  • a subject shows signs of cognitive deficits and Alzheimer's disease neuropathology.
  • the subjects are suspectible to, or suffer from Alzheimer's disease.
  • the term “healthy subject” means a subject, in particular a mammal, having no diagnosed disease, disorder, infirmity, or ailment, more particularly a disease, disorder, infirmity or ailment known to impair or otherwise diminish memory.
  • diagnosis refers to the recognition of a disease by its signs and symptoms (e.g., resistance to conventional therapies), or genetic analysis, pathological analysis, histological analysis, and the like.
  • the term “modulate” refers to the activity of a compound (e.g., a compound of the formula I, II or III) to affect (e.g., to promote or retard) an aspect of cellular function, including, but not limited to, cell growth, proliferation, apoptosis, and the like.
  • a compound e.g., a compound of the formula I, II or III
  • affect e.g., to promote or retard an aspect of cellular function, including, but not limited to, cell growth, proliferation, apoptosis, and the like.
  • “Therapeutically effective amount” relates to the amount or dose of an active compound of the formula I, II or III or composition comprising the same, that will lead to one or more desired effects, in particular, one or more therapeutic effects or beneficial pharmacokinetic profiles.
  • a therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject.
  • a dosage regimen may be adjusted to provide the optimum therapeutic response or pharmacokinetic profile. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • the term “beneficial pharmacokinetic profile” refers to amounts or doses of a compound of the formula I, II or III that provide levels of the compound in plasma and/or brain or a required dose resulting in therapeutic effects in the prevention, treatment, or control of symptoms of a disease disclosed herein, in particular a neuroinflammatory disease, more particularly Alzheimer's disease.
  • the term “sustained pharmacokinetic profile” as used herein refers to a length of time efficacious levels of a biologically active compound of the formula I, II or III is in its environment of use.
  • a sustained pharmacokinetic profile can be such that a single or twice daily administration adequately prevents, treats, or controls symptoms of a disease disclosed herein.
  • a beneficial pharmacokinetic profile may provide therapeutically effective amounts of the compound of the formula I, II or III in the plasma and/or brain for about 12 to about 48 hours, 12 hours to about 36 hours, or 12 hours to about 24 hours.
  • a “therapeutic effect” refers to an effect of a composition, in particular a formulation or dosage form, or method disclosed herein, including improved biological activity, efficacy, and/or lower risk of side effects (e.g., lower risk of QT-related side effects).
  • a therapeutic effect may be a sustained therapeutic effect that correlates with a continuous plasma and/or brain concentration of a compound of the formula I, II or III over a dosing period, in particular a sustained dosing period.
  • a therapeutic effect may be a statistically significant effect in terms of statistical analysis of an effect of a compound of the formula I, II or III versus the effects without the compound.
  • “Statistically significant” or “significantly different” effects or levels may represent levels that are higher or lower than a standard. In aspects of the invention, the difference may be 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or 50 times higher or lower compared with the effect obtained without a compound of the formula I, II or III.
  • therapeutic effects of a compound or composition or treatment of the invention can manifest as one, two, three, four, five, six, seven, eight, or all of the following, in particular five or more, more particularly seven or more of the following:
  • therapeutic effects of compounds, compositions or treatments of the invention can manifest as (a) and (b); (a), (b) and (c); (a) through (d); (a) through (e); (a) through (f); (a) through (g); (a) through (h); (a) through (i), (a) through (j), and (a) through (k), (a) through (l), (a) through (m), or (a) through (n).
  • pharmaceutically acceptable carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
  • a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular composition.
  • carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art.
  • the compounds of the formula I, II or III disclosed herein also include “pharmaceutically acceptable salt(s)”.
  • pharmaceutically acceptable salts are meant those salts which are suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are described for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66:1.
  • Suitable salts include salts that may be formed where acidic protons in the compounds are capable of reacting with inorganic or organic bases.
  • Suitable inorganic salts include those formed with alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum.
  • Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Suitable salts also include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benezenesulfonic acid). When there are two acidic groups present, a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.
  • organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • Suitable salts also include
  • a compound of the formula I, II or III can contain one or more asymmetric centers and may give rise to enantiomers, diasteriomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.
  • compounds of the formula I, II or III include all possible diasteriomers and enantiomers as well as their racemic and optically pure forms.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • a compound of the formula I, II or III contains centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and A geometric isomers. All tautomeric forms are also included within the scope of a compound of the formula I, II or III.
  • a compound of the formula I, II or III includes crystalline forms which may exist as polymorphs. Solvates of the compounds formed with water or common organic solvents are also intended to be encompassed within the term. In addition, hydrate forms of the compounds and their salts are encompassed within this invention. Further prodrugs of compounds of the formula I, II or III are encompassed within the term.
  • solvate means a physical association of a compound with one or more solvent molecules or a complex of variable stoichiometry formed by a solute (for example, a compound of the invention) and a solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, the solvents selected do not interfere with the biological activity of the solute. Solvates encompass both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, methanolates, and the like.
  • hydrate means a solvate wherein the solvent molecule(s) is/are H 2 O, including, mono-, di-, and various poly-hydrates thereof. Solvates can be formed using various methods known in the art.
  • Crystalline compounds of the formula I, II or III can be in the form of a free base, a salt, or a co-crystal. Free base compounds can be crystallized in the presence of an appropriate solvent in order to form a solvate. Acid salt compounds of the formula I, II or III (e.g. HCl, HBr, benzoic acid) can also be used in the preparation of solvates. For example, solvates can be formed by the use of acetic acid or ethyl acetate. The solvate molecules can form crystal structures via hydrogen bonding, van der Waals forces, or dispersion forces, or a combination of any two or all three forces.
  • Acid salt compounds of the formula I, II or III e.g. HCl, HBr, benzoic acid
  • solvates can be formed by the use of acetic acid or ethyl acetate.
  • the solvate molecules can form crystal structures via hydrogen bonding, van der Waals forces, or dispersion forces, or a combination
  • the amount of solvent used to make solvates can be determined by routine testing. For example, a monohydrate of a compound of the formula I, II or III would have about 1 equivalent of solvent (H 2 O) for each equivalent of a compound of the invention. However, more or less solvent may be used depending on the choice of solvate desired.
  • Compounds of the formula I, II or III may be amorphous or may have different crystalline polymorphs, possibly existing in different solvation or hydration states.
  • crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility.
  • prodrug means a covalently-bonded derivative or carrier of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
  • prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood, and generally include esters and amide analogs of the parent compounds.
  • the prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
  • prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
  • Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g. N,N-dimethylaminocarbonyl) of hydroxy functional groups on compounds of the formula I, II or III, and the like
  • a compound of the formula I, II or III can include a pharmaceutically acceptable co-crystal or a co-crystal salt.
  • a pharmaceutically acceptable co-crystal includes a co-crystal that is suitable for use in contact with the tissues of a subject or patient without undue toxicity, irritation, allergic response and has the desired pharmacokinetic properties.
  • co-crystal as used herein means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as structure, melting point, and heats of fusion.
  • Co-crystals can be formed by an active pharmaceutical ingredient (API) and a co-crystal former either by hydrogen bonding or other non-covalent interactions, such as pi stacking and van der Waals interactions.
  • API active pharmaceutical ingredient
  • An aspect of the invention provides for a co-crystal wherein the co-crystal former is a second API.
  • the co-crystal former is not an API.
  • the co-crystal comprises more than one co-crystal former.
  • co-crystal formers can be incorporated in a co-crystal with an API.
  • pharmaceutically acceptable co-crystals are described, for example, in “Pharmaceutical co-crystals,” Journal of Pharmaceutical Sciences, Volume 95 (3) Pages 499-516, 2006. The methods producing co-crystals are discussed in the United States Patent Application 20070026078.
  • a co-crystal former which is generally a pharmaceutically acceptable compound, may be, for example, benzoquinone, terephthalaldehyde, saccharin, nicotinamide, acetic acid, formic acid, butyric acid, trimesic acid, 5-nitroisophthalic acid, adamantane-1,3,5,7-tetracarboxylic acid, formamide, succinic acid, fumaric acid, tartaric acid, malic acid, tartaric acid, malonic acid, benzamide, mandelic acid, glycolic acid, fumaric acid, maleic acid, urea, nicotinic acid, piperazine, p-phthalaldehyde, 2,6-pyridinecarboxylic acid, 5-nitroisophthalic acid, citric acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benezenesulfonic acid.
  • a compound of the formula I, II or III may be pure or substantially pure.
  • the term “pure” in general means better than 90%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% pure, and “substantially pure” means a compound synthesized such that the compound, as made or as available for consideration into a composition or therapeutic dosage described herein, has only those impurities that can not readily nor reasonably be removed by conventional purification processes.
  • alkyl group optionally substituted with a halo group means that the halo may but need not be present, and the description includes situations where the alkyl group is substituted with a halo group and situations where the alkyl group is not substituted with the halo group.
  • a compound of the formula I, II or III includes derivatives.
  • derivatives of a compound of the formula I, II or III refers to a chemically modified compound wherein the chemical modification takes place either at a functional group or ring of the compound.
  • Non-limiting examples of derivatives of compounds of the formula I, II or III may include N-acetyl, N-methyl, N-hydroxy groups at any of the available nitrogens in the compound.
  • Derivative groups that may be used to modify the compounds of the formula I, II or III can be found in U.S. Patent Application No. 20030176437 (herein incorporated by reference in its entirety for all purposes).
  • a compound of the formula I, II or III is a pharmaceutically functional derivative.
  • a “pharmaceutically functional derivative” includes any pharmaceutically acceptable derivative of a compound of the formula I, II or III, for example, an ester or an amide, which upon administration to a subject is capable of providing (directly or indirectly) a compound of the formula I, II or III or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation (see for example Burger's Medicinal Chemistry and Drug Discovery, 5.sup.th Edition, Vol 1: Principles and Practice, which has illustrative pharmaceutically functional derivatives).
  • a compound of the formula I, II or III may include a carrier.
  • Suitable carriers include a polymer, carbohydrate, or a peptide.
  • a “polymer” refers to molecules comprising two or more monomer subunits that may be identical repeating subunits or different repeating subunits.
  • a monomer generally comprises a simple structure, low-molecular weight molecule containing carbon. Polymers may optionally be substituted. Polymers that can be used in the present invention include without limitation vinyl, acryl, styrene, carbohydrate derived polymers, polyethylene glycol (PEG), polyoxyethylene, polymethylene glycol, poly-trimethylene glycols, polyvinylpyrrolidone, polyoxyethylene-polyoxypropylene block polymers, and copolymers, salts, and derivatives thereof.
  • the polymer is poly(2-acrylamido-2-methyl-1-propanesulfonic acid); poly(2-acrylamido-2-methyl-1-propanesulfonic acid-coacrylonitrile, poly(2-acrylamido-2-methyl-1-propane sulfonic acid-co-styrene), poly(vinylsulfonic acid); poly(sodium 4-styrenesulfonic acid); and sulfates and sulfonates derived therefrom; poly(acrylic acid), poly(methylacrylate), poly(methyl methacrylate), and poly(vinyl alcohol).
  • a “carbohydrate” as used herein refers to a polyhydroxyaldehyde, or polyhydroxyketone and derivatives thereof.
  • the term includes monosaccharides such as erythrose, arabinose, allose, altrose, glucose, mannose, threose, xylose, gulose, idose, galactose, talose, aldohexose, fructose, ketohexose, ribose, and aldopentose.
  • the term also includes carbohydrates composed of monosaccharide units, including disaccharides, oligosaccharides, or polysaccharides. Examples of disaccharides are sucrose, lactose, and maltose.
  • Oligosaccharides generally contain between 3 and 9 monosaccharide units and polysaccharides contain greater than 10 monosaccharide units.
  • a carbohydrate group may be substituted at one two, three or four positions, other than the position of linkage to a compound of the formula I, II or III.
  • a carbohydrate may be substituted with one or more alkyl, amino, nitro, halo, thiol, carboxyl, or hydroxyl groups, which are optionally substituted.
  • Illustrative substituted carbohydrates are glucosamine, or galactosamine.
  • the carbohydrate is a sugar, in particular a hexose or pentose and may be an aldose or a ketose.
  • a sugar may be a member of the D or L series and can include amino sugars, deoxy sugars, and their uronic acid derivatives.
  • the carbohydrate is a hexose
  • the hexose is glucose, galactose, or mannose, or substituted hexose sugar residues such as an amino sugar residue such as hexosamine, galactosamine, glucosamine, in particular D-glucosamine (2-amino-2-doexy-D-glucose) or D-galactosamine (2-amino-2-deoxy-D-galactose).
  • Illustrative pentose sugars include arabinose, fucose, and ribose.
  • a sugar residue may be linked to a compound of the formula I, II or III from a 1,1 linkage, 1,2 linkage, 1,3 linkage, 1,4 linkage, 1,5 linkage, or 1,6 linkage.
  • a linkage may be via an oxygen atom of a compound of the formula I, II or III.
  • An oxygen atom can be replaced one or more times by —CH 2 — or —S— groups.
  • glycoproteins such as lectins (e.g. concanavalin A, wheat germ agglutinin, peanutagglutinin, seromucoid, and orosomucoid) and glycolipids such as cerebroside and ganglioside.
  • lectins e.g. concanavalin A, wheat germ agglutinin, peanutagglutinin, seromucoid, and orosomucoid
  • glycolipids such as cerebroside and ganglioside.
  • a “peptide” carrier for use in the practice of the present invention includes one, two, three, four, or five or more amino acids covalently linked through a peptide bond.
  • a peptide can comprise one or more naturally occurring amino acids, and analogs, derivatives, and congeners thereof.
  • a peptide can be modified to increase its stability, bioavailability, solubility, etc.
  • “Peptide analogue” and “peptide derivative” as used herein include molecules which mimic the chemical structure of a peptide and retain the functional properties of the peptide.
  • a carrier for use in the present invention can be an amino acid such as alanine, glycine, proline, methionine, serine, threonine, histidine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl.
  • a carrier can be a polypeptide such as albumin, antitrypsin, macroglobulin, haptoglobin, caeruloplasm, transferring, ⁇ - or ⁇ -lipoprotein, ⁇ - or ⁇ -globulin or fibrinogen.
  • a peptide can be attached to a compound of the formula I, II or III through a functional group on the side chain of certain amino acids (e.g. serine) or other suitable functional groups.
  • a carrier may comprise four or more amino acids with groups attached to three or more of the amino acids through functional groups on side chains.
  • the carrier is one amino acid, in particular a sulfonate derivative of an amino acid, for example cysteic acid.
  • alkyl either alone or within other terms such as “thioalkyl” and “arylalkyl”, means a monovalent, saturated hydrocarbon radical which may be a straight chain (i.e. linear) or a branched chain.
  • An alkyl radical for use in the present invention generally comprises from about 1 to 20 carbon atoms, particularly from about 1 to 10, 1 to 8 or 1 to 7, more particularly about 1 to 6 carbon-atoms, or 3 to 6.
  • Illustrative alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, undecyl, n-dodecyl, n-tetradecyl, pentadecyl, n-hexadecyl, heptadecyl, n-octadecyl, nonadecyl, eicosyl, dosyl, n-tetracosyl, and the like, along with branched variations thereof.
  • an alkyl radical is a C 1 -C 6 lower alkyl comprising or selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl, tributyl, sec-butyl, tert-butyl, tert-pentyl, and n-hexyl.
  • An alkyl radical may be optionally substituted with substituents as defined herein at positions that do not significantly interfere with the preparation of compounds of the formula I, II or III and do not significantly reduce the efficacy of the compounds.
  • an alkyl radical is substituted with one to five substituents including halo, lower alkoxy, lower aliphatic, a substituted lower aliphatic, hydroxy, cyano, nitro, thio, amino, keto, aldehyde, ester, amide, substituted amino, carboxyl, sulfonyl, sulfinyl, sulfenyl, sulfate, sulfoxide, substituted carboxyl, halogenated lower alkyl (e.g.
  • CF 3 halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, cycloaliphatic, substituted cycloaliphatic, or aryl (e.g., phenylmethyl (i.e. benzyl)), heteroaryl (e.g., pyridyl), and heterocyclic (e.g., piperidinyl, morpholinyl). Substituents on an alkyl group may themselves be substituted.
  • aryl e.g., phenylmethyl (i.e. benzyl)
  • heteroaryl e.g., pyridyl
  • heterocyclic e.g., piperidinyl, morpholinyl
  • substituted alkyl includes an alkyl group substituted by, for example, one to five substituents, and preferably 1 to 3 substituents, such as alkyl, alkoxy, oxo, alkanoyl, aryl, aralkyl, aryloxy, alkanoyloxy, cycloalkyl, acyl, amino, hydroxyamino, alkylamino, arylamino, alkoxyamino, aralkylamino, cyano, halogen, hydroxyl, carboxyl, carbamyl, carboxylalkyl, keto, thioketo, thiol, alkylthiol, arylthio, aralkylthio, sulfonamide, thioalkoxy, and nitro.
  • substituents such as alkyl, alkoxy, oxo, alkanoyl, aryl, aralkyl, aryloxy, alkanoyloxy, cycl
  • substituted aliphatic refers to an alkyl or an alkane possessing less than 10 carbons.
  • substituted aliphatic refers to an alkyl or an alkane possessing less than 10 carbons where at least one of the aliphatic hydrogen atoms has been replaced by a halogen, an amino, a hydroxy, a nitro, a thio, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic, etc.). Examples of such groups include, but are not limited to, 1-chloroethyl and the like.
  • lower-alkyl-substituted-amino refers to any alkyl unit containing up to and including eight carbon atoms where one of the aliphatic hydrogen atoms is replaced by an amino group. Examples of such include, but are not limited to, ethylamino and the like.
  • lower-alkyl-substituted-halogen refers to any alkyl chain containing up to and including eight carbon atoms where one of the aliphatic hydrogen atoms is replaced by a halogen. Examples of such include, but are not limited to, chlorethyl and the like.
  • acetylamino shall mean any primary or secondary amino that is acetylated. Examples of such include, but are not limited to, acetamide and the like.
  • alkenyl refers to an unsaturated, acyclic branched or straight-chain hydrocarbon radical comprising at least one double bond.
  • An alkenyl radical may contain from about 2 to 24 or 2 to 10 carbon atoms, in particular from about 3 to 8 carbon atoms and more particularly about 3 to 6 or 2 to 6 carbon atoms.
  • Suitable alkenyl radicals include without limitation ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), and prop-2-en-2-yl), buten-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
  • An alkenyl radical may be optionally substituted similar to alkyl.
  • substituted alkenyl includes an alkenyl group substituted by, for example, one to three substituents, preferably one to two substituents, such as alkyl, alkoxy, haloalkoxy, alkylalkoxy, haloalkoxyalkyl, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino, alkanoylamino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, carbamyl, keto, thioketo, thiol, alkylthio, sulfonyl, sulfonamido, thioalkoxy, aryl, nitro, and the like.
  • substituents such as alkyl, alkoxy, haloalkoxy, alkylalkoxy, haloalkoxy
  • alkynyl refers to an unsaturated, branched or straight-chain hydrocarbon radical comprising one or more triple bonds.
  • An alkynyl radical may contain about 1 to 20, 1 to 15, or 2 to 10 carbon atoms, particularly about 3 to 8 carbon atoms and more particularly about 3 to 6 carbon atoms.
  • Suitable alkynyl radicals include without limitation ethynyl, such as prop-1-yn-1-yl and prop-2-yn-1-yl, butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, and but-3-yn-1-yl, pentynyls such as pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, and 3-methylbutyn-1-yl, hexynyls such as hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, and 3,3-dimethylbutyn-1-yl radicals and the like.
  • alkenyl groups include ethenyl (—CH ⁇ CH 2 ), n-propenyl (—CH 2 CH ⁇ CH 2 ), iso-propenyl (—C(CH 3 ) ⁇ CH 2 ), and the like.
  • An alkynyl may be optionally substituted similar to alkyl.
  • cycloalkynyl refers to cyclic alkynyl groups.
  • substituted alkynyl includes an alkynyl group substituted by, for example, a substituent, such as, alkyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino, alkanoylamino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, carbamyl, keto, thioketo, thiol, alkylthio, sulfonyl, sulfonamido, thioalkoxy, aryl, nitro, and the like.
  • a substituent such as, alkyl, alkoxy, alkanoyl, alkanoyloxy, cycloalkyl, cycloalkoxy, acyl, acylamino, acyloxy, amino, alkylamino,
  • alkylene refers to a linear or branched radical having from about 1 to 10, 1 to 8, 1 to 6, or 2 to 6 carbon atoms and having attachment points for two or more covalent bonds. Examples of such radicals are methylene, ethylene, propylene, butylene, pentylene, hexylene, ethylidene, methylethylene, and isopropylidene.
  • alkenylene radical is present as a substituent on another radical it is typically considered to be a single substituent rather than a radical formed by two substituents.
  • alkenylene refers to a linear or branched radical having from about 2 to 10, 2 to 8 or 2 to 6 carbon atoms, at least one double bond, and having attachment points for two or more covalent bonds.
  • alkenylene radicals include 1,1-vinylidene (—CH 2 ⁇ C—), 1,2-vinylidene (—CH ⁇ CH—), and 1,4-butadienyl (—CH ⁇ CH—CH ⁇ CH—).
  • halo refers to a halogen such as fluorine, chlorine, bromine or iodine atoms.
  • hydroxyl or “hydroxy” refers to an —OH group.
  • cyano refers to a carbon radical having three of four covalent bonds shared by a nitrogen atom, in particular —C—N.
  • a cyano group may be substituted with substituents described herein.
  • alkoxy refers to a linear or branched oxy-containing radical having an alkyl portion of one to about ten carbon atoms, such as a methoxy radical, which may be substituted.
  • an alkoxy radical may comprise about 1-10, 1-8, 1-6 or 1-3 carbon atoms.
  • an alkoxy radical comprises about 1-6 carbon atoms and includes a C 1 -C 6 alkyl-O-radical wherein C 1 -C 6 alkyl has the meaning set out herein.
  • alkoxy radicals include without limitation methoxy, ethoxy, propoxy, butoxy, isopropoxy and tert-butoxy alkyls.
  • alkoxy radical may optionally be substituted with one or more substitutents disclosed herein including alkyl atoms to provide “alkylalkoxy” radicals; halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals (e.g. fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropox) and “haloalkoxyalkyl” radicals (e.g. fluoromethoxymethyl, chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl, and trifluoroethoxymethyl).
  • halo atoms such as fluoro, chloro or bromo
  • alkenyloxy refers to linear or branched oxy-containing radicals having an alkenyl portion of about 2 to 10 carbon atoms, such as an ethenyloxy or propenyloxy radical.
  • An alkenyloxy radical may be a “lower alkenyloxy” radical having about 2 to 6 carbon atoms. Examples of alkenyloxy radicals include without limitation ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy alkyls.
  • alkenyloxy radical may be substituted with one or more substitutents disclosed herein including halo atoms, such as fluoro, chloro or bromo, to provide “haloalkenyloxy” radicals (e.g. trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy).
  • haloalkenyloxy e.g. trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyloxy, and fluoropropenyloxy.
  • a “carbocylic” includes radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 member organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon.
  • Examples of carbocyclic radicals are cycloalkyl, cycloalkenyl, aryl, in particular phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluoyl, xylenyl, indenyl, stilbenzyl, terphenylyl, diphenylethylenyl, phenylcyclohexyl, acenapththylenyl, anthracenyl, biphenyl, bibenzylyl, and related bibenzylyl homologs, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimeth
  • cycloalkyl refers to radicals having from about 3 to 15, 3 to 10, 3 to 8, or 3 to 6 carbon atoms and containing one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused.
  • cycloalkyl refers to an optionally substituted, saturated hydrocarbon ring system containing 1 to 2 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C 3 -C 7 carbocylic ring.
  • cycloalkyl groups include single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclododecyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • the cycloalkyl radicals are “lower cycloalkyl” radicals having from about 3 to 10, 3 to 8, 3 to 6, or 3 to 4 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the term “cycloalkyl” also embraces radicals where cycloalkyl radicals are fused with aryl radicals or heterocyclyl radicals.
  • a cycloalkyl radical may be optionally substituted with groups as disclosed herein.
  • substituted cycloalkyl includes cycloalkyl groups having from 1 to 5 (in particular 1 to 3) substituents including without limitation alkyl, alkenyl, alkoxy, cycloalkyl, substituted cycloalkyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, keto, thioketo, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxyamino, alkoxyamino, and nitro.
  • cycloaliphatic refers to a cycloalkane possessing less than 8 carbons or a fused ring system consisting of no more than three fused cycloaliphatic rings. Examples of such groups include, but are not limited to, decalin and the like.
  • substituted cycloaliphatic refers to a cycloalkane possessing less than 8 carbons or a fused ring system consisting of no more than three fused rings, and where at least one of the aliphatic hydrogen atoms has been replaced by a halogen, a nitro, a thio, an amino, a hydroxy, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such groups include, but are not limited to, 1-chlorodecalyl and the like.
  • cycloalkenyl refers to radicals comprising about 4 to 16, 2 to 15, 2 to 10, 2 to 8, 4 to 10, 3 to 8, 3 to 7, 3 to 6, or 4 to 6 carbon atoms, one or more carbon-carbon double bonds, and one, two, three, or four rings wherein such rings may be attached in a pendant manner or may be fused.
  • the cycloalkenyl radicals are “lower cycloalkenyl” radicals having three to seven carbon atoms. Examples of cycloalkenyl radicals include without limitation cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • a cycloalkenyl radical may be optionally substituted with groups as disclosed herein, in particular 1, 2, or 3 substituents which may be the same or different.
  • cycloalkoxy refers to cycloalkyl radicals (in particular, cycloalkyl radicals having 3 to 15, 3 to 8 or 3 to 6 carbon atoms) attached to an oxy radical.
  • examples of cycloalkoxy radicals include cyclohexoxy and cyclopentoxy.
  • a cycloalkoxy radical may be optionally substituted with groups as disclosed herein.
  • aryl refers to a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be fused.
  • an aryl radical comprises 4 to 24 carbon atoms, in particular 4 to 10, 4 to 8, or 4 to 6 carbon atoms.
  • aryl radicals includes without limitation aromatic radicals such as phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl, preferably phenyl.
  • An aryl radical may be optionally substituted with groups as disclosed herein, in particular hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and/or halo, in particular a substituted aryl includes without limitation arylamine and arylalkylamine.
  • substituted aryl includes an aromatic ring, or fused aromatic ring system consisting of no more than three fused rings at least one of which is aromatic, and where at least one of the hydrogen atoms on a ring carbon has been replaced by a halogen, an amino, a hydroxy, a nitro, a thio, an alkyl, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such include, but are not limited to, hydroxyphenyl, chlorophenyl and the like.
  • an aryl radical may be optionally substituted with one to four substituents such as alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, aryloxy, aralkyloxy, amino, alkylamino, arylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfona
  • a substituent may be further substituted by hydroxy, halo, alkyl, alkoxy, alkenyl, alkynyl, aryl or aralkyl.
  • an aryl radical is substituted with hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, and/or halo.
  • aralkyl refers to an aryl or a substituted aryl group bonded directly through an alkyl group, such as benzyl.
  • substituted aryl radicals include chlorobenyzl, and amino benzyl.
  • aryloxy refers to aryl radicals, as defined above, attached to an oxygen atom.
  • exemplary aryloxy groups include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
  • arylalkoxy refers to an aryl group attached to an alkoxy group.
  • Representative examples of arylalkoxy groups include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
  • aroyl refers to aryl radicals, as defined above, attached to a carbonyl radical as defined herein, including without limitation benzoyl and toluoyl.
  • An aroyl radical may be optionally substituted with groups as disclosed herein.
  • heteroaryl refers to fully unsaturated heteroatom-containing ring-shaped aromatic radicals having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen.
  • a heteroaryl radical may contain one, two or three rings and the rings may be attached in a pendant manner or may be fused.
  • the term refers to fully unsaturated heteroatom-containing ring-shaped aromatic radicals having from 3 to 15, 3 to 10, 3 to 8, 5 to 15, 5 to 10, or 5 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
  • heteroaryl radicals include without limitation, an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like; an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, pteridinyl, quinolizidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
  • heterocyclic radicals are fused with aryl radicals, in particular bicyclic radicals such as benzofuranyl, benzothiophenyl, phthalazinyl, chromenyl, xanthenyl, and the like.
  • a heteroaryl radical may be optionally substituted with groups as disclosed herein, for example with an alkyl, amino, halogen, etc., in particular a heteroarylamine.
  • the term refers to an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like.
  • a heteroaryl radical may be optionally substituted with groups disclosed herein, for example with an alkyl, amino, halogen, etc., in particular a substituted heteroaryl radical is a heteroarylamine.
  • heterocyclic refers to saturated and partially saturated heteroatom-containing ring-shaped radicals having at least one heteroatom selected from carbon, nitrogen, sulfur and oxygen.
  • a heterocylic radical may contain one, two or three rings wherein such rings may be attached in a pendant manner or may be fused.
  • the term refers to a saturated and partially saturated heteroatom-containing ring-shaped radicals having from about 3 to 15, 3 to 10, 5 to 15, 5 to 10, or 3 to 8 ring members selected from carbon, nitrogen, sulfur and oxygen, wherein at least one ring atom is a heteroatom.
  • Examplary saturated heterocyclic radicals include without limitiation a saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g.
  • partially saturated heterocyclyl radicals include without limitation dihydrothiophene, dihydropyranyl, dihydrofuranyl and dihydrothiazolyl.
  • heterocyclic radicals include without limitation aziridinyl, azetidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, azepinyl, 1,3-dioxolanyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, pyrazolinyl, 1,4-dithianyl, thiomorpholinyl, 1,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiopyranyl, thioxanyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl
  • R 11 cannot be piperidinyl.
  • heterocyclic refers to a cycloalkane and/or an aryl ring system, possessing less than 8 carbons, or a fused ring system consisting of no more than three fused rings, where at least one of the ring carbon atoms is replaced by oxygen, nitrogen or sulfur.
  • groups include, but are not limited to, morpholino and the like.
  • substituted heterocyclic refers to a cycloalkane and/or an aryl ring system, possessing less than 8 carbons, or a fused ring system consisting of no more than three fused rings, where at least one of the ring carbon atoms is replaced by oxygen, nitrogen or sulfur, and where at least one of the aliphatic hydrogen atoms has been replaced by a halogen, hydroxy, a thio, nitro, an amino, a ketone, an aldehyde, an ester, an amide, a lower aliphatic, a substituted lower aliphatic, or a ring (aryl, substituted aryl, cycloaliphatic, or substituted cycloaliphatic). Examples of such groups include, but are not limited to 2-chloropyranyl.
  • heteroaryl and heterocyclic groups may be C-attached or N-attached (where such is possible).
  • sulfonyl used alone or linked to other terms such as alkylsulfonyl or arylsulfonyl, refers to the divalent radicals —SO 2 —.
  • the sulfonyl group may be attached to a substituted or unsubstituted hydroxyl, alkyl group, ether group, alkenyl group, alkynyl group, aryl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, heterocyclic group, carbohydrate, peptide, or peptide derivative.
  • sulfinyl used alone or linked to other terms such as alkylsulfinyl (i.e.—S(O)-alkyl) or arylsulfinyl, refers to the divalent radicals —S(O)—.
  • R 18 is an electron pair, hydrogen, alkyl, cycloalkyl, aryl, alkenyl, alkynyl, cycloalkenyl, cycloalkynyl, heterocyclic, carbohydrate, peptide, or peptide derivative.
  • R 19 is an electron pair, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic, carbohydrate, peptide or peptide derivative.
  • sulfoxide refers to the radical —S ⁇ O.
  • amino refers to a radical where a nitrogen atom (N) is bonded to three substituents being any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, heterocyclic, or heteroaryl which may or may not be substituted.
  • an “amino group” has the general chemical formula —NR 20 R 21 where R 20 and R 21 can be any combination of hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, aryl, carbonyl carboxyl, amino, silyl, heteroaryl, or heterocyclic which may or may not be substituted.
  • one substituent on the nitrogen atom may be a hydroxyl group (—OH) to provide an amine known as a hydroxylamine.
  • amino groups are amino (—NH 2 ), alkylamino, acylamino, cycloamino, acycloalkylamino, arylamino, arylalkylamino, and lower alkylsilylamino, in particular methylamino, ethylamino, dimethylamino, 2-propylamino, butylamino, isobutylamino, cyclopropylamino, benzylamino, allylamino, hydroxylamino, cyclohexylamino, piperidinyl, hydrazinyl, benzylamino, diphenylmethylamino, tritylamino, trimethylsilylamino, and dimethyl-tert.-butylsilylamino, which may or may not be substituted.
  • thiol means —SH.
  • a thiol may be substituted with a substituent disclosed herein, in particular alkyl (thioalkyl), aryl (thioaryl), alkoxy (thioalkoxy) or carboxyl.
  • sulfenyl used alone or linked to other terms such as alkylsulfenyl, refers to the radical —SR 22 wherein R 22 is not hydrogen.
  • R 22 is substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, silyl, silylalkyl, heterocyclic, heteroaryl, carbonyl, carbamoyl, alkoxy, or carboxyl.
  • thioalkyl refers to a chemical functional group where a sulfur atom (S) is bonded to an alkyl, which may be substituted.
  • S sulfur atom
  • alkyl examples include thiomethyl, thioethyl, and thiopropyl.
  • a thioalkyl may be substituted with a substituted or unsubstituted carboxyl, aryl, heterocylic, carbonyl, or heterocyclic.
  • thioaryl refers to a chemical functional group where a sulfur atom (S) is bonded to an aryl group with the general chemical formula —SR 23 where R 23 is aryl which may be substituted.
  • Illustrative examples of thioaryl groups and substituted thioaryl groups are thiophenyl, chlorothiophenyl, para-chlorothiophenyl, thiobenzyl, 4-methoxy-thiophenyl, 4-nitro-thiophenyl, and para-nitrothiobenzyl.
  • thioalkoxy refers to a chemical functional group where a sulfur atom (S) is bonded to an alkoxy group with the general chemical formula —SR 24 where R 24 is an alkoxy group which may be substituted.
  • a “thioalkoxy group” may have 1-6 carbon atoms i.e. a —S—(O)—C 1 -C 6 alkyl group wherein C 1 -C 6 alkyl have the meaning as defined above.
  • Illustrative examples of a straight or branched thioalkoxy group or radical having from 1 to 6 carbon atoms, also known as a C 1 -C 6 thioalkoxy include thiomethoxy and thioethoxy.
  • a thiol may be substituted with a substituted or unsubstituted heteroaryl or heterocyclic, in particular a substituted or unsubstituted saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and piperazinyl] or a saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl; sydnonyl], especially a substituted morpholinyl or piperidinyl.
  • a substituted or unsubstituted heteroaryl or heterocyclic in particular a substituted or unsubstituted saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, and pipe
  • carbonyl refers to a carbon radical having two of the four covalent bonds shared with an oxygen atom.
  • the term “carboxyl”, alone or in combination, refers to —C(O)OR 25 — or —C( ⁇ O)OR 25 wherein R 25 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, thiol, aryl, heteroaryl, thioalkyl, thioaryl, thioalkoxy, a heteroaryl, or a heterocyclic, which may optionally be substituted.
  • the carboxyl groups are in an esterified form and may contain as an esterifying group lower alkyl groups.
  • —C(O)OR 25 provides an ester or an amino acid derivative.
  • esterified form is also particularly referred to herein as a “carboxylic ester”.
  • a “carboxyl” may be substituted, in particular substituted with alkyl which is optionally substituted with one or more of amino, amine, halo, alkylamino, aryl, carboxyl, or a heterocyclic.
  • carboxyl groups are methoxycarbonyl, butoxycarbonyl, tert.alkoxycarbonyl such as tert.butoxycarbonyl, arylmethyoxycarbonyl having one or two aryl radicals including without limitation phenyl optionally substituted by for example lower alkyl, lower alkoxy, hydroxyl, halo, and/or nitro, such as benzyloxycarbonyl, methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyltert.butylcarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxy-carbonyl, benzhydroxycarbonyl, di-(4-methoxyphenyl-methoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, or 2-triphenylsily
  • Additional carboxyl groups in esterified form are silyloxycarbonyl groups including organic silyloxycarbonyl.
  • the silicon substituent in such compounds may be substituted with lower alkyl (e.g. methyl), alkoxy (e.g. methoxy), and/or halo (e.g. chlorine).
  • Examples of silicon substituents include trimethylsilyl and dimethyltert.butylsilyl.
  • the carboxyl group may be an alkoxy carbonyl, in particular methoxy carbonyl, ethoxy carbonyl, isopropoxy carbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, or heptyloxy carbonyl, especially methoxy carbonyl or ethoxy carbonyl.
  • carbamoyl refers to amino, monoalkylamino, dialkylamino, monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino radicals, attached to one of two unshared bonds in a carbonyl group.
  • carboxylate refers to the group —CONH—.
  • nitro means —NO 2 —.
  • acyl means a carbonyl or thiocarbonyl group bonded to a radical selected from, for example, optionally substituted, hydrido, alkyl (e.g. haloalkyl), alkenyl, alkynyl, alkoxy (“acyloxy” including acetyloxy, butyryloxy, iso-valeryloxy, phenylacetyloxy, benzoyloxy, p-methoxybenzoyloxy, and substituted acyloxy such as alkoxyalkyl and haloalkoxy), aryl, halo, heterocyclyl, heteroaryl, sulfinyl (e.g.
  • alkylsulfinylalkyl sulfonyl (e.g. alkylsulfonylalkyl), cycloalkyl, cycloalkenyl, thioalkyl, thioaryl, amino (e.g alkylamino or dialkylamino), and aralkoxy.
  • acyl radicals are formyl, acetyl, 2-chloroacetyl, 2-bromacetyl, benzoyl, trifluoroacetyl, phthaloyl, malonyl, nicotinyl, and the like.
  • acyl refers to a group —C(O)R 26 , where R 26 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • R 26 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • R 26 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • R 26 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, and heteroarylalkyl.
  • examples include, but are not limited to formy
  • phosphonate refers to a C—PO(OH) 2 or C—PO(OR 27 ) 2 group wherein R 27 is alkyl or aryl which may be substituted.
  • ureido refers to the group “—NHCONH—”.
  • a ureido radical includes an alkylureido comprising a ureido substituted with an alkyl, in particular a lower alkyl attached to the terminal nitrogen of the ureido group.
  • alkylureido include without limitation N′-methylureido, N′-ethylureido, N′-n-propylureido, N′-i-propylureido and the like.
  • a ureido radical also includes a N′,N′-dialkylureido group containing a radical —NHCON where the terminal nitrogen is attached to two optionally substituted radicals including alkyl, aryl, heterocylic, and heteroaryl.
  • radicals including “alkyl”, “alkoxy”, “alkenyl”, “alkynyl”, “hydroxyl” etc. refer to both unsubstituted and substituted radicals.
  • substituted means that any one or more moiety on a designated atom (e.g., hydrogen) is replaced with a selection from a group disclosed herein, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or radicals are permissible only if such combinations result in stable compounds.
  • “Stable compound” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • a functional group or ring of a compound of the formula I, II or III may be modified with, or a radical in a compound of the formula I, II or III may be substituted with one or more groups or substituents apparent to a person skilled in the art including without limitation alkyl, alkoxy, alkenyl, alkynyl, alkanoyl, alkylene, alkenylene, hydroxyalkyl, haloalkyl, haloalkylene, haloalkenyl, alkoxy, alkenyloxy, alkenyloxyalkyl, alkoxyalkyl, aryl, alkylaryl, haloalkoxy, haloalkenyloxy, heterocyclic, heteroaryl, alkylsulfonyl, sulfinyl, sulfonyl, sulfenyl, alkylsulfinyl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkeny
  • a chemical substituent is “pendant” from a radical if it is bound to an atom of the radical.
  • the substituent can be pending from a carbon atom of a radical, a carbon atom connected to a carbon atom of the radical by a chain extender, or a heteroatom of the radical.
  • the term “fused” means that a second ring is present (i.e, attached or formed) by having two adjacent atoms in common or shared with the first ring.
  • a “dosage form” refers to a composition or device comprising a compound of the formula I, II or III and optionally pharmaceutically acceptable carrier(s), excipient(s), or vehicles.
  • a dosage form may be an immediate release dosage form or a sustained release dosage form.
  • An “immediate release dosage form” refers to a dosage form which does not include a component for sustained release i.e., a component for slowing disintegration or dissolution of an active compound. These dosage forms generally rely on the composition of the drug matrix to effect the rapid release of the active ingredient agent.
  • sustained release dosage form is meant a dosage form that releases active compound for many hours.
  • a sustained dosage form includes a component for slowing disintegration or dissolution of the active compound.
  • a dosage form may be a sustained release formulation, engineered with or without an initial delay period.
  • Sustained release dosage forms may continuously release drug for sustained periods of at least about 4 hours or more, about 6 hours or more, about 8 hours or more, about 12 hours or more, about 15 hours or more, or about 20 hours to 24 hours.
  • a sustained release dosage form can be formulated into a variety of forms, including tablets, lozenges, gelcaps, buccal patches, suspensions, solutions, gels, etc. In aspects of the invention the sustained release form results in administration of a minimum number of daily doses.
  • a “disease” that can be treated and/or prevented using a compound, composition, or method of the invention includes a condition associated with or requiring modulation of one or more of inflammation (e.g. neuroinflammation); signaling pathways involved in inflammation (e.g., neuroinflammation); cell signaling molecule production; activation of glia or glial activation pathways and responses; proinflammatory cytokines or chemokines (e.g., interleukin (IL), in particular IL-1 ⁇ ) or tumor necrosis factor (TNF, in particular TNF ⁇ ); activation of astrocytes or astrocyte activation pathways and responses; activation of microglia or microglial activation pathways and responses; oxidative stress-related responses such as nitric oxide synthase production and nitric oxide accumulation; acute phase proteins; loss of synaptophysin and/or 95; components of the complement cascade; loss or reduction of synaptic function; protein kinase activity (e.g., death associated protein kinase
  • a disease is a neurological disease or condition including without limitation, dementing disorder, a neurodegenerative disorder, a CNS demyelinating disorder, a pain disorder, an autoimmune disorder, or a peripheral inflammatory disease.
  • a disease may be characterized by an inflammatory process due to the presence of macrophages activated by an amyloidogenic protein or peptide.
  • a method of the invention may involve inhibiting macrophage activation and/or inhibiting an inflammatory process.
  • a method may comprise decreasing, slowing, ameliorating, or reversing the course or degree of macrophage invasion or inflammation in a patient.
  • diseases that can be treated and/or prevented using the compounds, compositions and methods of the invention include Alzheimer's disease and related disorders, presenile and senile forms; amyloid angiopathy; mild cognitive impairment; Alzheimer's disease-related dementia (e.g., vascular dementia or Alzheimer dementia); AIDS related dementia, tauopathies (e.g., argyrophilic grain dementia, corticobasal degeneration, dementia pugilistica, diffuse neurofibrillary tangles with calcification, frontotemporal dementia with parkinsonism, Prion-related disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian Motor Neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic parkinsonism, cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and tangle
  • the disease is Alzheimer's disease, vascular dementia, dementia associated with Parkinson's disease, visuospatial deficits, Williams syndrome, encephalitis, meningitis, fetal alcohol syndrome, Korsakoffs syndrome, anoxic brain injury, cardiopulmonary resuscitation injuries, diabetes, Sjogren's syndrome, strokes, ocular diseases such as cataracts and macular degeneration, sleep disorders, and cognitive impairments caused by high cholesterol levels.
  • a compound, composition, or method disclosed herein may be utilized to prevent and/or treat a disease involving neuroinflammation (i.e., neuroinflammatory disease).
  • neuroinflammation is a characteristic feature of disease pathology and progression in a diverse array of neurodegenerative disorders that are increasing in their societal impact (for a recent review, see, e.g., Prusiner, S. B. (2001) New Engl. J. Med. 344, 1516-1526).
  • These neuroinflammation-related disorders include Alzheimer's disease (AD), amyotrophic lateral sclerosis, autoimmune disorders, priori diseases, stroke and traumatic brain injury.
  • Neuroinflammation is brought about by glial cell (e.g., astrocytes and microglia) activation, which normally serves a beneficial role as part of an organism's homeostatic response to injury or developmental change.
  • glial cell e.g., astrocytes and microglia
  • disregulation of this process through chronic or excessive activation of glia contributes to the disease process through the increased production of proinflammatory cytokines and chemokines, oxidative stress-related enzymes, acute phase proteins, and various components of the complement cascades.
  • the disease is a neurodegenerative disease or neurodegenerative disorder including such diseases and impairments as Alzheimer's disease, dementia, MCI, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other similar diseases and disorders disclosed herein.
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid
  • neurofibrillary tangles are associated with glial activation, neuronal loss and cognitive decline.
  • a ⁇ ⁇ -amyloid
  • ⁇ -amyloid A ⁇
  • ⁇ -amyloid A ⁇
  • neurofibrillary tangles are associated with glial activation, neuronal loss and cognitive decline.
  • NOS nitric oxide synthase
  • NOS nitric oxide synthase
  • iNOS nitric oxide synthase
  • iNOS is induced as part of the glial activation response and is an oxidative stress-related enzyme that generates NO.
  • IL-1 ⁇ The pro-inflammatory cytokine IL-1 ⁇ is also overexpressed in activated glia in AD brain and polymorphisms in IL-1 ⁇ genes are associated with an increased risk of early onset sporadic AD (See, e.g., Du et al., (2000) Neurology 55, 480-483). IL-1 ⁇ can also influence amyloid plaque development and is involved in additional glial inflammatory and neuronal dysfunction responses (See, e.g., Griffin, et al., (1998) Brain Pathol. 8, 65-72; and Sheng, et al., (1996) Neurobiol.
  • glial activation and specific glial products are associated with neurodegenerative disorders (e.g., Alzheimer's disease)
  • the compounds and compositions disclosed herein that are capable of modulating cell signaling pathways e.g., glial activation pathways
  • a compound, composition, or method disclosed herein may be utilized to prevent and/or treat a disease involving disregulation of protein kinase signaling.
  • Disregulation of protein kinase signaling often accompanies disregulation of cell signaling pathways (e.g., glial cell activation pathways).
  • Protein kinases are a large family of proteins that play a central role in regulating a number of cellular functions including cell growth, differentiation and death. There are thought to be more than 500 protein kinases and 130 protein phosphatases exerting tight control on protein phosphorylation. Each protein kinase transfers the ⁇ -phosphate of ATP to a specific residue(s) of a protein substrate.
  • Protein kinases can be further categorized as tyrosine, serine/threonine or dual specific based on acceptor residue.
  • serine/threonine kinases include MAP kinase, MAPK kinase (MEK), Akt/PKB, Jun kinase (INK), CDKs, protein kinase A (PRA), protein kinase C(PKC), and calmodulin (CaM)-dependent kinases (CaMKs).
  • Disregulated protein kinase activity leads to abnormal protein phosphorylation, underlying a great number of diseases including diabetes, rheumatoid arthritis, inflammation, hypertension, and proliferative diseases such as cancer. Therefore, because aberrant kinase activity is associated with inflammatory disease (e.g., neurodegenerative disorders like Alzheimer's disease), the compounds and compositions that are disclosed herein that are capable of modulating kinases involved in cell signaling pathways will have particular application for treatment and prevention of inflammatory disease.
  • inflammatory disease e.g., neurodegenerative disorders like Alzheimer's disease
  • Demyelinating Diseases refers to diseases in which myelin is the primary target. These diseases can be divided into two groups: Acquired Diseases and Hereditary Metabolic Disorders. Acquired Demyelinating Diseases include Multiple sclerosis (MS) including its alternating relapsing/remitting phases. Hereditary Metabolic Disorders includes the leukodystrophies such as metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher disease and Alexander's disease.
  • MS Multiple sclerosis
  • Hereditary Metabolic Disorders includes the leukodystrophies such as metachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacher disease and Alexander
  • Diseases that may also be treated and/or prevented according to the invention include “Demyelinating Conditions”.
  • the term refers to conditions that result in deficient myelination. Such conditions include, but are not limited to, Spinal Cord Injury, Traumatic Brain Injury and Stroke.
  • SCI Spinal Cord Injury
  • TBI Traumatic Brain Injury
  • a head injury may be a closed head injury or penetrating head injury.
  • a closed head injury may occur when the head is hit by a blunt object causing the brain to interact with the hard bony surface inside the skull.
  • a closed head injury may also occur without direct external trauma to the head if the brain undergoes a rapid forward or backward movement, (e.g. whiplash).
  • a penetrating head injury may occur when a fast moving object such as a bullet pierces the skull.
  • a closed or penetrating head injury may result in localized and widespread, or diffuse, damage to the brain which may manifest as memory loss, emotional disturbances, motor difficulties, including paralysis, damage to the senses, and death.
  • the term also includes secondary damage that follows an injury including swelling and fluid buildup and the accumulation of substances toxic to surrounding neurons such as the neurotransmitter glutamate.
  • Stroke refers to a sudden loss of brain function caused by the interruption of the flow of blood to the brain (an ischemic stroke) or the rupture of blood vessels in the brain (a hemorrhagic stroke). The interruption of the blood flow or the rupture of blood vessels causes neurons in the affected area to die.
  • stroke rehabilitation refers to the intervention resulting in the full or partial recovery of functions that have been lost due to stroke.
  • a pain disorder may also be treated and/or prevented according to the invention.
  • a “pain disorder” refers to a disorder or condition involving pain and includes without limitation acute pain, persistent pain, chronic pain, inflammatory pain, neuropathic pain, neurogenic pain, and chemokine-induced pain.
  • a pain disorder includes without limitation pain resulting from soft tissue and peripheral damage such as acute trauma; complex regional pain syndrome also referred to as reflex sympathetic dystrophy; postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; pain associated with osteoarthritis and rheumatoid arthritis; musculo-skeletal pain such as pain associated with strains, sprains and trauma such as broken bones; spinal pain, central nervous system pain such as pain due to spinal cord or brain stem damage; lower back pain, sciatica, dental pain, myofascial pain syndromes, episiotomy pain, gout pain, and pain resulting from burns; deep and visceral pain, such as heart pain; muscle pain, eye pain, inflammatory pain, orofacial pain, for example, odontalgia; abdominal pain, and gynecological pain, for example, dysmenorrhoe
  • Neuroneuropathic pain refers to pain initiated or caused by a primary lesion or dysfunction in the nervous system.
  • Neuroogenic Pain which is defined as pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral or central nervous system.
  • the uses of the present invention include central or peripheral neuropathic pain or neurogenic pain.
  • neuropathic pain includes the pain caused by either mononeuropathy or polyneuropathy.
  • Neuropathic pain also includes Chemokine-Induced Pain.
  • Peripheral neuropathic pain refers to a pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system and “peripheral neurogenic pain” refers to a pain initiated or caused by a primary lesion, dysfunction or transitory perturbation in the peripheral nervous system.
  • a peripheral neuropathic pain can be allodynia (i.e., a pain due to a stimulus which does not normally provoke pain); causalgia (i.e., a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes); hyperalgesia (i.e., an increased response to a stimulus which is normally painful); hyperesthesia (i.e., increased sensitivity to stimulation, excluding the senses); hyperpathia.
  • allodynia i.e., a pain due to a stimulus which does not normally provoke pain
  • causalgia i.e., a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes
  • hyperalgesia i.e., an increased response to a stimulus which is normally painful
  • hyperesthesia i.
  • neuropathic pain i.e., a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold
  • neuritis i.e., inflammation of a nerve or nerves
  • neuropathy i.e., a disturbance of function or pathological change in a nerve.
  • neuropathic pain examples include infective (e.g., post herpetic neuralgia and HIV neuropathy), metabolic (e.g., diabetic neuropathy and Fabry's disease), toxic (e.g., from lead or chemotherapy), traumatic/stretch injury (e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia), and idiopathic (e.g., trigeminal neuralgia/tic douloureux).
  • infective e.g., post herpetic neuralgia and HIV neuropathy
  • metabolic e.g., diabetic neuropathy and Fabry's disease
  • toxic e.g., from lead or chemotherapy
  • traumatic/stretch injury e.g., post incisional, trauma, phantom limb pain, and reflex sympathetic dystrophy/complex regional pain syndrome/causalgia
  • idiopathic e.g.
  • Neuropathic Pain include post-herpetic neuralgia, painful diabetic neuropathy, phantom limb pain, central post-stroke pain, HIV neuropathy, Fabry's disease, peripheral neuropathy, trigeminal neuralgia, post incisional neuropathic pain, phantom limb pain, reflex sympathetic dystrophy, causalgia, anesthesia dolorosa, intercoastal neuralgia, post-traumatic localized pain, atypical facial neuralgia pain after tooth extraction and the like, complex regional pain syndrome, neuropathic pain caused by trauma, lead, or chemotherapy, cancer pain resistant to narcotic analgesics such as morphine.
  • Treatment of neuropathic pain may be defined as administration of a therapeutic dose of a compound of the formula I, II or III to reduce and preferably eliminate pain that results from nerve injury.
  • Treatment of nerve injury may be defined as administration of a therapeutic dose of a compound of the formula I, II or III to ameliorate injury and to increase the rate of recovery.
  • An increased rate of recovery is defined as a reduction of indications of pain from peripheral nerve injury, such as thermal hyperalgesia and mechanical allodynia, more quickly than would be accomplished without pharmacological or other medical intervention.
  • “Chemokine-Induced Pain” refers to pain that occurs in response, in whole or in part, to chemokines, in particular pro-inflammatory cytokines (e.g. fractalkine, CCL2, and CCL5).
  • chemokine-induced pain is arthritic pain.
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfate, sulfenyl, sulfinyl, sulfonyl, sulf
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , and R 14 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyl, C 1 -C 6 acyl
  • the invention further contemplates the use of isolated and pure, in particular, substantially pure, compounds of the formula II wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfonate, amino, imino, azido, thiol, thioalkyl, thioalk
  • R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acy
  • R 1 in a compound of the formula I or II is alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl.
  • R 1 in a compound of the formula I or II is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 3 -C 10 cycloalkyl.
  • R 1 is lower alkyl.
  • R 1 is cyclohexyl.
  • R 1 in a compound of the formula I or II is aryl, in particular phenyl, benzyl, naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, azulenyl, tetrahydronaphthyl, indanyl, biphenyl, acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl.
  • R 1 is aryl substituted with one or more of hydroxyl, alkyl, carbonyl, carboxyl, thiol, amino, nitro, ketone, aldehyde, ester, amide, lower aliphatic, aryl, cycloalkyl, and halo.
  • R 1 in a compound of the formula I or II comprises two fused aromatic rings.
  • R 1 in a compound of the formula I or II is aryloxy, in particular C 6 -C 10 aryloxy.
  • R 1 in a compound of the formula I or II is napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
  • R 1 in a compound of the formula I or II is arylalkoxy, in particular C 6 -C 10 aryloxy or C 6 -C 10 aryl-C 1 -C 3 alkoxy.
  • R 1 in a compound of the formula I or II is 2-phenylethoxy, 3-naphth-2-ylpropoxy, and 5-phenylpentyloxy.
  • R 1 in a compound of the formula I or II is aroyl, in particular C 6 -C 10 aroyl.
  • R 1 in a compound of the formula I or II is benzoyl or toluoyl.
  • R 1 in a compound of the formula I or II is a heteroaryl, in particular C 6 -C 10 heteroaryl.
  • R 1 in a compound of the formula I or II comprises one or two rings attached in a pendant manner or fused.
  • R 1 in a compound of the formula I or II is: (a) an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, most particularly, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like; (b) an unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, in particular, indolyl, isoindolyl, indolizinyl, indazolyl, quinazolinyl, pteridinyl, quinolizidinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl,
  • R 1 in a compound of the formula I or II is a heterocyclic fused with an aryl, in particular benzofuranyl, benzothiophenyl, phthalazinyl, chromenyl, xanthenyl, and the like.
  • R 1 in a compound of the formula I or II is:
  • R 15 , R 16 and R 17 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfonate, silyl, silyloxy, silylalkyl, silylthio, ⁇ O, ⁇ S, phosphonate, ureido, carboxyl,
  • R 15 , R 16 and R 17 are independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 , ⁇ NR 28 , ⁇ O, ⁇ S, nitro, cyano,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkoxy, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, sulfoxide, sulfate, sulfonyl, sulfenyl, sulfinyl, sulfonate,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Cl C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 ,
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 in a compound of the formula III cannot all be hydrogen.
  • a compound of the formula III is provided wherein both of R 10 and R 11 are not hydrogen.
  • a compound of the formula II is provided wherein R 11 is not hydrogen.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, silyl, silyloxy, silylalkyl, silylthio, ⁇ O, ⁇ S, carboxyl, carbonyl, carb
  • R 11 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 —NR 28 R 29 , ⁇ NR 28 , —S(O) 2 R 28 , —SH, —SO 3 H, nitro, cyano, halo, hal
  • a compound of the formula III is employed wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are hydrogen, hydroxyl, alkyl, and one or both of R 10 and R 11 are independently substituted or unsubstituted hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkoxy, alkenyloxy, cycloalkyl, cycloalkenyl, aryl, aryloxy, arylalkoxy, aroyl, heteroaryl, heterocyclic, acyl, acyloxy, sulfonyl, sulfinyl, sulfenyl, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, ureido,
  • R 10 and R 11 are independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 , ⁇ NR 28 , —S(O) 2 R 28 , —SH, —SO 3 H, nitro,
  • a compound of the formula III is employed wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are hydrogen; and R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 3 -C 10 cycloalkoxy, C 6 -C 10 aryl, C 6 -C 10 aryloxy, C 6 -C 10 aryl-C 1 -C 3 alkoxy, C 6 -C 10 aroyl, C 6 -C 10 heteroaryl, C 3 -C 10 heterocyclic, C 1 -C 6 acyl, C 1 -C 6 acyloxy
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are hydrogen;
  • R 10 is hydrogen, hydroxyl, alkyl (e.g., C 1 -C 6 alkyl), aryl [e.g., C 6 -C 10 aryl, in particular, phenyl which is optionally substituted (e.g., with halide)], C 3 -C 10 heterocyclic (e.g., piperazinyl which may be substituted, for example substituted with a pyrimidinyl; or morpholinyl which may be substituted), —NR 3 OR 31 wherein R 30 is hydrogen or alkyl, and R 31 is phenyl which may be substituted or alkyl (e.g., C 1 -C 6 alkyl) which may be substituted [e.g.
  • R 32 is phenyl which may be substituted; and R 11 is hydrogen, alkyl, or aryl (e.g., C6-C 10 aryl, in particular, e.g. phenyl) which may be substituted.
  • R 11 is alkyl, halo, aryl, substituted aryl (e.g. alkylaryl), or an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms
  • R 11 is lower alkyl (e.g., C 1 -C 6 alkyl) or a branched alkyl.
  • R 11 is C 6 -C 10 aryl, in particular phenyl.
  • R 11 is halo.
  • R 11 is an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl and the like.
  • R 11 is pyridinyl.
  • a compound of the formula III is employed wherein R 10 is hydrogen, halo, optionally substituted hydroxyl, alkyl, pyridinyl, phenyl, benzyl, piperazinyl, amino, morpholinyl, or —SR 33 wherein R 33 is alkyl or aryl.
  • R 10 is —NH[CH 2 ] m NR 34 R 35 wherein m is 1 to 6, in particular 2 to 4, R 34 is hydrogen, R 35 is a carboxyl, in particular —COOC(CH 3 ) 3 .
  • one of R 10 and R 11 in a compound of the formula III is a heteroaryl in particular an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, more particularly pyridinyl, and the other of R 10 and R 11 is hydrogen.
  • a compound of the formula III is employed wherein R 11 is hydrogen, halo, optionally substituted alkyl, pyridinyl, piperidinyl, morpholinyl, piperazinyl, or phenyl.
  • a compound of the formula III is used wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are hydrogen, alkyl, alkoxy, sulfonyl, sulfinyl, halo, thiol, or carboxyl, and R 11 is alkyl, alkenyl, alkoxy, alkenyloxy, aryl, heteroaryl, acyl, acyloxy, amino, imino, azido, thiol, thioalkyl, thioalkoxy, thioaryl, nitro, cyano, halo, silyl, ⁇ O, ⁇ S, carboxyl, carbonyl, carbamoyl, or carboxamide; or an isomer or a pharmaceutically acceptable salt thereof.
  • R 11 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 6 -C 10 aryl, C 6 -C 10 heteroaryl, C 1 -C 6 acyl, C 1 -C 6 acyloxy, —NH 2 , —NHR 28 , —NR 28 R 29 , ⁇ NR 28 , —S(O) 2 R 28 , —SH, —SO 3 H, nitro, cyano, halo, haloalkyl, haloalkoxy, —CO 2 H, —CO 2 R 28 , —NHC(O)R 28 , —C(O)NH 2 , —C(O)NHR 28 , —C(O)NR 28 R 29 , —NHS(O) 2 R 28 , wherein R 28 and R 29 are independently selected from C 1 -C 6 alkyl,
  • a compound of the formula III is employed wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are hydrogen, and R 11 is alkyl, alkenyl, alkynyl, alkylene, alkoxy, aryl, or an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are hydrogen and R 11 is alkyl or pyridinyl, more particularly R 11 is alkyl.
  • one of R 10 and R 11 in a compound of the formula III is alkyl, in particular C 1 -C 6 alkyl and the other of R 10 and R 11 is hydrogen.
  • one of R 10 and R 11 in a compound of the formula III is aryl in particular C 6 -C 10 aryl, more particularly phenyl or benzyl, and the other of R 10 and R 11 is hydrogen.
  • the compound of the formula II is a compound in Table 1 or 2.
  • the compound of the formula III is MW01-6-189WH, MW01-5-188WH, or MW01-2-151SRM, and/or a salt or derivatives thereof.
  • the compound of the formula II is 4-methyl-6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-2-151SRM), and/or a salt or derivative thereof.
  • the compound of the formula II is 4,6-diphenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-5-188WH), and/or a salt or derivative thereof.
  • a compound of the formula I, II or III may be in the form of a prodrug that is converted in vivo to an active compound.
  • one or more of R 10 and R 11 may comprise a cleavable group that is cleaved after administration to a subject to provide an active (e.g., therapeutically active) compound, or an intermediate compound that subsequently yields the active compound.
  • a cleavable group can be an ester that is removed either enzymatically or non-enzymatically.
  • a compound of the formula I, II or III may comprise a carrier, such as one or more of a polymer, carbohydrate, peptide or derivative thereof, which may be directly or indirectly covalently attached to the compound.
  • a carrier may be substituted with substituents described herein including without limitation one or more alkyl, amino, nitro, halogen, thiol, thioalkyl, sulfate, sulfonyl, sulfinyl, sulfoxide, hydroxyl groups.
  • the carrier is an amino acid including alanine, glycine, praline, methionine, serine, threonine, asparagine, alanyl-alanyl, prolyl-methionyl, or glycyl-glycyl.
  • a carrier can also include a molecule that targets a compound of the formula I, II or III to a particular tissue or organ.
  • a carrier may facilitate or enhance transport of a compound of the formula I, II or III to the brain.
  • the starting materials, intermediates, and compounds of the formula I, II or III may be isolated and purified using conventional techniques, such as precipitation, filtration, distillation, crystallization, chromatography, and the like.
  • the compounds of the formula I, II or III may be characterized using conventional methods, including physical constants and spectroscopic methods, in particular HPLC.
  • the compounds of the formula I, II or III which are basic in nature can form a wide variety of different salts with various inorganic and organic acids.
  • a compound of the formula I, II or III from the reaction mixture as a pharmaceutically unacceptable salt and then convert the latter to the free base compound by treatment with an alkaline reagent and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of the formula I, II or III are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • Compounds of the formula I, II or III which are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • These salts may be prepared by conventional techniques by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are typically employed to ensure completeness of reaction and maximum product yields.
  • the present invention provides methods of making the compounds disclosed herein, comprising the steps provided (See, for example, the Figures and Examples).
  • the invention provides a process for preparing a compound of the formula III wherein R 11 is hydrogen and R 10 is an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl, which comprises reacting a compound of the formula III wherein R 10 is halo, in particular chloro, and R 11 is hydrogen with boronic acid substituted with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyri
  • the invention provides a process for preparing a compound of the formula III wherein R 11 is hydrogen and R 10 is a substituted aryl which comprises reacting a compound of the formula III wherein R 10 is halo, in particular chloro, and R 11 is hydrogen, with a substituted aryl boronic acid under suitable conditions to prepare a compound of the formula III wherein R 11 is hydrogen and R 10 is a substituted aryl.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is alkyl which comprises reacting a compound of the formula III wherein R 11 is halo, in particular chloro, and R 10 is hydrogen, with an alkyl boronic acid under suitable conditions to prepare a compound of the formula III wherein R 10 is hydrogen and R 11 is alkyl.
  • R 11 is lower alkyl, in particular methyl or ethyl
  • a compound of the formula III wherein R 11 is chloro is reacted with lower alkyl boronic acid, in particular methyl or ethyl boronic acid under suitable conditions.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is aryl which comprises reacting a compound of the formula III wherein R 10 is hydrogen and R 11 is halo (e.g., chloro), with pyridazine substituted at the C3 position with halo (e.g., chloro), at the C4 position with aryl, and at the 6 position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine under suitable conditions to prepare a compound of the formula III wherein R 10 is hydrogen and R 11 is aryl.
  • R 11 is phenyl.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl which comprises reacting a compound of the formula III wherein R 11 is halo, in particular chloro, and R 10 is hydrogen, with a boronic acid substituted with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is pyridinyl which comprises reacting a compound of the formula III wherein R 11 is halo, in particular chloro, and R 10 is hydrogen, with a pyridinyl boronic acid under suitable conditions to prepare a compound of the formula III wherein R 10 is hydrogen and R 11 is pyridinyl.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, or tetrazolyl, more particularly pyridinyl which comprises reacting a pyridazine substituted at the C3 position with halo, at the C4 position with an unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, in particular, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyrid
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is pyridinyl which comprises reacting a pyridazine substituted at the C3 position with halo, at the C4 position with pyridinyl, and at the 6 position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine under suitable conditions to prepare a compound of the formula III wherein R 10 is hydrogen and R 11 is pyridinyl.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is piperidinyl or substituted piperidinyl which comprises reacting a compound of the formula II wherein R 11 is halo, in particular chloro, and R 10 is hydrogen with piperazinyl or substituted piperazinyl under suitable conditions to prepare a compound of the formula II wherein R 10 is hydrogen and R 11 is piperidinyl or substituted piperidinyl.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is an alkyl which comprises reacting a pyridazine substituted at the C3 position with halo (e.g., chloro), at the C4 position with alkyl, and at the 6 position with phenyl, with 2-(piperidin-4-yloxy)pyrimidine under suitable conditions to prepare a compound of the formula III wherein R 10 is hydrogen and R 11 is an alkyl.
  • R 11 is methyl or ethyl.
  • the invention provides a process for preparing a compound of the formula III wherein R 10 is hydrogen and R 11 is alkyl comprising reacting a compound of the formula IV
  • R 1′ is halo, in particular chloro or bromo, more particularly chloro and R 2′ is alkyl with 2-(piperazin-1-yl)pyrimidine under suitable conditions, in particular under reflux conditions to produce a compound of the formula III wherein R 10 is hydrogen and R 11 is alkyl.
  • Therapeutic efficacy and toxicity of compounds, compositions and methods of the invention may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals such as by calculating a statistical parameter such as the ED 50 (the dose that is therapeutically effective in 50% of the population) or LD 50 (the dose lethal to 50% of the population) statistics.
  • the therapeutic index is the dose ratio of therapeutic to toxic effects and it can be expressed as the ED 50 /LD 50 ratio.
  • Pharmaceutical compositions which exhibit large therapeutic indices are preferred.
  • one or more of the therapeutic effects can be demonstrated in a subject or disease model, for example, a TgCRND8 mouse with symptoms of Alzheimer's disease.
  • the invention provides dosage forms, formulations, and methods that provide advantages, in particular lower risk of side effects (e.g. lower risk of QT-related side effects) and/or beneficial pharmacokinetic profiles, more particularly sustained pharmacokinetic profiles.
  • a compound of the formula I, II or III can be utilized in dosage forms in pure or substantially pure form, in the form of its pharmaceutically acceptable salts, and also in other forms including anhydrous or hydrated forms.
  • a beneficial pharmacokinetic profile may be obtained by administering a formulation or dosage form suitable for once, twice a day, or three times a day or more administration comprising one or more compound of the formula I, II or III present in an amount sufficient to provide the required concentration or dose of the compound to an environment of use to treat a disease disclosed herein, in particular a neuroinflammatory disease.
  • the environment of use is the brain and/or plasma.
  • Embodiments of the invention relate to a dosage form comprising one or more compound of the formula I, II or III that provides peak plasma concentrations of the compound, C max , of between about 0.001 to 2 mg/ml, 0.001 to 1 mg/ml, 0.002 to 2 mg/ml, 0.005 to 2 mg/ml, 0.01 to 2 mg/ml, 0.05 to 2 mg/ml, 0.1 to 2 mg/ml, 0.001 to 0.5 mg/ml, 0.002 to 1 mg/ml, 0.005 to 1 mg/ml, 0.01 to 1 mg/ml, 0.05 to 1 mg/ml, or 0.1 to 1 mg/ml.
  • the invention provides a formulation or dosage form comprising one or more compound of the formula I, II or III that provides an elimination t 1/2 of 0.5 to 20 hours, 0.5 to 15 hours, 0.5 to 10 hours, 0.5 to 6 hours, 1 to 20 hours, 1 to 15 hours, 1 to 10 hours, or 1 to 6 hours.
  • composition or dosage form comprising one or more compound of the formula I, II or III that provides an AUC for plasma of about 3 to 2000 ng ⁇ h/ml, 3 to 3000 ng ⁇ h/ml, 3 to 4000 ng ⁇ h/ml, 2 to 2000 ng ⁇ h/ml, 2 to 3000 ng ⁇ h/ml, 2 to 4000 ng ⁇ h/ml, 1 to 2000 ng ⁇ h/ml, 1 to 3000 ng ⁇ h/ml, 1 to 4000 ng ⁇ h/ml, 1, and in particular 3 to 3000 ng ⁇ h/ml
  • a subject may be treated with a compound of the formula I, II or III or composition or unit dosage thereof on substantially any desired schedule. They may be administered one or more times per day, in particular 1 or 2 times per day, once per week, once a month or continuously. However, a subject may be treated less frequently, such as every other day or once a week, or more frequently.
  • a compound or composition may be administered to a subject for about or at least about 24 hours, 2 days, 3 days, 1 week, 2 weeks to 4 weeks, 2 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, 2 weeks to 24 months, or for more than 24 months, periodically or continuously.
  • a beneficial pharmacokinetic profile can be obtained by the administration of a formulation or dosage form suitable for once, twice, or three times a day administration, preferably twice a day administration comprising one or more compound of the formula I, II or III present in an amount sufficient to provide the required dose of the compound.
  • the required dose of a compound of the formula I, II or III administered once twice, three times or more daily is about 0.01 to 3000 mg/kg, 0.01 to 2000 mg/kg, 0.5 to 2000 mg/kg, about 0.5 to 1000 mg/kg, 0.1 to 1000 mg/kg, 0.1 to 500 mg/kg, 0.1 to 400 mg/kg, 0.1 to 300 mg/kg, 0.1 to 200 mg/kg, 0.1 to 100 mg/kg, 0.1 to 50 mg/kg, 0.1 to 20 mg/kg, 0.1 to 10 mg/kg, 0.1 to 6 mg/kg, 0.1 to 5 mg/kg, 0.1 to 3 mg/kg, 0.1 to 2 mg/kg, 0.1 to 1 mg/kg, 1 to 1000 mg/kg, 1 to 500 mg/kg, 1 to 400 mg/kg, 1 to 300 mg/kg, 1 to 200 mg/kg, 1 to 100 mg/kg, 1 to 50 mg/kg, 1 to 20 mg/kg, 1 to 10 mg/kg, 1 to 6 mg/kg, 1 to 5 mg/kg, or 1
  • Certain dosage forms and formulations may minimize the variation between peak and trough plasma and/or brain levels of compounds of the formula I, II or III and in particular provide a sustained therapeutically effective amount of the compounds.
  • the invention also contemplates a formulation or dosage form comprising amounts of one or more compound of the formula I, II or III that results in therapeutically effective amounts of the compound over a dosing period, in particular a 24 hour dosing period.
  • the therapeutically effective amounts of a compound of the formula I, II or III are between about 0.1 to 1000 mg/kg, 0.1 to 500 mg/kg, 0.1 to 400 mg/kg, 0.1 to 300 mg/kg, 0.1 to 200 mg/kg, 0.1 to 100 mg/kg, 0.1 to 75 mg/kg, 0.1 to 50 mg/kg, 0.1 to 25 mg/kg, 0.1 to 20 mg/kg, 0.1 to 15 mg/kg, 0.1 to 10 mg/kg, 0.1 to 9 mg/kg, 0.1 to 8 mg/kg, 0.1 to 7 mg/kg, 0.1 to 6 mg/kg, 0.1 to 5 mg/kg, 0.1 to 4 mg/kg, 0.1 to 3 mg/kg, 0.1 to 2 mg/kg, or 0.1 to 1 mg/kg.
  • a medicament or treatment of the invention may comprise a unit dosage of at least one compound of the formula I, II or III to provide therapeutic effects.
  • a “unit dosage” or “dosage unit” refers to a unitary, i.e. a single dose, which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically and chemically stable unit dose comprising either the active agents as such or a mixture with one or more solid or liquid pharmaceutical excipients, carriers, or vehicles.
  • a formulation or dosage form of the invention may be an immediate release dosage form or a non-immediate release delivery system, including without limitation a delayed-release or sustained-release dosage form.
  • the invention provides a sustained-release dosage form of a compound of the formula I, II or III which advantageously achieves a more sustained drug plasma and/or brain level response while mitigating or eliminating drug concentration spikes by providing a substantially steady release of the compound over time.
  • a substantially constant plasma concentration preferably correlates with one or more therapeutic effects disclosed herein.
  • the sustained-release dosage form is for oral administration.
  • a composition, in particular a dosage form or formulation may be in any form suitable for administration to a subject, including without limitation, a form suitable for oral, parenteral, intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular administration.
  • a dosage form or formulation may be a pill, tablet, caplet, soft and hard gelatin capsule, lozenge, sachet, cachet, vegicap, liquid drop, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium) suppository, sterile injectable solution, and/or sterile packaged powder.
  • a dosage form or formulation is an oral dosage form or formulation such as tablets, caplets, soft and hard gelatin capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the dosage form or formulation is a parenteral dosage form such as an active substance in a sterile aqueous or non-aqueous solvent, such as water, isotonic saline, isotonic glucose solution, buffer solution, or other solvents conveniently used for parenteral administration.
  • a compound of the formula I, II or III of the invention may be formulated into a pharmaceutical composition for administration to a subject by appropriate methods known in the art.
  • Pharmaceutical compositions of the present invention or fractions thereof comprise suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices. Suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21 st Edition. 2005, University of the Sciences in Philadelphia (Editor), Mack Publishing Company), and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • the active components can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, mannitol, sorbital, and the like.
  • the drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Suitable binders e.g. gelatin, starch, corn sweeteners, natural sugars including glucose; natural and synthetic gums, and waxes
  • lubricants e.g.
  • compositions as described herein can further comprise wetting or emulsifying agents, or pH buffering agents.
  • a composition of the invention can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the compositions can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc.
  • Various delivery systems are known and can be used to administer a composition of the invention, e.g. encapsulation in liposomes, microparticles, microcapsules, and the like.
  • Formulations for parenteral administration may include aqueous solutions, syrups, aqueous or oil suspensions and emulsions with edible oil such as cottonseed oil, coconut oil or peanut oil.
  • Dispersing or suspending agents that can be used for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.
  • compositions for parenteral administration may include sterile aqueous or non-aqueous solvents, such as water, isotonic saline, isotonic glucose solution, buffer solution, or other solvents conveniently used for parenteral administration of therapeutically active agents.
  • a composition intended for parenteral administration may also include conventional additives such as stabilizers, buffers, or preservatives, e.g. antioxidants such as methylhydroxybenzoate or similar additives.
  • a composition of the invention may be sterilized by, for example, filtration through a bacteria retaining filter, addition of sterilizing agents to the composition, irradiation of the composition, or heating the composition.
  • the compounds or compositions of the present invention may be provided as sterile solid preparations e.g. lyophilized powder, which are readily dissolved in sterile solvent immediately prior to use.
  • compositions After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition.
  • labeling would include amount, frequency, and method of administration.
  • kits comprising a compound of the formula I, II or III or a formulation of the invention in kit form.
  • the kit can be a package which houses a container which contains compounds of the formula I, II or III or formulations of the invention and also houses instructions for administering the compounds or formulations to a subject.
  • the invention further relates to a commercial package comprising compounds of the formula I, II or III or formulations of the invention together with instructions for simultaneous, separate or sequential use.
  • a label may include amount, frequency, and method of administration.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a composition of the invention to provide a therapeutic effect.
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the invention also relates to articles of manufacture and kits containing materials useful for treating a disease disclosed herein.
  • An article of manufacture may comprise a container with a label. Examples of suitable containers include bottles, vials, and test tubes which may be formed from a variety of materials including glass and plastic.
  • a container holds compounds of the formula I, II or III or formulations of the invention which are effective for treating a disease disclosed herein.
  • the label on the container indicates that the compounds of the formula I, II or III or formulations of the invention are used for treating a disease disclosed herein and may also indicate directions for use.
  • a medicament or formulation in a container may comprise any of the medicaments or formulations disclosed herein.
  • kits comprising one or more of compounds of the formula I, II or III.
  • a kit of the invention comprises a container described herein.
  • a kit of the invention comprises a container described herein and a second container comprising a buffer.
  • a kit may additionally include other materials desirable from a commercial and user standpoint, including, without limitation, buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods disclosed herein (e.g., methods for treating a disease disclosed herein).
  • a medicament or formulation in a kit of the invention may comprise any of the formulations or compositions disclosed herein.
  • kits may be useful for any of the methods disclosed herein, including, without limitation treating a subject suffering from Alzheimer's disease.
  • Kits of the invention may contain instructions for practicing any of the methods described herein.
  • compositions and methods described herein are indicated as therapeutic agents or methods either alone or in conjunction with other therapeutic agents or other forms of treatment. They may be co-administered, combined or formulated with one or more therapies or agents used to treat a condition described herein. Compositions of the invention may be administered concurrently, separately, or sequentially with other therapeutic agents or therapies.
  • compounds of the formula I, II or III may be co-administered with one or more additional therapeutic agents for treating diseases disclosed herein including without limitation beta-secretase inhibitors, alpha-secretase inhibitors, and epsilon-secretase inhibitors, acetylcholinesterase inhibitors, agents that are used for the treatment of complications resulting from or associated with a disease disclosed herein, or general medications that treat or prevent side effects.
  • additional therapeutic agents for treating diseases disclosed herein including without limitation beta-secretase inhibitors, alpha-secretase inhibitors, and epsilon-secretase inhibitors, acetylcholinesterase inhibitors, agents that are used for the treatment of complications resulting from or associated with a disease disclosed herein, or general medications that treat or prevent side effects.
  • FIG. 2 depicts a synthetic scheme for the preparation of 2-(4-(6-phenylpyridazin-3-yl)piperazin-1-yl)pyrimidine (MW01-3-183WH).
  • Reagents and conditions (a) 1-BuOH, NH 4 Cl, and 2-(piperazin-1-yl)pyrimidine.
  • a typical reaction mixture comprising about 0.01 mol of 3-chloro-6-phenylpyridazine by 2-(piperazin-1-yl)pyrimidine, about 0.05 mol of 2-(piperazin-1-yl)pyrimidine and about 0.01 mol of ammonium hydrochloride was prepared in about 15 ml of 1-BuOH. The mixture was stirred at about 130° C.
  • the reaction mixture is heated to reflux, and the color of the reaction suspension changes to dark green upon heating.
  • the reaction is complete (after refluxing for 2 h)
  • the flask is removed from the oil bath and cooled to ambient temperature.
  • the reaction is cooled in an ice-water bath and 150 mL of ice-water is added to quench the reaction.
  • the mixture is stirred vigorously for 10 minutes to give a gray precipitate and blue liquid containing copper (I) chloride.
  • the precipitate is collected by filtration (pH of the filtrate is 0-1) and washed with 100 mL of 1N HCl solution, then 100 mL of water 5 times.
  • the filter cake is stirred in 150 mL of 1N HCl solution for 0.5 h and filtered. The filter cake is subsequently washed with Milli-Q water until the filtrate is at pH 7 (approximately 7 washes). The solid is dried over a medium frit sintered glass funnel in vacuo to give 3 as a light gray powder in 93.8% yield.
  • Ice water (150 mL) is slowly poured into the reaction mixture with stirring to decompose the phosphorus oxychloride into IC 1 and H 3 PO 4 , resulting in formation of a pink solid.
  • the solid is collected by filtration and washed three times with 50 mL of Milli-Q water.
  • the solid is transferred to a 250 mL beaker, followed by addition of 100 mL of water to form a suspension.
  • the solid is filtered and washed 3 times with 100 mL of water to wash out the excess base.
  • 3-chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al., supra.
  • 6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol (22.0 g, 66 mmol) was suspended in 75 ml phosphorus oxychloride and heated with stirring at 100° C. for 3 h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+).
  • 3-chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al. supra.
  • the compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14 g, 68 mmol).
  • a mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0 mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130° C. for 3 days.
  • the solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension.
  • the solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid yielding white solid (22.1 g, 66 mmol, 97.3%).
  • 6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol (22.0 g, 66 mmol) was suspended in 75 ml phosphorus oxychloride and heated with stirring at 100° C. for 3 h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid (21.3 g, 60.3 mmol, 91.4%). ESI-MS: m/z 353.4 (M+H+).
  • 3-chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al., supra.
  • 3-chloro-6-phenylpyridazin-4-ol was synthesized according to the procedure described by Coudert, P., et al., supra.
  • This compound was prepared from 3-chloro-4-hydroxy-6-phenylpyridazine (14 g, 68 mmol).
  • a mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0 mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130° C. for 3 days.
  • the solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension.
  • the solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid yielding white solid (22.1 g, 66 mmol, 97.3%).
  • 6-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazin-4-ol 1 h (22.0 g, 66 mmol) was suspended in 75 ml phosphorus oxychloride and heated with stirring at 100° C. for 3 h. After cooling to room temperature the mixture was poured onto crushed ice. The mixture was then neutralized with NaOH solution to give white suspension. The precipitation was filtered off, washed with water, dried over filter funnel to provide white solid (21.3 g, 60.3 mmol, 91.4%).
  • the protected pyridazinone MW01-7-053WH (1.0 equiv.) was mixed with arylboronic acid (1.37 equiv.), Pd(PPh 3 ) 4 (0.05 equiv.) and K 2 CO 3 (3.1 equiv) and 200 mL of DME in a 350 ml of pressure vessel, flushed with argon for 3 min, and the mixture was then stirred and refluxed (oil bath, 120° C.) until the starting material had disappeared. After cooling, the solution was concentrated to dryness under reduced pressure, the residue was treated with water and filtered off. The filter cake was washed with water over filter funnel and then used for next step directly.
  • FIG. 13 A synthetic reaction scheme for the preparation of 4,6-diphenyl-3-piperazinylpyridazine (MW01-7-133WH) is depicted in FIG. 13 , and synthesis was carried out as described herein.
  • the compound was prepared from 3-chloro-4,6-diphenylpyridazine (533 mg, 20 mmole) in the same manner as described for MW01-7-057WH, yielding light yellow solid (550 mg, 17.4 mmole, yield 86.9%).
  • ESI-MS m/z 317.3 (M+H+).
  • FIG. 14 A synthetic reaction scheme for the preparation of 2-(4-(6-phenyl-4-(piperidin-1-yl)pyridazin-3-yl)piperazin-1-yl)pyrimidine (MW01-7-107WH) is depicted in FIG. 14 , and synthesis was carried out as described herein.
  • the compound was prepared from MW01-6-127WH (200 mg, 0.57 mmole) in the same manner as described for MW01-7-057WH, yielding light yellow solid (220 mg, 0.55 mmole, yield 96.3%).
  • ESI-MS m/z 402.5 (M+H+).
  • FIG. 15 A synthetic reaction scheme for the preparation of 6-methyl-4-phenyl-3-(4-pyrimidin-2-ylpiperazin-1-yl)pyridazine (MW01-7-057) is depicted in FIG. 15 , and synthesis was carried out as described herein.
  • a mixture of 3-chloro-6-methyl-4-phenylpyridazine (100 mg, 0.5 mmol), 1-(2-pyrimidyl)piperazine (400 mg, 2.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130° C. for 7 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension.
  • the following assays can be used to confirm the activity of the pyridazine compounds.
  • Cell culture assays Cell-based assays of the concentration-dependent activity of a compound of the invention will be conducted using methods previously described (Mirzoeva et al., J Med Chem 45:563-566, 2002).
  • BV-2 mouse microglial cells (1.25 ⁇ 10 4 cells/well in a 48-well plate) will be cultured for one day in ⁇ MEM media containing 10% fetal bovine serum (FBS), and then treated in serum-free media for 16 hrs with either control buffer or the standard glial activating stimulus lipopolysaccharide (LPS, from Salmonella typhimurium; 100 ng/ml final concentration) in the presence of diluent or compound.
  • Stock solutions (20 mM) of compounds will be prepared in dimethylsulfoxide (DMSO). Solutions for cell treatments will be prepared by dilution of stock solutions into serum-free media immediately before adding to the cells. Control wells will contain the same final concentration of DMSO as the compound-containing wells.
  • rat primary mixed glia will be prepared and stimulated with human oligomeric A ⁇ 1-42 (10 ⁇ M) as previously described (Mirzoeva et al., 2002, supra).
  • Antibodies and dilutions used for Western blots will be as follows: anti-COX-2 (1:1000, Santa Cruz), anti-iNOS (1:1000, Transduction Laboratories), anti-apoE (1:1000). Antibody against M-actin (1:500,000 dilution, Sigma) will be used to confirm equal protein loading among the samples.
  • In vivo efficacy studies in mice. The study design and treatment paradigm for intracerebroventricular (ICV) infusion of human oligomeric A ⁇ 1-42 into the mouse will be as described previously (Craft et al., Neurobiol Aging 25:1283-1292, 2004b), except that compound administration will be by mouth.
  • Female C57Bl/6 mice (Harlan) weighing 20-25 g (3-4 months old) will be housed in a pathogen free facility under an approximate 12 h/12 h dark and light cycle and they will have access ad libitum to food and water.
  • mice will be administered by oral gavage either test compound (2.5 mg/kg/day) or solvent control (10% DMSO) in a 0.5% (w/v) carboxymethylcellulose suspension.
  • test compound 2.5 mg/kg/day
  • solvent control 10% DMSO
  • a 0.5% (w/v) carboxymethylcellulose suspension a 0.5% (w/v) carboxymethylcellulose suspension.
  • Y maze test of spontaneous alternation will be used to evaluate hippocampus-dependent spatial learning as described previously (Craft et al., J Mol Neurosci 24:115-122, 2004a). Briefly, each mouse will be placed in the “start” arm and then released to choose one of the two other arms.
  • mice will be blocked from exiting the chosen arm for 30s then they will be placed back in the start arm and released again to choose one of the two other arms. If the second choice is different from the first one, the mouse will be scored as alternating. Mice will be tested for 10 days with one trial per day, and a mean percent alternation will be calculated for each mouse.
  • mice At day 60 after start of A ⁇ ICV infusion, mice will be anesthetized with pentobarbital (50 mg/kg) and perfused with a HEPES buffer (10 mM, pH 7.2) containing a protease inhibitor cocktail (1 ⁇ g/ml leupeptin, 1 ⁇ M dithithreitol, 2 mM sodium vanadate, 1 ⁇ M phenylmethylsulphonylfluoride). The brain will be removed and longitudinally bisected as described previously (Craft et al., Neurobiolo Aging 25:1283-1292, 2004b). The right half of the brain will be fixed in 4% (v/v) paraformaldehyde and paraffin-embedded for histology.
  • the hippocampus will be dissected from the left half of the brain and snap-frozen for subsequent biochemical evaluation.
  • Hippocampal extract supernatants will be prepared by dounce and sonication in the HEPES buffer containing a protease inhibitor cocktail, followed by centrifugation as described (Craft et al., 2004b, supra).
  • IL-1 ⁇ and TNF ⁇ in hippocampal supernatants will be measured by ELISA (Biosource International) per the manufacturer's instructions. S100B levels in hippocampal supernatants will be measured by a europium-based ELISA essentially as previously described (Van Eldik and Griffin, Biochem Biophys Acta 1223:398-403, 1994). Synaptophysin levels in hippocampal supernatants will be quantified by ELISA following the procedure described previously (Craft et al, 2004b, supra). PSD-95 levels will be determined by Western blots using anti-PSD-95 antibodies (1:100,000 dilution; Upstate Biotechnology) as described (Craft et al., 2004b).
  • Immunohistochemical detection of activated astrocytes and microglia will be performed on 10 ⁇ m sections as described previously (Craft et al, 2004b, supra), with anti-GFAP (1:1500; Sigma) and anti-F4/80 (1:100; Serotek) antibodies, respectively, using the mouse on mouse or Vectastain Universal Elite ABC immunodetection kits (Vector/Novocastra) and development with diaminobenzidine (DAB) substrate.
  • Cell bodies will be manually counted in the hippocampus of three GFAP and F4/80 labeled sections positioned at ⁇ 1.8, ⁇ 2.1, and ⁇ 2.3 mm from bregma.
  • a ⁇ immunohistochemistry will be done with a rabbit anti-human A ⁇ antibody as previously described (Craft et al., 2004b, supra). Cell counts and amyloid plaque counts will be determined by two blinded observers and amyloid plaque area will be determined as previously described (Craft et al., 2004b, supra). Peroxynitrite-mediated neuronal damage will be measured with an anti-nitrotyrosine antibody (1:125; Chemicon), using the Vectastain Rabbit Elite ABC kit.
  • the HPLC system (Dionex Corp., Sunnyvale, Calif.) includes a Dionex P480 pump, a Phenomenex Luna C18 column (250 ⁇ 2.0 mm, 5 ⁇ m) with a guard column (Phenomenex, Torrance, Calif.) and a Dionex UVD340U Ultraviolet (UV) detector.
  • the mobile phase will consist of 0.1% formic acid as reagent A and 0.08% formic acid/water in 80% acetonitrile as reagent B, at a flow rate of 0.2 ml per minute.
  • the gradient will consist of the following linear and isocratic gradient elution changes in reagent B: isocratic at 60% from 0 to 5 min, 60% to 90% from 5 to 39 min, isocratic at 90% until 44 min. Peak quantification will be done based on absorption measured at 260 nm relative to a standard curve obtained by using serial dilutions of the compound.
  • a compound 2.5 mg/kg will be administered to mice by oral gavage in a 0.5% (w/v) carboxymethylcellulose suspension.
  • pentobarbital 50 mg/kg
  • Blood will be harvested by intracardiac puncture, collected in heparinized tubes, and plasma will be obtained by centrifugation.
  • mice will be perfused with a HEPES buffer (10 mM, pH 7.2) containing a protease inhibitor cocktail (1 ⁇ g/ml leupeptin, 1 ⁇ M dithithreitol, 2 mM sodium vanadate, 1 ⁇ M phenylmethylsulphonylfluoride), and brains will be removed and weighed. Brain homogenates will be prepared by dounce and sonication in the HEPES buffer containing a protease inhibitor cocktail. Brain homogenates will be centrifuged at 12000 ⁇ g for 10 minutes and the supernatant acidified by diluting 1:3 with 0.1% formic acid (Fluka).
  • a protease inhibitor cocktail 1 ⁇ g/ml leupeptin, 1 ⁇ M dithithreitol, 2 mM sodium vanadate, 1 ⁇ M phenylmethylsulphonylfluoride
  • Solid phase extraction followed by HPLC analysis will be used to quantify the amount of compound in brain supernatants. Briefly, cartridges (Sep-Pak® C18, Waters) will be conditioned with 1 ml of acetonitrile (HPLC grade, EMD Biosciences) and equilibrated with 1 ml of water. A structural analog of the compound will be used as an internal standard. The acidified brain supernatant will be added to the cartridge followed by a 1 ml wash with 30% acetonitrile. The compound will be eluted from the cartridge using 80% acetonitrile.
  • the eluate will be evaporated to dryness, reconstituted in 0.08% formic acid/water in 80% acetonitrile and analyzed by HPLC using the following gradient in reagent B: 0% to 60% from 2 to 5 min, isocratic at 65% until 7 min, 65% to 80% from 7 to 12 min, isocratic at 80% until 15 min, 89% to 100% from 15 to 18 min and isocratic at 100% until 23 min.
  • Plasma samples will be deproteinized in 0.1M perchloric acid and centrifuged at 12000 ⁇ g for 10 min. The supernatant will be neutralized with 1M NaOH then extracted with dichloromethane, and the layers separated at 3000 ⁇ g for 5 min.
  • the organic phases from three successive extractions will be pooled and then evaporated to dryness under reduced pressure.
  • the dried residue will be reconstituted in 50 ⁇ l of reagent B, and 10 ⁇ l of the reconstituted material will be analyzed by HPLC using the gradient described above for brain supernatants.
  • mice will be administered by oral gavage of compound (2.5 mg/kg/day) or diluent (10% DMSO) in a 0.5% (w/v) carboxymethylcellulose suspension once daily for two weeks. After the last administration, mice will be injected intraperitoneally (i.p) with 10 mg/kg of LPS. Control mice will be injected with saline. Six hours after the LPS challenge, mice will be anesthetized with pentobarbital (50 mg/kg) and blood will be drawn by intracardiac puncture, allowed to clot, and centrifuged for serum preparation. Brains will be removed and processed as described above. Levels of IL-1 ⁇ and TNF ⁇ in brain supernatants and serum will be measured using a MSD multiplex assay per the manufacturer's instructions (Meso Scale Discovery, Gaithersburg, Md.).
  • mice Liver toxicity after chronic in vivo administration of Compound.
  • Mice will be administered by oral gavage either test compound (2.5 mg/kg/day) or diluent (10% DMSO) in a 0.5% (w/v) carboxymethylcellulose suspension once daily for two weeks. Mice will be anesthetized and sacrificed as described above. Livers will be removed, fixed in 4% (v/v) paraformaldehyde and paraffin-embedded for histology. To assess histological toxicity, 4 ⁇ m liver sections will be stained with haematoxylin and eosin. Two independent observers blinded to the treatment groups will perform microscopic assessment of the tissue for injury.
  • the animal When the platform is kept in the same position, the animal quickly learns to use distal cues to locate the position of the platform, even if the mouse is placed in the pool at different starting positions.
  • the experimental protocol for the Morris maze test is as described in Ohno et al, (Eur. J. Neurosci. 2006, 23(8): 2235-40; Learn Mem 2005, 12(3): 211-5). Briefly, the pool is 1.2 m in diameter and made of white metal. The water is maintained at 25 ⁇ 1° C. and is made opaque with nontoxic white paint to hide the square, white escape platform (10 cm ⁇ 10 cm). During training, the platform is submerged (1 cm) below the water surface and remains in the same position to avoid quandrant biases.
  • mice receive six trials per day for 4 days (3 blocks of two trials; 1 min intertrial intervals, 1-hour interblock intervals).
  • the mouse is placed into the water facing the wall of the pool and is allowed to search for the platform.
  • the starting position varies among four locations in a pseudorandom manner for each trial.
  • the trial ends when an animal climbs onto the platform or when a maximum of 60 sec has elapsed.
  • the mouse is placed on the platform for 60 sec before and after each trial.
  • All mice are given a probe test with the platform removed from the pool.
  • the behaviour of the mouse is recorded by a video camera and analyzed computationally for several parameters such as latency to finding the platform, total distance traveled, and percent of time spent in the target quadrant.
  • mice At post-operative day 60 mice will be anesthetized and perfused with a Hepes buffer containing a protease inhibitor cocktail. The brains are then removed and longitudinally bisected. The right half of the brain is fixed in a paraformaldehyde/phosphate buffer solution and embedded in paraffin for histological examination, while the hippocampus is isolated from the left hemisphere and snap frozen for biochemical evaluation of endpoints.
  • MW01-2-151SRM will be tested in the Tg6799 mouse at 5, 10 and 25 mg/kg.
  • neuroinflammation and synaptic dysfunction biochemical endpoints and Y-maze behavioral endpoint will be determined.
  • a higher dose is proposed based on the start of administration to animals that are already showing signs of pathology based on characterization of strain. More animals needed for significance are compared to the infusion model and longer time due to required expansion of colony via breeding.
  • the following eight compounds were synthesized: MW01-4-179LKM; MW01-2-151SRM; MW01-7-107WH; MW01-6-189WH; MW01-7-084WH; MW01-7-085WH7) MW01-7-133WH; and MW01-7-057WH (See FIGS. 1 to 15 and Example 1).
  • nitric oxide IL-1 ⁇
  • All eight compounds inhibited LPS-induced IL-1 ⁇ production in BV-2 microglia cells in a concentration-dependent manner.
  • Most compounds were also selective, in that they did not inhibit production of nitric oxide (NO).
  • NO nitric oxide
  • the lack of an effect on NO production was further validated by showing no effect on up-regulated levels of iNOS. No effect over the same concentration range was seen on up-regulation of COX-2.
  • MW01-2-151SRM MW01-4-179LKM
  • MW01-6-189WH MW01-7-084WH
  • MW01-7-085WH MW01-7-133WH
  • MW01-7-057WH One compound, MW01-7-107WH, was non-selective in that it also inhibited production of NO, iNOS and COX-2 over the same concentration ranges.
  • MW01-2-151SRM MW01-6-189WH
  • MW01-7-084WH MW01-7-085WH
  • MW01-7-057WH The best compounds in vivo were MW01-2-151SRM and MW01-6-189WH. These two compounds blocked the up-regulation of IL-1 ⁇ and S100B, and prevented the loss of PSD-95.
  • MW01-2-151SRM also prevented the loss of synaptophysin.
  • MW01-6-189WH showed a trend toward preventing the synaptophysin loss; however, statistical significance was not reached due to limitations in sample size.
  • MW01-7-084WH and MW01-7-085WH blocked the upregulation of IL-1 ⁇ and S100B, and prevented loss of PSD-95. They were not as effective as MW01-2-151SRM in preventing the synaptophysin loss. MW01-7-057WH blocked S100B upregulation and synaptophysin loss, but did not block IL-1 ⁇ upregulation or PSD-95 loss. (See FIGS. 24 to 28 showing the results of in vivo activity of MW01-2-151SRM; MW01-6-189WH; MW01-7-084WH; MW01-7-085WH; and MW01-7-057WH in the A ⁇ infusion mouse model.) C.
  • the lead compounds were tested in the human A ⁇ infusion mouse model using the Y-maze behavioral assay at 1.25, 2.5, 5, and 10 mg/kg.
  • Neuroinflammation biochemical endpoints hippocampus levels of IL-1 ⁇ , TNF ⁇
  • a synaptic dysfunction biochemical endpoint hippocampus levels of synaptophysin
  • MW01-2-151SRM, MW01-6-189WH, and MW01-7-057WH were significantly effective in preventing the Y-maze behavioral deficit brought about by human A ⁇ infusion.
  • MW01-7-084WH and MW01-7-085WH showed a trend toward preventing the Y maze behavioral deficit.
  • hERG human ether-a-go-go
  • the hERG channel conducts rapidly activating delayed rectifier potassium currents that critically contribute to cardiac repolarization. Mutations in the hERG channel gene and drug-induced blockade of the currents have been linked to delayed repolarization of action potentials resulting in prolonged QT interval (Finlayson et al., 2004; Recanatini et al., 2005; Roden, 2004). QT prolongation is considered a significant risk factor against cardiac safety of new drugs.
  • the initial assay is a radioligand binding assay that tests the ability of the test compound to compete with 3 H-astemizole (a reference standard that binds to hERG channels with nM affinity) for binding to recombinant hERG channels stably expressed on human HEK-293 cells.
  • 3 H-astemizole a reference standard that binds to hERG channels with nM affinity
  • This cell line was chosen because it is of human origin, has been fully characterized with regard to hERG electrophysiology and pharmacology and displays the expected characteristics of I Kr current as well as expected pharmacological sensitivities, and is easy to maintain in culture (Zhou et al., J. Gen Physiol. 1998, 111(6): 781-94).
  • test compound A single concentration (10 ⁇ M) of test compound is assayed, and % inhibition of 3 H-astemizole binding is calculated. Generally, any compounds that show >50% inhibition are tested further in the hERG channel activity assay. This is usual for medium throughout screens but is not recommended in the FDA document and tends to give false positives, as evidenced by the results reported below.
  • the hERG channel activity inhibition assay provides whole cell electrophysiological data about compound effects on the hERG K + channel function.
  • Whole cell patch clamp methodology is generally considered to be the gold-standard determination of ion channel activity, rather than simply measuring channel binding.
  • the standard testing procedure is to use 3 to 5 concentrations of compound at log dilutions with each concentration tested in triplicate (three cells). This allows a balance between achieving a reasonably accurate IC 50 measurement against a broad concentration range, and reducing cell attrition that would occur during more protracted experiment durations.
  • a known hERG channel inhibitor such as astemizole, is applied as a positive control.
  • hERG channel activity assay can give false positives and false negatives
  • the QT interval studies are performed by evaluating compounds for effects on QT interval in Lead II electrocardiograms measured in anesthetized guinea pigs (Hirohashi et al., 1991, Arzneim.-Forsch./Drug Res 41:9-18), one of the species recommended in the FDA white paper. Vehicle or compound is administered orally at 15 mg/kg (dosing volume of 10 ml/kg) to groups of male guinea pigs (weighing 330-350 g), with 5 animals per group.
  • This dose corresponds approximately to 20-fold the therapeutic dose by taking into account the body surface area of the animals.
  • Heart rate, arterial blood pressure, and QT intervals are measured at baseline, and at 15, 30, 45, and 60 min after compound administration. Sotalol administered iv at 0.3 mg/kg serves as the positive control compound.
  • the QT intervals are corrected for changes in heart rate using both Bazett's and Fridericia's formulae. Any increase in QT interval values over baseline values exceeding the upper 95% confidence limit of the mean changes at the corresponding time point in the vehicle-treated control group for two consecutive observation times indicates significant QT interval prolongation in the individually treated animals.
  • This functional testing in early discovery provides a rapid and cost-effective method to better anticipate and eliminate compounds that may have adverse QT prolongation potential in humans.
  • MW01-5-188WH, MW01-2-151SRM, and MW01-6-127WH were tested at 10 ⁇ M concentration.
  • MW01-5-188WH showed 91% inhibition at 10 ⁇ M.
  • MW01-2-151SRM and MW01-6-189WH were tested at three concentrations (0.1, 1, 10 ⁇ M). These compounds showed minimal inhibition, with IC 50 values of 4.81 ⁇ M for MW01-6-189WH and 9.21 ⁇ M for MW01-2-151SRM.
  • a test substance (e.g., MW01-2-151SRM) was evaluated for possible effects on QT interval in Lead II electrocardiogram measure in anesthetized guinea pigs.
  • the QT intervals (QTc) were corrected for changes in heart rate using both Bazett's and Fridericia's formulae. Any increase in QTc values over baseline values exceeding the upper 95% confidence limit of the change at corresponding time point in the vehicle-treated control group for 2 consecutive observation times indicates significant QTc prolongation in the individually treated animals.
  • the test substance at 15 mg/kg PO did not cause any significant prolongation in QTc interval in all of the 5 treated animals during the 60-minute period post-dosing ( FIGS. 29 and 31 ).
  • MW01-5-188WH and MW01-2-151SRM were administered PO at 15 mg/kg to 5 guinea pigs (330-350 g weight).
  • QT intervals were obtained at baseline and at 15 min, 30 min, 45 min, and 60 min after compound administration. Neither compound increased cardiac QT interval above the mean+2SD of corresponding values in the vehicle control group. There were also no significant effects on mean blood pressure or heart rate after compound administration.
  • Example data for MW01-5-188WH are shown in FIG. 33 .
  • the positive control compound, sotalol induces a significant increase in cardiac QTc interval.
  • test substance was dissolved in 2% Tween 80 and administered by oral administration.
  • the substance was treated at 15 mg/kg with a dosing volume of 10 ml/kg with a dosing volume of 10 ml/kg.
  • Duncan Hartley derived guinea pigs provided by MDS Pharma Services—Taiwan Ltd were used. Sotalol was obtained from Sigma, USA.
  • Liver toxicity is an especially important initial consideration for orally administered compounds, as the liver is the major site of initial drug metabolism and is critical to overall metabolism and homeostasis of an animal. Liver injury is also a component of idiopathic tissue injury seen in certain chronically administered drugs. Therefore, it is important to do initial assessments of liver toxicity after oral administration of compounds to mice.
  • mice For the escalating-dose, acute toxicity assays, mice (5 per experimental group) are administered either compound or vehicle in 0.5% carboxymethylcellulose (alternatively, castor oil or sesame oil can be used) by oral gavage once daily for 3 days. Standard compound doses are 3.1, 12.5, and 50 mg/kg; the highest dose is 20 ⁇ a therapeutic dose. On the 4 th day, mice are sacrificed and the liver harvested and fixed for histology.
  • Paraffin-embedded, hematoxylin & eosin (H&E)-stained sections of liver tissue are analyzed microscopically for injury by two individuals blinded to the treatment groups.
  • a semi-quantitative histological scoring system from 0 (best) to 9 (worst) is applied that considers architecture features (normal to extensive fibrosis), cellular features (normal to extensive edema and widespread necrosis), and degree of inflammatory infiltrate (normal to extensive infiltrate). For each acute toxicity assay, 15 mg of compound is required.
  • mice For the therapeutic dose, chronic toxicity assays, mice (5 per experimental group) are administered either compound or vehicle in 0.5% carboxymethylcellulose by oral gavage once daily for 2 weeks at a therapeutic dose of 2.5 mg/kg/day. After two weeks of treatment, mice are sacrificed and liver toxicity analyzed as described above. For each chronic toxicity assay, 5 mg of compound is required.
  • MW01-5-188WH has been tested in the acute, escalating-dose assay and the chronic, therapeutic dose assay. There was no histological evidence of tissue toxicity at the lower doses but some vacuolisation was observed at the 50 mg/kg dose.
  • MW01-2-151SRM has been tested in the chronic, therapeutic dose assay. There was no histological evidence of tissue toxicity; no differences were seen by histology in livers from mice treated with vehicle or with compound.
  • MW01-6-189WH has been tested in the chronic, therapeutic dose assay. There was no histological evidence of tissue toxicity; no differences were seen by histology in livers from mice treated with vehicle or with compound.
  • MW01-5-188WH was tested in the chronic, therapeutic dose assay.
  • mice were administered by oral gavage either MW01-5-188WH (2.5 mg/kg) or diluent (10% DMSO) in a 0.5% (w/v) carboxymethylcellulose suspension once daily for 2 weeks.
  • Mice were anesthetized and killed as described above. Livers were removed, fixed in 4% (v/v) paraformaldehyde, and paraffin-embedded for histology.
  • 41m liver sections were stained with hematoxylin and eosin. Two independent observers blinded to the treatment groups performed microscopic assessment of the tissue for injury. Histological assessment of liver tissue showed that oral administration of MW01-5-188WH at 2.5 mg/kg daily for 2 weeks did not induce any indices of hepatotoxic tissue injury compared with mice treated with the diluent.
  • the HPLC system (Dionex, Sunnyvale, Calif.) includes a Dionex P680 pump, a Phenomenex (Torrance, Calif.) Luna C18 column (250 ⁇ 2.0 mm; 5 ⁇ m) with a guard column, and a Dionex UVD340U ultraviolet detector.
  • the mobile phase consisted of 0.1% formic acid as reagent A and 0.08% formic acid/water in 80% acetonitrile as reagent B at a flow rate of 0.2 ml per minute.
  • the gradient consisted of the following linear and isocratic gradient elution changes in reagent B: isocratic at 60% from 0 to 5 min, 60-90% from 5 to 39 min, isocratic at 90% until 44 min.
  • Peak quantification was done based on absorption measured at 260 nm relative to a standard curve obtained by using serial dilutions of MW01-5-188WH.
  • MW01-5-188WH 2.5 mg/kg was administered to mice by oral gavage in a 0.5% (w/v) carboxymethylcellulose suspension.
  • pentobarbital 50 mg/kg.
  • Blood was harvested by intracardiac puncture, collected in heparinized tubes, and plasma obtained by centrifugation. Mice were perfused with PBS.
  • Brain homogenates were centrifuged at 12,000 ⁇ g for 10 min and the supernatant acidified by diluting 1:3 with 0.1% formic acid (Fluka, Sigma-Aldrich, St. Louis, Mo.). Solid phase extraction followed by HPLC analysis was used to quantify the amount of compound in brain supernatants. Briefly, cartridges (Sep-Pak C18; Waters Associates, Milford, Mass.) were conditioned with 1 ml of acetonitrile (HPLC grade; EMD Biosciences, San Diego, Calif.) and equilibrated with 1 ml of water. A structural analog of MW01-5-188WH was used as an internal standard.
  • the acidified brain supernatant was added to the cartridge followed by a 1 ml wash with 30% acetonitrile.
  • MW01-5-188WH was eluted from the cartridge using 80% acetonitrile.
  • the eluate was evaporated to dryness, reconstituted in 0.08% formic acid/water in 80% acetonitrile, and analyzed by HPLC using the following gradient in reagent B: 0-60% from 2 to 5 min, isocratic at 65% until 7 min, 65-80% from 7 to 12 min, isocratic at 80% until 15 min, 89-100% from 15 to 18 min, and isocratic at 100% until 23 min.
  • Plasma samples were deproteinized in 0.1 M perchloric acid and centrifuged at 12,000 ⁇ g for 10 min. The supernatant was neutralized with 1 M NaOH, then extracted with dichloromethane, and the layers separated at 3000 ⁇ g for 5 min. The organic phases from three successive extractions were pooled and then evaporated to dryness under reduced pressure. The dried residue was reconstituted in 50 ⁇ l of reagent B, and 10 ⁇ l of the reconstituted material was analyzed by HPLC using the gradient described above for brain supernatants.
  • Integrative chemical biology tools for neurosciences and CNS targeted drugs must exhibit appropriate bioavailability and brain uptake or penetration of the blood-brain barrier.
  • Daily oral administration is the preferred method of administration for longer-term and time-delimited in vivo studies using animal models and is the preferred mode in drug development for a variety of reasons, including better patient compliance.
  • it is critical to demonstrate bioavailability and appropriate rates of initial brain uptake for an inhibitor, to fully interpret the outcomes from in vivo studies. Therefore, the rate of MW01-5-188WH concentration change in the blood after oral administration (oral bioavailability) and its rate of change in the brain were determined.
  • the MW01-5-188WH peak brain/blood concentration ratio is >3.3, comparable with those of CNS drugs in clinical use.
  • the brain/blood ratio for minaprine, a 6-phenylaminopyridazine CNS drug is about 2 (Caccia et al., 1985 Xenobiotica, 15(12): 1111-9).
  • MW01-5-188WH was administered daily at a standard therapeutic dose (2.5 mg/kg) by oral gavage for 2 weeks, and then mice were challenged with an intraperitoneal injection of bacterial LPS. Six hours after the LPS challenge, the serum and brain levels of IL-1 ⁇ and TNF- ⁇ were measured. As anticipated, the LPS challenge induced an increase in the levels of IL-1 ⁇ and TNF- ⁇ in the serum (FIG. 35 C,D) and brain (FIG.
  • PK parameters that will be derived include C max , T max , t 1/2 , AUC, CI/F, V d and MRT.
  • Dosing formulation oral gavage/CMC solution.
  • a study may be performed utilizing 14 C-labelled minozac (MW01-2-151SRM) to analyze excretion (urine, feces) and plasma distribution.
  • Dose level 1 10 mg/kg
  • Dose level 2 100 mg/kg
  • Dose level 3 500 mg/kg
  • Dose level 4 1000 mg/kg
  • Dose level 5 3000 mg/kg
  • Result An estimated single-dose MTD/MFD (sdMTD)
  • Phase B of the study may be performed.
  • Oral dose level 1 30 mg/kg
  • Oral dose level 2 100 mg/kg
  • Oral dose level 3 300 mg/kg
  • IV dose 1 100 mg/kg
  • IV dose 2 300 mg/kg
  • Oral dose level 4 1000 mg/kg
  • Oral dose level 5 3000 mg/kg.
  • PK parameters to be derived include C max , T max , t 1/2 , AUC, CI/F, V d and MRT.
  • the dosing will be by oral gavage with CMC solution.
  • Results: PK (plasma and CSF drug levels) will be determined at Day 1 and Day 28. Necropsy will be determined after the completion of treatment. Mortality, clinical observations, body weights, food consumption, clinical pathology, opthalmoscopy, gross pathology, and organ weights will be determined. Histopathology will be determined on control and high dose groups.
  • Necropsy will be determined after 28 days additional follow-up period. Mortality, clinical observations, body weights, food consumption, clinical pathology, opthalmoscopy, gross pathology, and organ weights will also be determined. Histopathology will be determined if required by observation of treatment effects.
  • PK Pla and CSF drug levels
  • Necropsy will be determined after the completion of treatment. Mortality, clinical observations, body weights, food consumption, clinical pathology, gross pathology, and organ weights will be determined. Histopathology will be done on all dose groups
  • Necropsy will be determined after 28 days additional follow-up period. Mortality, clinical observations, body weights, food consumption, clinical pathology, opthalmoscopy, gross pathology, and organ weights will be determined. Histopathology if required will be determined by observation of treatment effects.
  • HPLC traces were obtained on a Rainin Instruments HPLC on commercially available SUPELCO C18 reverse phase column (25 ⁇ 4.6 mm, 5 ⁇ m).
  • the mobile phase consisted of 0.1% formic acid in Milli-Q water as reagent A and 0.08% formic acid/Milli-Q water in 80% acetonitrile as reagent B.
  • the flow rate of 1.5 ml/min was used in a gradient of 0 to 100% of reagent B over 22 minutes.
  • the HPLC traces were tracked by UV absorption at 260 nm.
  • HPLC system (Dionex, Sunnyvale, Calif.) consisted of the following components: a Dionex P680 pump, a Dionex ASI-100 autosampler, a Phenomenex (Torrance, Calif.) Luna C18 column (250 ⁇ 2.0 mm; 5 ⁇ m) with a guard column, and a Dionex UVD1700 ultraviolet detector.
  • the mobile phase consisted of 0.1% formic acid in Milli-Q water as reagent A and 0.08% formic acid/Milli-Q water in 80% acetonitrile as reagent B. The flow rate of 0.2 mL/min was used, unless stated otherwise in the text.
  • the gradient consisted of a linear change from 0 to 100% of reagent B over 30 minutes. UV absorption was monitored at four wavelengths (215, 230, 260 and 300 nm) with the 260 nm trace being reported. Compounds were injected at concentrations 100-times greater than the lower detection limit of the instrument (500 ng injected).
  • the reaction mixture was then cooled to ambient temperature and quenched with either 33% hydrogen peroxide or 10% sodium hydroxide.
  • the aqueous layer was extracted with ether (3 ⁇ 30 mL) and the ethereal layers are combined and evaporated under reduced pressure.
  • the crude mixture is run on a silica gel column and eluted with hexanes:ethyl acetate (1:1 v/v).
  • the product 2 is obtained as a pale pink solid in 45% yield.
  • This compound was prepared via the pyrazine triflate with 1-(2-pyrimidyl)piperazine as the amine following the procedure of Adams et al ( Synlett 2004, 11, 2031-2033). Pyridine was used as an anhydrous reagent kept under argon in a sure-seal bottle (Aldrich). The compound 24 (100 mg, 0.52 mmol) and DMAP (65.7, 0.52 mmol) were dissolved in pyridine and methylene chloride (0.5: 4 ml v/v), and cooled to 0° C. The trifluoromethane sulfonic acid (0.8 mmol, 135.5 ⁇ L) was added dropwise and stirred for 15 min at 0° C.
  • a NaOH solution was used to absorb the HCl that escapes from dry tube.
  • the reaction mixture was cooled to ambient temperature, and placed into an ice-water bath. 150 mL of ice-water was added to quench the reaction. The mixture was stirred vigorously for 10 minutes to give a gray precipitate and blue liquid containing copper (I) chloride. The precipitate was then collected by filtration (pH of the filtrate is 0-1) and washed first with 1N HCl (100 mL), then with Milli-Q water (5 ⁇ 100 mL). To remove remaining copper by-products, the filter cake was stirred in 1N HCl (150 mL) for 0.5 h and then filtered.
  • the HPLC system (Dionex Corp., Sunnyvale, Calif.) consisted of the following components: a Dionex P680 Pump, a Dionex ASI-100 autosampler, a Phenomenex (Torrance, Calif.) Luna C18 column (250 ⁇ 2.0 mm; 5 ⁇ M) with a guard column, and a Dionex UVD170U detector.
  • the mobile phase consisted of 0.1% formic acid (Fluka) in Milli-Q water as solvent A and 80% acetonitrile (Burdick & Jackson), with 0.08% formic acid in Milli-Q water as solvent B. Peak quantification was performed based upon absorption at 254 nm relative to a standard curve obtained by serial dilutions of the compound.
  • Capillary tubes used in the micro scale aqueous solubility determination were purchased from Büchi, Switzerland. The weighting of the compounds was performed on SartoriusAG (Germany) analytical balance. Milli-Q water was obtained using Millipore System (Bedford, Mass.). The orbital shaker/incubator was purchased from Barnstead International (Melrose Park, Ill.).
  • Dry, clean borosilicate capillary tubes were weighed using an analytical balance. Between 17-30 mg of 16 was weighed and added to the tubes. Distilled, purified Milli-Q water was added to the tubes to create solutions with concentrations ranging from 1-2 g/ml. Sample tubes were mixed manually to ensure sufficient wetting and were placed in an incubator set at 37° C. overnight. A sample was collected from each tube, centrifuged at 10,000 rpm for 10 min, and injected onto a reversed-phase HPLC.
  • the partition coefficients of 16 and 26 were determined using 1-octanol (Sigma) and water. Between 0.5-1 mg/ml of each compound was dissolved in Milli-Q water and allowed to partition into presaturated octanol. The samples were placed horizontally in an orbital shaker/incubator at 37° C. for 1 hour. After 1 h, the samples were centrifuged for 5 min at 1500 rpm and the aqueous phase separated. The concentration of compound in both the aqueous and octanol phases was determined.
  • BV-2 mouse microglial cells were cultured for one day in multiwell plates and then treated in serum-free media for 16 hrs with either control buffer or the standard glial activating stimulus lipopolysaccharide (LPS, from Salmonella typhimurium; 100 ng/ml) in the presence of diluent or different concentrations of compounds.
  • LPS standard glial activating stimulus lipopolysaccharide
  • nitrite the stable metabolite of nitric oxide (NO)
  • BV-2 conditioned media by the Griess assay as previously described (Hu W, Ralay Ranaivo et al., Current Alzheimer's Research 2005, 2:197-205; Mirzoeva S, et al., J Med Chem 2002, 45:563-566; Mirzoeva S, et al., Brain Res 1999, 844:126-134).
  • Levels of IL-1 ⁇ , TNF ⁇ , MCP-1 and IL-1 ⁇ in cell lysates were measured by the Mesoscale Discovery system as per the manufacturer's instructions.
  • mice To estimate oral bioavailability (concentration of compound in the blood as a function of time after oral administration) and to gain insight into potential brain uptake, compound 5 (2.5 mg/kg) was administered to mice by oral gavage in a 0.5% (w/v) carboxymethylcellulose suspension (Ralay Ranaivo H, et al., J Neurosci 2006, 26:662-670). At 5, 15, 30, 60 and 120 min after oral administration, mice were sacrificed, perfused and their blood and brain were harvested. Brains were homogenized in acetonitrile and then centrifuged at 12000 ⁇ g for 10 minutes. Next, the plasma and the brain supernatant were acidified by diluting with 0.1% formic acid (Fluka) 1:1 and 1:3, respectively.
  • Fluka formic acid
  • Solid phase extraction followed by HPLC analysis was used to quantify the amount of compound in the plasma brain supernatants. Briefly, cartridges (Sep-Pak® C18, Waters) were conditioned with 1 ml of acetonitrile (HPLC grade, EMD Biosciences) and equilibrated with 1 ml of water. A structural analog, 6-methyl-4-phenyl-3-(4(pyrimidin-2-yl)piperazin-1-yl)pyridazine (MW01-7-057WH), was used as an internal recovery standard. Acidified samples were loaded to the cartridge followed by a 1 ml wash with 10% acetonitrile. Compound 5 was eluted from the cartridge using 80% acetonitrile.
  • the eluate was evaporated to dryness, reconstituted in 0.08% formic acid/water in 80% acetonitrile and analyzed by HPLC with 0.1% formic acid in water as reagent A and 0.1% formic acid in acetonitrile as reagent B using the following gradient in reagent B: 0% to 50% to 3 min, isocratic at 50% until 6 min, 50% to 70% from 6 to 10 min, isocratic at 70% until 13 min, 70% to 80% from 13 to 18 min, isocratic at 80% until 21 min, 80% to 70% from 21 to 23 min, and finally returning from 70% to 0% from 23 to 28 min.
  • mice Female C57Bl/6 mice (Harlan) weighing 20-25 g (3-4 months old) were housed in a pathogen free facility under an approximate 12 h/12 h dark and light cycle and had access ad libitum to food and water. All animal procedures were approved by the Northwestern Animal Care and Use Committee.
  • mice were administered by oral gavage either compound 5 (2.5 mg/kg/day) or solvent control (10% DMSO) in a 0.5% (w/v) carboxymethylcellulose suspension, once per day treatment began at day 21 after start of A ⁇ ICV infusion and continued for 14 days (Ralay Ranaivo H, et al., J Neurosci 2006, 26:662-670). Beginning at day 50 after start of A ⁇ ICV infusion, the Y maze test of spontaneous alternation was used to evaluate hippocampus-dependent spatial learning as described previously (Ralay Ranaivo H, et al., J Neurosci 2006, 26:662-670).
  • mice were sacrificed, perfused with a HEPES buffer (10 mM, pH 7.2) containing a protease inhibitor cocktail and brain was harvested and dissected as described previously (Ralay Ranaivo H, et al., J Neurosci 2006, 26:662-670).
  • HEPES buffer 10 mM, pH 7.2
  • protease inhibitor cocktail a protease inhibitor cocktail
  • brain was harvested and dissected as described previously (Ralay Ranaivo H, et al., J Neurosci 2006, 26:662-670).
  • Levels of IL-1 ⁇ and TNF ⁇ , S100B, synaptophysin, PSD-95, levels in hippocampal supernatants were measured as previously described (Ralay Ranaivo H, et al., J Neurosci 2006, 26:662-670; Craft J M, et al., Neurobiol Aging 2004, 25: 1283-1292; Eldik, L J, 1994).

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