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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
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  • A61K31/33—Heterocyclic compounds
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
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  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
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  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
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Definitions

• the field generally relates to organic compounds that act as nicotinic receptor antagonists.
• the field further relates to the use of nicotinic receptor antagonists for use nicotinic receptor antagonists as a prophylaxis or treatment for both small and non-small cell lung cancer, HIV, and mammalian exposure to various neurological toxins.
• Nicotinic acetylcholine receptors belong to the Cys-loop subfamily of pentameric ligand-gated ion channels and can be classified into muscle- type and neuronal subtypes.
• the neuronal nAChRs comprise twelve subunits (a2-al0 and b2-b4) with different arrangements, while the muscle-type is consisted of four subunits in a single arrangement of alcalbld (c is replaced by e in the adult).
• a4b2 and a7 Two major neuronal receptors a4b2 and a7 have been identified in the central nervous system. (Flores, C. et al., Mol.
• the neuronal a7 nAChR has been proposed as a potential therapeutic target for a broad range of neurodegenerative and psychiatric diseases, including Alzheimer's disease, schizophrenia, anxiety, and epilepsy.
• a variety of selective partial and full agonists have been developed for the a7 nAChR as potential therapeutics. (Jensen A. et al., Prog., Brain Res. 1996)
• Several a7 nAChR selective agonists e.g., TC-5619 and MEM-3454 have advanced to clinical trials for Alzheimer's disease and
• a-BTX krait Bungarus multicinctus derived peptide toxin a-bungarotoxin
• MAA Delphinum isolated nonpetide toxin methyllycaconitine
• a-BTX is a potent antagonist for muscle-type nAChRs as well, and both compounds also inhibit nAChR subtypes a9 and a9al0.
• nAChR subtypes a9 and a9al0.
• subtype-selective antagonists may possess intrinsic value as tools to define the roles played by a7 nAChRs in the physiological and pathophysiological processes.
• nicotinic acetylcholine receptors have been implicated as possible drug targets in a myriad of various disease states and for use as a possible measure for counter-terrorism purposes.
• SCLC small cell lung carcinoma
• NSCLC non-small cell lung cancer
• alpha-7 nAChRs has been found in lung cancer cells where activation by either natural molecules or compounds in tobacco smoke are shown to promote cancer growth. It has been found that those same alpha-7 nAChRs are upregulated in immune cells in AIDS. This suggests that over activation of alpha- 7 receptors in macrophages by the AIDS virus protein, may cause premature cell death. Thus, and at the very least, antagonists to nAChRs are needed to continue to exploit the relationship between cancer, AIDS and nAChR activity, and thus provide treatments for these disease states.
• novel the nicotinic receptor antagonists disclosed herein may be used in a broad array of clinical or medicinal facets.
• the novel nicotinic receptor antagonists be used to inhibit the growth cycle of non-small cell lung cancer cells.
• the nicotinic receptor antagonists of the present invention will be used as a counter measure to treat exposure, or potential exposure, to a wide array of potential neurotoxins.
• the AChRs are activated by acetylcholine (ACh), which is hydrolyzed to choline by acetylcholineesterase
• AChE cholinergic syndrome
• organophosphorus nerve agents like DFP and sarin
• mAChRs peripheral and central muscarinic AChRs
• nAChRs nAChRs
• mAChR antagonist atropine used in concert with an oxime reactivator of AChE (e.g., pralidoxime).
• AChE oxime reactivator of AChE
• nAChR antagonists 7i and 8 when tested in a DFP toxicity animal model to investigate their anti-seizure activity, (Unpublished data; Racine, R. J. Electroencephalogr. Clin. Neurophysiol.
• novel a7 nAChR selective antagonists are administered in an effective therapeutic dose causing some measure of reduced symptomology or total ablation of the disease state.
• novel a7 nAChR selective antagonists may be used as research or diagnostic tools. It is further contemplated that novel a7 nAChR selective antagonists could be used as a research tool in elucidating signal transduction in neuronal tissue. It is also contemplated that novel a7 nAChR selective antagonists could be used as a research tool in elucidating signal transduction pathway in non-neuronal tissue as well.
• the present invention contemplates nicotinic acetylcholine receptor antagonists of Formula I:
• may be a benzyl, phenethyl, 2-methoxyethyl, isobutyl, or cyclopentyl group.
• R2 may be a hydrogen or methyl group.
• R3 may be a chlorine, methoxyethyl, methyl, flourine or cyclopentyl group.
• the present invention contemplates nicotinic acetylcholine receptor antagonists of Form
• Ri may be a benzyl, methyl, or hydrogen group
• R 2 may be a propyl, methyl, cyclopropyl, and 4-tolyl group.
• R3 may be a hydrogen, fluorine, chlorine, or furyl group.
• the present invention provides Method I for the treatment or prophylaxis of a disease or disorder characterized by the activation of an acetylcholine receptor pathway, comprising administering to the patient an effective amount of a a7 nicotinic acetylcholine receptor antagonists according to Formula I or Formula II in a free or pharmaceutically acceptable salt form, for example:
• Method I wherein said disease or disorder is small cell lung cancer.
• Method I wherein said disease or disorder is non-small cell lung cancer.
• Method I wherein said disease or disorder is organophosphorus nerve agent intoxication
• Method I wherein said disease or disorder is infection via the human immunodeficiency virus (HIV).
• HAV human immunodeficiency virus
• Method I wherein said disease or disorder is the result of autoimmune deficiency syndrome (AIDS).
• AIDS autoimmune deficiency syndrome
• Method I or any of methods 1.1-1.5, wherein the patient is a human.
• Method I or any of methods 1.1-1.7, wherein the disease or disorder is characterized by benign cancerous cells.
• Method I or any of methods 1.1 -1.8, wherein said disease or disorder characterized by the presence of cancerous cells may be selected from the following group of diseases or disorders: squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and pleuroa mesothelioma.
• Method I or any of methods 1.1 -1.9, wherein said disease or disorder is a solid tumor carcimona.
• Method I or any of methods 1.1-1.10, wherein a patient is suffering from or at risk for developing cancer.
• Method I or any of methods 1.1-1.1 1 , wherein a patient is administered an effective amount of a novel a7 nicotinic acetylcholine receptor antagonist of Formula I in a pharmaceutically acceptable carrier.
• a second treatment for cancer selected from the group consisting of: capecitabine, trastuzumab, pertuzumab, cisplatin and irinotecan.
• the terms “treating”, “treatment”, and the like are used herein to generally mean obtaining a desired pharmacological and physiological effect.
• the novel a7 nAChRs described herein which are used to treat a subject with cancer generally are provided in a therapeutically effective amount to achieve any one or more of the following: inhibited tumor growth, reduction in tumor mass, loss of metastatic lesions, inhibited development of new metastatic lesions after treatment has started, or reduction in tumor such that there is no detectable disease (as assessed by, e.g., radiologic imaging, biological fluid analysis, cytogenetics, fluorescence in situ hybridization, immunocytochemistry, colony assays, multiparameter flow cytometry, or polymerase chain reaction).
• treatment covers any treatment of a disease in any mammal., particularly a human, known to those that are skilled in the art
• the term "subject" or "patient” as used herein is meant to include a mammal.
• the mammal is a human.
• the mammal is a domestic animal.
• compositions as used herein refers to the effectiveness of a particular treatment regime.
• Pharmaceutical efficacy can be measured based on such characteristics, for example, as: inhibition of tumor growth, reduction of tumor mass or rate of growth, lack of detectable tumor associated antigens, and any other diagnostic measurement tool that is known in the field.
• Pharmaceutical efficacy can also be measured based on such characteristics, for example, as: inhibition of the HIV virus and/or reduction and eradication of AIDS related symptoms. Moreover, pharmaceutical efficacy can also be measured based upon the reduction of the onset of symptoms that are related to the induction of organophosphorus nerve agent intoxication.
• pharmaceutically effective amount refers to the amount of an agent, reagent, compound, composition, or combination of reagents disclosed herein that when administered to a mammal that are determined to be sufficiently effective against cancer that is the object of the treatment or HIV/AIDS.
• a pharmaceutically effective amount will be known to those skilled in the art.
• tumor is meant to include both benign and malignant growths or cancer.
• cancer is meant to encompass, unless otherwise stated, both benign and malignant growths.
• the tumor referred to is malignant.
• the tumor can be a solid tissue tumor such as a melanoma, or a soft tissue tumor such as a lymphoma, a leukemia, or a bone cancer.
• primary tumor is meant the original neoplasm and not a metastatic lesion located in another tissue or organ in the patient's body.
• metalastatic disease metalastases
• metalastatic lesion are meant a group of cells which have migrated to a site distant relative to the primary tumor.
• AIDS HIV infection: HIV, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
• the treatment of AIDS refers to the inhibition of HIV virus, the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment or the delay in the onset of consequent pathological conditions such as AIDS.
• the prophylaxis of AIDS, treating AIDS, delaying the onset of AIDS, the prophylaxis of infection by HIV, or treating infection by HIV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
• nicotinic acetylcholine receptor refers to the endogenous acetylcholine receptor having binding sites for acetylcholine which also bind to nicotine.
• the term “nicotinic acetylcholine receptor” includes the term “neuronal nicotinic acetylcholine receptor.”
• nicotinic acetylcholine receptor and “nicotinic acetylcholine receptor subtype” refer to various subunit combinations of the nicotinic acetylcholine receptor, and may refer to a particular homomeric or heteromeric complex, or multiple homomeric or heteromeric complexes.
• agonist refers to a substance which interacts with a receptor and increases or prolongs a physiological response (i.e. activates the receptor).
• partial agonist refers to a substance which interacts with and activates a receptor to a lesser degree than an agonist.
• antagonist refers to a substance which interacts with and decreases the extent or duration of a physiological response of that receptor.
• central nervous system associated disorders includes any cognitive, neurological, and mental disorders causing aberrant or pathological neural signal transmission, such as disorders associated with the alteration of normal neurotransmitter release in the brain.
• Example 1 details binding affinity of nicotinic acetylcholine receptor antagonists, determined by radiolabeled binding, according to Formula I for the native a7 nAChR in rat brain membranes at 10 ⁇ . Nicotinic acetylcholine receptor antagonists according to Formula I are listed as follows (from top to bottom):
• Example 2 details binding affinity of nicotinic acetylcholine receptor antagonists, determined by radiolabeled binding, according to Formula II for the native a7 nAChR in rat brain membranes at 10 ⁇ . Nicotinic acetylcholine receptor antagonists according to Formula II are listed as follows (from top to bottom):
• Example 3 details a representative dose response curves of Compound I and Compound 2 on the native neuronal alpha-7 nAChR in rat brain membranes.
• the line containing square-point designations indicates percent inhibition results regarding Compound 1 , while the line containing triangle-point designations indicates the results regarding Compound 2.
• Example 4 illustrates the inhibition of human a7 AChR responses expressed in Xenopus oocytes.
• the line containing solid square-point designations indicates percent inhibition results regarding Compound 1, while the line containing triangle-point designations indicates the results regarding Compound 2.
• the line containing hollow square-point designations indicates results regarding Compound 1 i.
• the functional activity of representative compounds (1 , l i, and 2) is determined by electrophysiological experiments on Xenopus oocytes expressing human alpha-7 nAChR.
• Compound 1 is represented by the solid bar while Compound 2 is represented by the empty bar.
• Example 6 details the concentration of Compound 1 and Compound 2 after cassette dosing at 1 Omg kg in mouse via intraperitoneal administration.
• Chart a) details the results regarding compounds according to formula I, while chart b) details results regarding compounds according to formula II.
• Brain and blood samples were collected at specific time points after drug administration.
• the area under the curve (AUC) ratios of brain to plasma were 2.8 and 3.1 for Compound 1 and Compound 2, respectively, suggesting good brain penetration for both compounds.
• Compound 2 achieved high concentration in brain (9 1M).
• Cassette dosing of compounds can lead to incorrect estimates of plasma drug levels by drug-drug interactions such as at the level of Cytochrome P450 enzymes or by interfering with transporter systems.
• Example 7 illustrates the neuroprotective activities of Compound li and Compound 2 against seizure induced by the nerve agent diisopropylfluorophosphate (DFP).
• DFP nerve agent diisopropylfluorophosphate
• the acetylcholine receptors (AChRs) are activated by acetylcholine (ACh), which is hydrolyzed to choline by acetylcholineesterase (AChE).
• AChE acetylcholine
• organophosphorus nerve agents like DFP and sarin the uncontrolled accumulation of ACh at peripheral and central muscarinic AChRs (mAChRs) and nAChRs causes the cholinergic syndrome.
• This syndrome is characterized by sweating, pupillary constriction, convulsions, tachycardia, and eventually death.
• the mainstay treatment for nerve agent intoxication is the mAChR antagonist atropine together with an oxime reactivator of AChE (e.g., pralidoxime).
• AChE oxime reactivator of AChE
• This treatment regimen does not directly target nicotinic receptors although both mAChRs and nAChRs are involved in nerve agent toxicity.
• the new nAChR antagonists, Compounds 1 i and 2 were tested in a DFP toxicity animal model to investigate their anti-seizure activity.
• neuroprotection against seizure-like behaviors induced by DFP may be useful for treatment of organophosphus nerve agent intoxication.
• Three dimensional (3D) pharmacophore models may be developed and, subsequently conducted ligand-based virtual screening may also be conducted to search for novel a7 nAChR selective ligands.
• six potent and selective a7 ligands are representative of a selected training set for the pharmacophore model.
• the structures of all compounds may be built with Molecular Operating Environment (MOE). Energy minimization may be conducted for the protonated forms using AMI since all these compounds could be protonated at physiological conditions (pH 7.4).
• Flexible structural alignments may be performed to identify the common chemical features responsible for the alpha 7 receptor binding using the Flexible Alignment module within MOE. This alignment method uses a stochastic search algorithm to simultaneously explore the conformation space of all compounds in the training set.
• This operation generates several scores to quantify the quality of each alignment with lower scores indicating better alignments.
• the alignment with the lowest S score may be selected for the 3D pharmacophore development.
• a six-point pharmacophore model may be obtained based on the unified scheme within MOE (Fig. 2).
• Feature Fl is a hydrogen bond acceptor withradius 1.5 A.
• Feature F2 is a cation atom (radius: 1.0 A)— the basic nitrogen, which exists in most known nAChR ligands.
• Features F3 and F4 are characterized as aromatic rings with radius 1.5 A.
• Extended Lipinski's rules include seven filters: 100 ⁇ molecular weight 6 500, _2 6 Clog P 6 5, number of hydrogen bond donors 65, number of hydrogen bond acceptors 610, topological polar surface area 6120 A2, number of rings 65, and number of rotatable bonds 610. These property filters may be chosen to eliminate compounds that lacked sufficient drug-like properties to become drugs.
• Reactive groups are defined according to the Oprea set, including heteroatom-heteroatom single bonds, acyl halides, sulfonyl halides, perhalo ketone, and Michael acceptors. These groups can interfere with high-throughput biochemical screening assays and therefore often appear as false positives.
• a halogen filter may used to avoid pesticides that often contain many (>4) non-fluorine halogen atoms.
• the majority of known nAChR ligands contain a nitrogen atom protonated at physiological conditions (pH 7.4), and this nitrogen atom has been shown to be involved in extensive cation-p interactions between ligand and receptor.
• a basic nitrogen filter may be selected to remove compounds that lack this chemical feature. This filter greatly reduced the size of the compound database and therefore improved the speed of conformer generation and pharmacophore matching. Altogether, compounds violating P2 Lipinski's rules or any functional group filters were eliminated from our selection.
• the resulting compounds are subjected to conformation sampling using the Conformational Import Module, a high- throughput method to generate 3D low-energy conformers in MOE. Recent studies revealed that this method performed as well as the established Catalyst FAST module.
• the ensemble of conformers were then screened by the six-point pharmacophore model by enabling exact match of features F1-F4 and partial match of features F5 and F6. The consequent hits were subjected to database diversity and clustering analyses with the aim to remove close analogs and maximize the chemotypes of the selected compounds for biological tests.
• the MDL MACCS fingerprints implemented in MOE are calculated for all compounds and fingerprint-based clustering may be
• a bulky benzyl group at Rl yielded more potent receptor binding than a less bulky methyl or free base (2 vs 2h and 2i). More hydrophobic substitutions at R3 improved receptor binding (2f vs 2h).
• the R4 position tolerated different substitutions (e.g., hydrogen and halogen).

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