WO2004019947A1 - Alpha-7 nicotinic receptor agonists and statins in combination - Google Patents

Alpha-7 nicotinic receptor agonists and statins in combination Download PDF

Info

Publication number
WO2004019947A1
WO2004019947A1 PCT/SE2003/001352 SE0301352W WO2004019947A1 WO 2004019947 A1 WO2004019947 A1 WO 2004019947A1 SE 0301352 W SE0301352 W SE 0301352W WO 2004019947 A1 WO2004019947 A1 WO 2004019947A1
Authority
WO
WIPO (PCT)
Prior art keywords
azabicyclo
oct
carboxamide
octane
thiophene
Prior art date
Application number
PCT/SE2003/001352
Other languages
French (fr)
Inventor
Richard Keith
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to US10/525,783 priority Critical patent/US20050256146A1/en
Priority to DE60313004T priority patent/DE60313004T2/en
Priority to SI200330803T priority patent/SI1545537T1/en
Priority to AU2003256203A priority patent/AU2003256203A1/en
Priority to DK03791540T priority patent/DK1545537T3/en
Priority to JP2004532517A priority patent/JP2006505530A/en
Priority to EP03791540A priority patent/EP1545537B9/en
Publication of WO2004019947A1 publication Critical patent/WO2004019947A1/en
Priority to HK05109104A priority patent/HK1077193A1/en
Priority to US12/186,915 priority patent/US20090192180A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is concerned with the treatment of neurological degenerative diseases and particularly with the treatment of Alzheimer's disease.
  • Alpha-7 nicotinic receptors are ligand-gated ion channels that allow for the entry into cells of calcium and other monovalent cations (Dani, 2001).
  • ⁇ 7-nAChR have been shown to play an important role in regulating neurotransmitter release, hippocampal synaptic function, neuroprotection against a variety of insults, and cognition (Dani, 200 Dahas-Bailador et. al., 2000; Rezvani and Levin, 2001).
  • a ⁇ has been shown to potently inhibit ⁇ 7- nAChR (Liu et. al., 2001). It has been proposed that this inhibitory effect of A ⁇ on ⁇ 7- nAChR function may contribute to cognitive deficits in Alzheimer's disease.
  • Neurodegeneration induced by the activation of NMD A glutamatergic receptors is also enhanced in the presence of A ⁇ (Kihara et. al., 2001). This A ⁇ induced neurodegeneration is inhibited by activation of ⁇ 7-nAChR.
  • HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta- amyloid peptide in vitro and in patients.
  • Nicotinic receptor transduces signals to phohphatidylinositol 3-kinase to block A ⁇ -amyloid-induced neurotoxicity. J Biol Chem 276: 13541-13546, 1998.
  • Jarvik GP Wijs an EM
  • Kukull WA Schellenberg GD
  • Yu C and Larson EB Interactions of apolipoprotein E genotype, total cholesterol, age, and sex in prediction of Alzheimer's disease.
  • Liu Q, Kawai H and Berg DK b-Amyloid peptide blocks the response of ⁇ 7- containing nicotinic receptors on hippocampal neurons. Proc NatlAcad Sci 97: 10197-10202, 2001.
  • statins and ⁇ 7-nAChR agonists in combination have the potential to alter the pathophysiology of Alzheimer's disease and symptoms.
  • statins by reducing the formation of the neurotoxic substance A ⁇ and ⁇ 7-nAChR agonists by blocking the cognitive impairing and neurotoxic effects of A ⁇ imply that a statin and an ⁇ 7-nAChR in combination will synergistically benefit patients suffering with neurological degenerative diseases and particularly patients suffering with Alzheimer's disease.
  • the invention is a method for treating neurological degenerative diseases and particularly Alzheimer's disease comprising treatment with a combination comprising an ⁇ 7-nAChR agonist and a statin.
  • a combination suitable for practicing the invention comprises a statin selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin sodium, simvastatin or rosuvastatin, or a pharmaceutically-acceptable salt thereof and an ⁇ 7-nAChR agonist selected from spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one,
  • Alpha-7-nAChR agonists contemplated to be useful in the present invention are described in international publications WO9606098. WO9730998. WO 9903859, WO9956745, WO0042044, WO0129034, WO0160821, WO0132622, WO0136417, WOO 132619, WO0132620, WOO 136417, WO0244176, WO0220521 , WO0216358, WO0216357, WO0216356, WO0216355, WO0215662 and WO0217358 and in publications EP1219622, EPl 184383, EPl 184384, EPl 184385, JP200203084.
  • Statins contemplated to be useful in the present inventions are atorvastatin calcium (Lipitor), cerivastatin sodium
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of an ⁇ 7-nAChR agonist and a statin as described herein together with a pharmaceutically-acceptable diluent or excipient.
  • the present invention comprises providing neuroprotection or analgesia in a method of treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease which method comprises administering a therapeutically effective amount of a combination as defined in Claim 1 to a patient.
  • the method of the invention is a method for the treatment or prophylaxis of Alzheimer's disease.
  • a further aspect of the invention is the use of a combination of an ⁇ 7-nAChR agonist and a statin as described herein in the preparation of a medicament for providing neuroprotection or analgesia in the treatment of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease.
  • a combination of an ⁇ 7-nAChR agonist and a statin as described herein is in the preparation of a medicament for the treatment or prophylaxis of Alzheimer's disease.
  • a particular combination for use in the present invention comprises rosuvastatin or a pharmaceutically-acceptable salt thereof and an ⁇ 7-nAChR agonist selected from spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3-yl)[E-3-(2- fhienyl)propenamide], or (2'R)-5'-(3-furanyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof.
  • an ⁇ 7-nAChR agonist selected from spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3-y
  • a particular pharmaceutical composition for use in the present invention comprises rosuvastatin or a pharmaceutically-acceptable salt thereof and an rx7-nAChR agonist selected from spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3- yl)[E-3-(2-thienyl)propenamide], or (2'R)-5'-(3-furanyl)spiro[l-azabicyclo[2.2.2]octane-3,2'- (3'H)-furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
  • an rx7-nAChR agonist selected from spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l-azabic
  • a particular method of the present invention is the provision of neuroprotection or analgesia for the treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease which method comprises administering a therapeutically effective amount of a combination of rosuvastatin or a pharmaceutically-acceptable salt thereof and an ⁇ 7-nAChR agonist selected from spiro[l -azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l- azabicyclo[2.2.2]oct-3-yl)[E-3-(2-thienyl)propenamide], or (2'R)-5'-(3-furanyl)spiro[ 1 - azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyr
  • a particular embodiment of the invention is the use of a combination rosuvastatin or a pharmaceutically-acceptable salt thereof and an ⁇ 7-nAChR agonist selected from spiro[l- azabicyc]o[2.2.2]octane-3,5 , -oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3-yl)[£-3-(2 : fhieny propenamide], or (2'R)-5'-(3-furanyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof in the preparation of a medicament providing neuroprotection or analgesia for the treatment of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and
  • Statins are compounds that inhibit HMG-CoA reductase, a rate-limiting enzyme in the biosynthetic pathway to cholesterol.
  • Statins are conventionally used to reduce plasma levels of cholesterol in patients with cardiovascular disease but can also reduce A ⁇ serum levels in patients.
  • Alpha-7-nAChR agonists beneficially activate ⁇ 7-nACh receptors and are useful for treating cognitive deficits and in the treatment of a range of disorders involving reduced cholinergic function such as Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, Tourette's syndrome, and Parkinson's disease.
  • statins by reducing the formation of A ⁇ , may be particularly effective in combination with ⁇ 7-nAChR agonists, which ameliorate cognitive deficits and inhibit neurodegeneration induced by A ⁇ , in the treatment of Alzheimer's disease. Therefore, the treatment of Alzheimer's disease with a combination of a statin and an ⁇ 7-nAChR agonist will result in enhanced efficacy over either type of agent if administered alone.
  • transgenic mice which over express A ⁇
  • animals with surgically generated fimbria-fornix lesions are known, understood and appreciated by those of skill in the relevant art.
  • Transgenic mice which over express A ⁇ exhibit some of the clinical manifestations of Alzheimer's disease, e.g., plaque deposition and, in some cases, cognitive deficits, but neurodegeneration is not observed.
  • Animals with fimbria-fornix lesions have cognitive and learning deficits and have been used to assess potential approaches to treat neurodegeneration.
  • No single experimental model exhibits the entire pathophysiological complex of Alzheimer's disease. However, to the extent that these models do mimic the pathophysiology of Alzheimer's disease they may be used to assess the effect of a statin and an ⁇ 7-nAChR agonist in combination.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Indole Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Combinations of α7-nAChR agonists and statins, pharmaceutical compositions containing the same and methods of using the same useful for treatment or prophylaxis of neurological degenerative diseases.

Description

Alpha-7 Nicotinic Receptor Agonists and Statins In Combination Field of Invention:
This invention is concerned with the treatment of neurological degenerative diseases and particularly with the treatment of Alzheimer's disease. Background
The etiology of Alzheimer's disease is complex and not entirely understood. Current hypotheses point to the oveφroduction of the amyloid peptide Aβ as a causative factor in the cognitive deficits and neurodegeneration associated with Alzheimer's disease (Selkoe, 2001 ; Walsh et. al., 2002). In addition, epidemiological studies have shown that hypercholesterolemia is a risk factor for Alzheimer's disease (Jarvik et. al., .1995; Notkola et. al., 1998). Further, it has recently been shown that the administration of statins is associated with a decreased risk of Alzheimer's disease (Jick'et. al., 2000; Wolozin et. al., 2000). Still further, another recent study has shown that the statin lovastatin reduced Aβ plasma levels in human subjects that had elevated plasma levels of low-density lipoprotein cholesterol (Buxbaum et. α/., 2002).
Alpha-7 nicotinic receptors (α7-nAChR) are ligand-gated ion channels that allow for the entry into cells of calcium and other monovalent cations (Dani, 2001). α7-nAChR have been shown to play an important role in regulating neurotransmitter release, hippocampal synaptic function, neuroprotection against a variety of insults, and cognition (Dani, 200 Dahas-Bailador et. al., 2000; Rezvani and Levin, 2001).
Recent studies imply an interaction between Aβ and α7-nAChR that may contribute to the pathophysiology of Alzheimer's disease. Aβ has been shown to potently inhibit α7- nAChR (Liu et. al., 2001). It has been proposed that this inhibitory effect of Aβ on α7- nAChR function may contribute to cognitive deficits in Alzheimer's disease.
Neurodegeneration induced by the activation of NMD A glutamatergic receptors is also enhanced in the presence of Aβ (Kihara et. al., 2001). This Aβ induced neurodegeneration is inhibited by activation of α7-nAChR. Background References: Buxbaum JD, Cullen El and Friedhoff LT: Pharmacological concentrations of the
HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta- amyloid peptide in vitro and in patients. Frontiers in Bioscience 7:a50-a59, 2002. Dajas-Bailador FA, Lima PA and Wonnacott S: The α7 nicotinic receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca2+ dependent mechanism. Neuropharmacology 39:2799-2807, 2000.
Dani JA: Overview of nicotinic receptors and their roles in the central nervous system. Biol Psychiatry 49: 166- 174, 2001.
Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Toshiaki K, and Akaike A: α7 Nicotinic receptor transduces signals to phohphatidylinositol 3-kinase to block Aβ-amyloid-induced neurotoxicity. J Biol Chem 276: 13541-13546, 1998.
Jick H, Zornberg GL, Jick SS, Seshadri S, and Drachman DA: Statins and the risk of dementia. Lancet 356: 1627- 1631, 2000.
Jarvik GP, Wijs an EM, Kukull WA, Schellenberg GD, Yu C and Larson EB: Interactions of apolipoprotein E genotype, total cholesterol, age, and sex in prediction of Alzheimer's disease. Neurology 45: 1092-1096, 1995.
Liu Q, Kawai H and Berg DK: b-Amyloid peptide blocks the response of α7- containing nicotinic receptors on hippocampal neurons. Proc NatlAcad Sci 97: 10197-10202, 2001.
Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J and Nissinen A: Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidememiology 17: 14-20, 1998. Rezvani AH and Levin ED: Cognitive effects of nicotine. Biol Psychiatry 49:25^.-267,
2001.
Selkoe, DJ: Alzheimer's disease: Genes, proteins, and therapy. Physiological Reviews 81 :741-766, 2001.
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, and Selkoe, DJ: Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535-539, 2002.
Wolozin B, Kellman W, Ruosseau P, Celesia GG, and Siegel G: Decreased prevalence of Alzheimer's disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neruol 57: 1439- 1443, 2000. Description of the Invention:
We have discovered that statins and α7-nAChR agonists in combination have the potential to alter the pathophysiology of Alzheimer's disease and symptoms. The different mechanisms by which statins and α7-nAChR agonists operate — statins by reducing the formation of the neurotoxic substance Aβ and α7-nAChR agonists by blocking the cognitive impairing and neurotoxic effects of Aβ — imply that a statin and an α7-nAChR in combination will synergistically benefit patients suffering with neurological degenerative diseases and particularly patients suffering with Alzheimer's disease. In one aspect the invention is a method for treating neurological degenerative diseases and particularly Alzheimer's disease comprising treatment with a combination comprising an α7-nAChR agonist and a statin.
A combination suitable for practicing the invention comprises a statin selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin sodium, simvastatin or rosuvastatin, or a pharmaceutically-acceptable salt thereof and an α7-nAChR agonist selected from spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one,
(+)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, (-)-spiro[ 1 -azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, spiro[l-azabicyclo[2.2.1]heptan-3,5'-oxazolidin-2'-one], 3'-methyl spiro-[l-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-bromospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-phenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-nitrospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], l '-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline],
5'-(phenylcarboxamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-(phenylaminocarbonylamino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine], 5'-(phenylsulfonylamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-methylaminospiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N,N-dimethylaminospiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
5'-N,N-diethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine],
5'-N-ethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine],
5'-N-benzylaminospiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-formamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-acetamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]quinoline], 5'-ethenylspiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine],
5'-(E)-(phenylethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
5'-(4-moφholino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(l-azetidinyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(E)-(2-(4-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-(E)-(2-(2-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
5'-(2-trimethylsilylethynyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-ethynylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(2-furyl)spiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(3-pyridyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-methylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carbonitrile],„ . spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carboxamide], 5'-N'-(3-chlorophenyl)aminocarbonylminospiro[l-azabicyclo[2.2.2]octane-3,2'- (3'H)-furo[2,3-b]pyridine],
5'-N'-(2-nitrophenyl)aminocarbonylaminospiro[l-azabicyclo[2.2.2]octane-3,2'- (3'H)-furo[2,3-b]pyridine],
4'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-methoxyspiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-phenylthiospiiO[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-(N-2-aminoethyl)aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
4'-phenylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-(4-N-methylpiperazin-l-yl)sρiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
4'-chloro-spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine], spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-7'-oxide], spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-fuiO[2,3-b]pyridine-6'-carbonitrile], 6'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine], 6'-fluorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine], N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-y])(5-(3-fluorophenyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide),
N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-thιenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-chlorophenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiazole-3-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiazole-3-carboxamide), N-( l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)thiophene-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyI)thiophene-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2- carbox amide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide),
N-(l-aza-bicyclo[2.2.2]oct-3-yl)(5-(3-(4-moφholinyl)phenyl)thiophene-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2- carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide) , N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)furan-2- carboxamide),
N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide); N- (l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide), (R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide), (R N-(l-azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide), (R;-N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide),
(Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide), R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide), (R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide); (Rj-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide),
(R -N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide), (R -N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide), (R -N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide),
(R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide), R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide), R/)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide), Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide), (R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide), (R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(4-fluorophenyI)furan-2-carboxamide),
(Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide), R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide), (R;-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide),
(R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide), (R)-N-(l-azabicyclo[2.2.2]oct-3-y])(5-(3-pyridyl)thiophene-2-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide), (R/)-N-(l-azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide), (R N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridyl)thiophene-2-carboxamide),
(R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2- carboxamide), RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide), RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2- carboxamide),
(R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide), (R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2- carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxarnide), (Rj-N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide), (Ry)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2- carboxamide), (Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2- carboxamide),
(R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)[ 5-(4-chlorophenyl)furan-2-carboxamide), (R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiazole-3-carboxamide), (R>N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiazole-3-carboxamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(NN-dimethylamino)phenyl)thiophene-2- carboxamide),
(R -N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide), (SJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide); (SJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide), (S/)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide), (S/)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide),
(RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide), (R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide), (R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2- carboxamide),
(R -N-(l -aza-bicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide), (R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide), (R )-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide), (Ry)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(4-moφholinyl)phenyl)thiophene-2- carboxamide),
(R N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2- carbox amide),
(Ry)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide) , (Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(NN-dimethylamino)phenyl)furan-2- carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide), or (Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2- carboxamide), or a pharmaceutically-acceptable salt thereof. In general, it is contemplated that any statin when used in combination with any alpha-7-nAChR agonist will be useful in practicing the present invention.
Alpha-7-nAChR agonists contemplated to be useful in the present invention are described in international publications WO9606098. WO9730998. WO 9903859, WO9956745, WO0042044, WO0129034, WO0160821, WO0132622, WO0136417, WOO 132619, WO0132620, WOO 136417, WO0244176, WO0220521 , WO0216358, WO0216357, WO0216356, WO0216355, WO0215662 and WO0217358 and in publications EP1219622, EPl 184383, EPl 184384, EPl 184385, JP200203084. Statins contemplated to be useful in the present inventions are atorvastatin calcium (Lipitor), cerivastatin sodium
(Baycol), fluvastatin sodium (Lescol), lovastatin (Mevacor), pravastatin sodium (Pravachol), simvastatin (Zocor) and rosuvastatin (Crestor).
In another aspect the invention is a pharmaceutical composition comprising a combination of an α7-nAChR agonist and a statin as described herein together with a pharmaceutically-acceptable diluent or excipient.
In another aspect the present invention comprises providing neuroprotection or analgesia in a method of treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease which method comprises administering a therapeutically effective amount of a combination as defined in Claim 1 to a patient.
In a particular aspect the method of the invention is a method for the treatment or prophylaxis of Alzheimer's disease.
A further aspect of the invention is the use of a combination of an α7-nAChR agonist and a statin as described herein in the preparation of a medicament for providing neuroprotection or analgesia in the treatment of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease. In a particular aspect the use of a combination of an α7-nAChR agonist and a statin as described herein is in the preparation of a medicament for the treatment or prophylaxis of Alzheimer's disease.
A particular combination for use in the present invention comprises rosuvastatin or a pharmaceutically-acceptable salt thereof and an α7-nAChR agonist selected from spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3-yl)[E-3-(2- fhienyl)propenamide], or (2'R)-5'-(3-furanyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof. A particular pharmaceutical composition for use in the present invention comprises rosuvastatin or a pharmaceutically-acceptable salt thereof and an rx7-nAChR agonist selected from spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3- yl)[E-3-(2-thienyl)propenamide], or (2'R)-5'-(3-furanyl)spiro[l-azabicyclo[2.2.2]octane-3,2'- (3'H)-furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier.
A particular method of the present invention is the provision of neuroprotection or analgesia for the treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease which method comprises administering a therapeutically effective amount of a combination of rosuvastatin or a pharmaceutically-acceptable salt thereof and an α7-nAChR agonist selected from spiro[l -azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, N-(l- azabicyclo[2.2.2]oct-3-yl)[E-3-(2-thienyl)propenamide], or (2'R)-5'-(3-furanyl)spiro[ 1 - azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof to a patient. In particular the method is useful for the treatment or prophylaxis Alzheimer's disease.
A particular embodiment of the invention is the use of a combination rosuvastatin or a pharmaceutically-acceptable salt thereof and an α7-nAChR agonist selected from spiro[l- azabicyc]o[2.2.2]octane-3,5,-oxazolidine]-2'-one, N-(l-azabicyclo[2.2.2]oct-3-yl)[£-3-(2: fhieny propenamide], or (2'R)-5'-(3-furanyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof in the preparation of a medicament providing neuroprotection or analgesia for the treatment of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease. In particular the invention comprises the use of such a combination in the preparation of a medicament for the treatment of Alzheimer's disease.
Statins are compounds that inhibit HMG-CoA reductase, a rate-limiting enzyme in the biosynthetic pathway to cholesterol. Statins are conventionally used to reduce plasma levels of cholesterol in patients with cardiovascular disease but can also reduce Aβ serum levels in patients. Alpha-7-nAChR agonists beneficially activate α7-nACh receptors and are useful for treating cognitive deficits and in the treatment of a range of disorders involving reduced cholinergic function such as Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia, Tourette's syndrome, and Parkinson's disease. Accordingly, the hypothetical basis of the present invention lies in the realization that statins, by reducing the formation of Aβ, may be particularly effective in combination with α7-nAChR agonists, which ameliorate cognitive deficits and inhibit neurodegeneration induced by Aβ, in the treatment of Alzheimer's disease. Therefore, the treatment of Alzheimer's disease with a combination of a statin and an α7-nAChR agonist will result in enhanced efficacy over either type of agent if administered alone. Experimental: Assessment of the efficacy of a statin and an α7-nAChR agonist in combination in animal models is not straightforward. Existing experimental models of Alzhiemer's disease include transgenic mice, which over express Aβ, and animals with surgically generated fimbria-fornix lesions. These models and the uses to which they may be put are known, understood and appreciated by those of skill in the relevant art. Transgenic mice which over express Aβ exhibit some of the clinical manifestations of Alzheimer's disease, e.g., plaque deposition and, in some cases, cognitive deficits, but neurodegeneration is not observed. Animals with fimbria-fornix lesions have cognitive and learning deficits and have been used to assess potential approaches to treat neurodegeneration. No single experimental model exhibits the entire pathophysiological complex of Alzheimer's disease. However, to the extent that these models do mimic the pathophysiology of Alzheimer's disease they may be used to assess the effect of a statin and an α7-nAChR agonist in combination.

Claims

Claims:
1. A combination comprising: a statin selected from atorvastatin, ceπvastatin, fluvastatin, lovastatin, pravastatin sodium, simvastatin or rosuvastatin, or a pharmaceutically-acceptable salt thereof and an α7-nAChR agonist selected from spiro[l-azabicyclo[2.2.2]octane-3,5'- oxazolidine]-2'-one,
(+)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, (-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, spirof 1 -azabicyclo[2.2.1 ]heptan-3,5'-oxazolidin-2'-one],
3'-methyl spiro-[l-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one], spiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-bromospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-phenylspiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-nitrospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], l '-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline], 5'-(phenylcarboxamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-(phenylaminocarbonylamino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-(phenylsulfonylamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-methylaminospiro[ l -azabicycIo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N,N-dimethylaminospiro[ l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-N,N-diethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-ethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-benzylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-N-formamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridinel,
5'-N-acetamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], spirof l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline], spiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2.3-b]quinoline], 5'-ethenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(E)-(phenylethenyl)spiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
5'-(4-morpholino)spiro[ l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(l-azetidinyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]ρyridine],
5'-(E)-(2-(4-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine],
5'-(E)-(2-(2-pyridyl)ethenyl)sρiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine], 5'-(2-trimethylsilylethynyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
5'-ethynylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(2-furyl)spiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-(3-pyridyl)spiro[ l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 5'-methylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carbonitrile], spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carboxamide], 5'-N'-(3-chlorophenyl)aminocarbonylminospiro[l-azabicyclo[2.2.2]octane-3,2'- (3'H)-furo[2,3-b]pyridine], 5'-N'-(2-nitropheny])aminocarbonylaminospiro[l-azabicyclo[2.2.2]octane-3,2'; .
(3'H)-furo[2,3-b]pyridine],
4'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-methoxyspiro[ l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-phenylthiospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-(N-2-aminoethyl)aminospiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
4'-phenylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine], 4'-(4-N-methylpiperazin-l-yl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- bjpyridine],
4'-chloro-spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine], spiro[ l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine], spiro[l -azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-7'-oxide], spiro[l -azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-6'-carbonitrile], 6'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine], 6'-fluorospiro[ l -azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine], N-( 1 -azabicyc!o[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)furan-2-carboxamide),
N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-thienyl)benzamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-fluoi"ophenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide),
N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide),
N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyI)thiophene-2-carboxamide), N-(l-azabicyc!o[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridyl)thiophene-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide), N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)fhiophene-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-chlorophenyl)furan-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiazole-3-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiazole-3-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(NN-dimethylamino)phenyl)thiophene-2- carboxa ide),
N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide), N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2- carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide), N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide), N-(l -aza-bicyclo[2.2.2]oct-3-yl)(5-(3-(4-moφholinyl)phenyl)thiophene-2- carboxamide),
N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2- carboxamide), N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide) , N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N,N-dimethylamino)phenyl)furan-2- carboxamide),
N-(l-azabicyclo[2.2.2]oct-3-yI)(5-(3-formylphenyl)thiophene-2-carboxamide); N- (l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylfuran-2-carboxamide), (R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-fluoiOphenyl)furan-2-carboxamide), (Rj-N-( l-azabicyclo[2.2.2]oct-3-yl)(3-(3-thienyl)benzamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-phenylbenzamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-pyridyl)benzamide),
(RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide), (R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(3-methoxyphenyl)benzamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(2-methoxyphenyl)benzamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3-(N-acetylamino)phenyl)benzamide); (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(3-fluorophenyl)benzamide), R -N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3-methylphenyl)benzamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl.)(3-(2-thienyl)benzamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(3-(3,5-dichlorophenyl)benzamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(3-(2-naphthyl)benzamide), RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(3-(4-fluorophenyl)benzamide),
(Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)furan-2-carboxamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-thienyl)furan-2-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-benzo[b]furanyl)furan-2-carboxamide), (Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)furan-2-carboxamide), (,Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-thienyl)furan-2-carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)furan-2-carboxamide), (RJ-N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(2-methoxyphenyl)furan-2-carboxamide), (,R -N-(l -azabicyclof2.2.2]oct-3-yl)(5-(4-fluoiOphenyl)furan-2-carboxamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-naphthyl)furan-2-carboxamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-methylphenyl)furan-2-carboxamide), (R N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-furyl)furan-2-carboxamide), (R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(2-furyl)furan-2-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)furan-2-carboxamide),
(R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide), (R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide), (R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide), R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(2-pyridyl)thiophene-2-carboxamide), (Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(4-pyridy])thiophene-2-carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(4-(3-pyridyl)thiophene-2-carboxamide), (RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)furan-2- carboxamide),
(RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-nitrophenyl)furan-2-carboxamide), (Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-trifluoromethylphenyl)furan-2- carboxamide),
(R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)furan-2-carboxamide), (R N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-acetylamino)phenyl)thiophene-2- carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-fluorophenyl)thiophene-2-carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-methoxyphenyl)thiophene-2-carboxamide), (R)-N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(3-ethoxyphenyI)thiophene-2-carboxamide), (R)-N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)furan-2- carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3,5-dimethylisoxazol-4-yl)thiophene-2- carboxamide),
(R)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)thiophene-2-carboxamide), Rj-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-3-carboxamide), (R,)-N-(l-azabicyclo[2.2.2]oct-3-yl)[ 5-(4-chlorophenyl)furan-2-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiazole-3-carboxamide),
(R)-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiazole-3-carboxamide), R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(NN-dimethylamino)phenyl)thiophene-2- carboxamide . (R)-N-( l -azabicyclo[2.2.2]oct-3-yl)(5-(8-quinolinyl)thiophene-2-carboxamide), (SJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridyl)thiophene-2-carboxamide); (SJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(4-pyridyl)thiophene-2-carboxamide), (SJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide), (S)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-2-carboxamide),
(R N-(l -azabicyclo[2.2.2]oct-3-yl)(5-phenylthiophene-3-carboxamide), (RJ-N-(l-azabicyclo[2.2.2]oct-3-yl)(4-phenylthiophene-2-carboxamide), R -N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-cyanophenyl)thiophene-2-carboxamide), (Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(N-methylamino)phenyl)thiophene-2- carboxamide),
(R/)-N-(l -aza-bicycIo[2.2.2]oct-3-yl)(5-(3-hydroxyphenyl)thiophene-2-carboxamide), (R N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-pyridylamino)thiophene-2-carboxamide), (R/)-N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-chlorophenyl)thiophene-2-carboxamide), (R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(4-moφholinyl)phenyl)thiophene-2- carboxamide),
(R -N-(l-azabicyclo[2.2.2]oct-3-yl)(5-(3-(aminomethyl)phenyl)thiophene-2- carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-phenoxythiophene-2-carboxamide), (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-aminophenyl)furan-2-carboxamide) , (R)-N-( 1 -azabicyclo[2.2.2]oct-3-yl)(5-(3-(NN-dimethylamino)phenyl)furan-2- carboxamide),
(RJ-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-formylphenyl)thiophene-2-carboxamide), or (Rj-N-(l -azabicyclo[2.2.2]oct-3-yl)(5-(3-(hydroxymethyl)phenyl)thiophene-2- carboxamide), or a pharmaceutically-acceptable salt thereof.
2. A pharmaceutical composition comprising a combination according to Claim 1 together with a pharmaceutically acceptable diluent or carrier.
3. A method providing neuroprotection or analgesia for the treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease which method comprises administering a therapeutically effective amount of a combination as defined in Claim 1 to a patient.
4. The method according to Claim 3, for treatment or prophylaxis of Alzheimer's disease.
5. The use of a combination according to Claim 1 in the preparation of a medicament providing neuroprotection or analgesia for the treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease.
6. The use of a combination according to Claim 5, in the preparation of a medicament for the treatment or prophylaxis of Alzheimer's disease.
7. A combination according to Claim 1, wherein said statin is rosuvastatin or a pharmaceutically-acceptable salt thereof and said α7-nAChR agonist is selected from: spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one; N-(l -Azabicyclo[2.2.2]oct-3-yl)[E-3-(2-thienyl)propenamide], or
(2'R)-5'-(3-furanyl)spiro[l -azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine] or a pharmaceutically-acceptable salt thereof.
8. A pharmaceutical composition comprising a combination according to Claim 7 together with a pharmaceutically acceptable diluent or carrier.
9. A method providing neuroprotection or analgesia for treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease which method comprises administering a therapeutically effective amount of a combination as defined in Claim 7 to a patient.
10. The method according to Claim 9. for treatment or prophylaxis of Alzheimer's disease.
11. The use of a combination according to Claim 7, in the preparation of a medicament providing neuroprotection or analgesia for the treatment or prophylaxis of a condition or disorder involving reduced cholinergic function selected from Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, schizophrenia, Tourette's syndrome, and Parkinson's disease.
12. The use of a combination according to Claim 1 1 , in the preparation of a medicament for the treatment or prophylaxis of Alzheimer's disease.
PCT/SE2003/001352 2002-09-02 2003-09-01 Alpha-7 nicotinic receptor agonists and statins in combination WO2004019947A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US10/525,783 US20050256146A1 (en) 2002-09-02 2003-09-01 Alpha-7 nicotinic receptor agonists and stains in combination
DE60313004T DE60313004T2 (en) 2002-09-02 2003-09-01 ALPHA-7 NICOTIC ACID RECEPTOR AGONISTS AND STATINE IN COMBINATION
SI200330803T SI1545537T1 (en) 2002-09-02 2003-09-01 Alpha-7 nicotinic receptor agonists and statins in combination
AU2003256203A AU2003256203A1 (en) 2002-09-02 2003-09-01 Alpha-7 nicotinic receptor agonists and statins in combination
DK03791540T DK1545537T3 (en) 2002-09-02 2003-09-01 Alpha-7 nicotine receptor agonists and statins in combination
JP2004532517A JP2006505530A (en) 2002-09-02 2003-09-01 Combination of alpha-7 nicotinic receptor agonist and statin
EP03791540A EP1545537B9 (en) 2002-09-02 2003-09-01 Alpha-7 nicotinic receptor agonists and statins in combination
HK05109104A HK1077193A1 (en) 2002-09-02 2005-10-14 Alpha-7 nicotinic receptor agonists and statins incombination
US12/186,915 US20090192180A1 (en) 2002-09-02 2008-08-06 Alpha-7 Nicotinic Receptor Agonists and Statins In Combination

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0202598-9 2002-09-02
SE0202598A SE0202598D0 (en) 2002-09-02 2002-09-02 Alpha-7 Nicotinic receptor agonists and statins in combination

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/186,915 Continuation US20090192180A1 (en) 2002-09-02 2008-08-06 Alpha-7 Nicotinic Receptor Agonists and Statins In Combination

Publications (1)

Publication Number Publication Date
WO2004019947A1 true WO2004019947A1 (en) 2004-03-11

Family

ID=20288874

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2003/001352 WO2004019947A1 (en) 2002-09-02 2003-09-01 Alpha-7 nicotinic receptor agonists and statins in combination

Country Status (13)

Country Link
US (2) US20050256146A1 (en)
EP (1) EP1545537B9 (en)
JP (1) JP2006505530A (en)
AT (1) ATE358485T1 (en)
AU (1) AU2003256203A1 (en)
DE (1) DE60313004T2 (en)
DK (1) DK1545537T3 (en)
ES (1) ES2283860T3 (en)
HK (1) HK1077193A1 (en)
PT (1) PT1545537E (en)
SE (1) SE0202598D0 (en)
SI (1) SI1545537T1 (en)
WO (1) WO2004019947A1 (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009017454A1 (en) * 2007-07-30 2009-02-05 Astrazeneca Ab New therapeutic combination of a gsk3 inhibitor and an a7-nicotinic agonist 960
WO2011128810A1 (en) * 2010-04-14 2011-10-20 Centre National De La Recherche Scientifique Statins for the prevention or treatment of drug addictions
WO2013004995A1 (en) 2011-07-07 2013-01-10 Takeda Pharmaceutical Company Limited Pyrimidinone compounds and their use
WO2013004996A1 (en) 2011-07-07 2013-01-10 Takeda Pharmaceutical Company Limited 5- or 6 - substituted 3 - hydroxy - 2 ( 1h) - pyridinones as d-amino acid oxidase (daao) inhibitors in therapy of diseases such as schizophrenia, cognitive disorder and pain
WO2013027000A1 (en) 2011-08-22 2013-02-28 Takeda Pharmaceutical Company Limited Pyridazinone compounds and their use as daao inhibitors
EP2593447A2 (en) * 2010-07-15 2013-05-22 Bayer Intellectual Property GmbH New heterocyclic compounds as pesticides
US8653257B2 (en) 2008-06-20 2014-02-18 Astrazeneca Ab Dibenzothiazepine derivatives and uses thereof—424
CN103923105A (en) * 2014-04-17 2014-07-16 北京大学 2-indolizine formylamine compound as well as preparation method and application thereof
WO2014122474A1 (en) 2013-02-07 2014-08-14 Takeda Pharmaceutical Company Limited Piperidin-1 -yl and azepin-1 -yl carboxylates as muscarinic m4 receptor agonists
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
US9108961B2 (en) 2010-05-17 2015-08-18 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride
US9156829B2 (en) 2014-02-20 2015-10-13 Takeda Pharmaceutical Company Limited Cycloalkyl and heterocycloalkyl compounds as orexin receptor antagonists
US9475795B2 (en) 2012-05-30 2016-10-25 Takeda Pharmaceutical Company Limited Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases
US9493432B2 (en) 2013-10-15 2016-11-15 Takeda Pharmaceuticals Company Limited Cyclopentylbenzamide derivatives and their use for the treatment of psychotic and cognitive disorders
US9585877B2 (en) 2012-05-08 2017-03-07 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
US9790201B2 (en) 2013-08-08 2017-10-17 Takeda Pharmaceutical Company Limited Piperidine and azepine derivatives as prokineticin receptor modulators
WO2018066718A1 (en) 2016-10-04 2018-04-12 Takeda Pharmaceutical Company Limited Therapeutic compounds
WO2018092921A1 (en) 2016-11-18 2018-05-24 Takeda Pharmaceutical Company Limited Mglur7 agonist compounds for treating mglur7- regulated diseases, disorders, or conditions
US10208016B2 (en) 2013-06-21 2019-02-19 Takeda Pharmaceutical Company Limited 1-sulfonyl piperidine derivatives as modulators of prokineticin receptors
US10562882B2 (en) 2013-11-27 2020-02-18 Takeda Pharmaceutical Company Limited Piperidine derivatives for use in the treatment or prevention of psychiatric and neurological conditions
EP3673906A1 (en) * 2011-03-18 2020-07-01 Genzyme Corporation Glucosylceramide synthase inhibitors
WO2021176273A1 (en) 2020-03-04 2021-09-10 Takeda Pharmaceutical Company Limited Oral solid preparations

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2013161871A1 (en) * 2012-04-25 2015-12-24 興和株式会社 Thiophene derivative having TLR inhibitory action

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006098A1 (en) * 1994-08-24 1996-02-29 Astra Aktiebolag Spiro-azabicyclic compounds useful in therapy
WO2000042044A1 (en) * 1999-01-15 2000-07-20 Astrazeneca Ab Novel aralkyl amines of spirofuropyridines useful in therapy
US6110914A (en) * 1997-07-18 2000-08-29 Astra Aktiebolag Spiroazabicyclic heterocyclic compounds
WO2001032620A1 (en) * 1999-11-03 2001-05-10 Astrazeneca Ab Positive modulators of nicotinic receptor agonists
US20020042429A1 (en) * 2000-08-21 2002-04-11 Myers Jason K. Quinuclidine-substituted heteroaryl moieties for treatment of disease

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6569865B2 (en) * 2001-06-01 2003-05-27 Astrazeneca Ab Spiro 1-azabicyclo[2.2.2]octane-3,2′(3′h)-furo[2,3-b]pyridine
US20050222122A1 (en) * 2002-04-02 2005-10-06 Sean Lilienfeld Statin therapy for enhancing cognitive maintenance
JP2006510662A (en) * 2002-12-11 2006-03-30 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー Treatment of diseases with combinations of α7 nicotinic acetylcholine receptor agonists and other compounds
KR101176670B1 (en) * 2004-03-25 2012-08-23 메모리 파마슈티칼스 코포레이션 Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006098A1 (en) * 1994-08-24 1996-02-29 Astra Aktiebolag Spiro-azabicyclic compounds useful in therapy
US6110914A (en) * 1997-07-18 2000-08-29 Astra Aktiebolag Spiroazabicyclic heterocyclic compounds
WO2000042044A1 (en) * 1999-01-15 2000-07-20 Astrazeneca Ab Novel aralkyl amines of spirofuropyridines useful in therapy
WO2001032620A1 (en) * 1999-11-03 2001-05-10 Astrazeneca Ab Positive modulators of nicotinic receptor agonists
US20020042429A1 (en) * 2000-08-21 2002-04-11 Myers Jason K. Quinuclidine-substituted heteroaryl moieties for treatment of disease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BUXBAUM JOSEPH D. ET AL.: "Pharmacological concentrations of the HMG-COA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients", FRONTIERS IN BIOSCIENCE, vol. 7, 1 April 2002 (2002-04-01), pages 50 - 59, XP002974322 *
JICK H. ET AL.: "Statins and the risk of dementia", LANCET, vol. 356, 11 November 2000 (2000-11-11), pages 1627 - 1631, XP004264153 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
WO2009017454A1 (en) * 2007-07-30 2009-02-05 Astrazeneca Ab New therapeutic combination of a gsk3 inhibitor and an a7-nicotinic agonist 960
US8653257B2 (en) 2008-06-20 2014-02-18 Astrazeneca Ab Dibenzothiazepine derivatives and uses thereof—424
WO2011128810A1 (en) * 2010-04-14 2011-10-20 Centre National De La Recherche Scientifique Statins for the prevention or treatment of drug addictions
FR2958850A1 (en) * 2010-04-14 2011-10-21 Centre Nat Rech Scient DRUGS FOR THE PREVENTION OR TREATMENT OF ADDICTIONS TO DRUGS
US20130109712A1 (en) * 2010-04-14 2013-05-02 Universite De Poitiers Statins for the Prevention or Treatment of Drug Addictions
US9550767B2 (en) 2010-05-17 2017-01-24 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
US9273044B2 (en) 2010-05-17 2016-03-01 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
US9108961B2 (en) 2010-05-17 2015-08-18 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride
EP2593447B1 (en) * 2010-07-15 2016-08-17 Bayer Intellectual Property GmbH 3-pyridyl-heteroarylcarboxamide compounds as pesticides
EP2593447A2 (en) * 2010-07-15 2013-05-22 Bayer Intellectual Property GmbH New heterocyclic compounds as pesticides
US9233951B2 (en) 2010-07-15 2016-01-12 Bayer Intellectual Property Gmbh Heterocyclic compounds as pesticides
EP3673906A1 (en) * 2011-03-18 2020-07-01 Genzyme Corporation Glucosylceramide synthase inhibitors
WO2013004995A1 (en) 2011-07-07 2013-01-10 Takeda Pharmaceutical Company Limited Pyrimidinone compounds and their use
WO2013004996A1 (en) 2011-07-07 2013-01-10 Takeda Pharmaceutical Company Limited 5- or 6 - substituted 3 - hydroxy - 2 ( 1h) - pyridinones as d-amino acid oxidase (daao) inhibitors in therapy of diseases such as schizophrenia, cognitive disorder and pain
WO2013027000A1 (en) 2011-08-22 2013-02-28 Takeda Pharmaceutical Company Limited Pyridazinone compounds and their use as daao inhibitors
US9585877B2 (en) 2012-05-08 2017-03-07 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
US10544126B2 (en) 2012-05-30 2020-01-28 Takeda Pharmaceutical Company Limited Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases
US9475795B2 (en) 2012-05-30 2016-10-25 Takeda Pharmaceutical Company Limited Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases
US11512066B2 (en) 2012-05-30 2022-11-29 Takeda Pharmaceutical Company Limited Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases
US10167273B2 (en) 2012-05-30 2019-01-01 Takeda Pharmaceutical Company Limited Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases
WO2014122474A1 (en) 2013-02-07 2014-08-14 Takeda Pharmaceutical Company Limited Piperidin-1 -yl and azepin-1 -yl carboxylates as muscarinic m4 receptor agonists
US10208016B2 (en) 2013-06-21 2019-02-19 Takeda Pharmaceutical Company Limited 1-sulfonyl piperidine derivatives as modulators of prokineticin receptors
US10308635B2 (en) 2013-06-21 2019-06-04 Takeda Pharmaceutical Company Limited 1-sulfonyl piperidine derivatives as modulators of prokineticin receptors
US9790201B2 (en) 2013-08-08 2017-10-17 Takeda Pharmaceutical Company Limited Piperidine and azepine derivatives as prokineticin receptor modulators
US10160745B2 (en) 2013-08-08 2018-12-25 Takeda Pharmaceutical Company Limited Piperidine and azepine derivatives as prokineticin receptor modulators
US9493432B2 (en) 2013-10-15 2016-11-15 Takeda Pharmaceuticals Company Limited Cyclopentylbenzamide derivatives and their use for the treatment of psychotic and cognitive disorders
US10562882B2 (en) 2013-11-27 2020-02-18 Takeda Pharmaceutical Company Limited Piperidine derivatives for use in the treatment or prevention of psychiatric and neurological conditions
US10689373B2 (en) 2014-02-20 2020-06-23 Takeda Pharmaceutical Company Limited 1,2-substituted cyclopentanes as orexin receptor antagonists
US9156829B2 (en) 2014-02-20 2015-10-13 Takeda Pharmaceutical Company Limited Cycloalkyl and heterocycloalkyl compounds as orexin receptor antagonists
CN103923105A (en) * 2014-04-17 2014-07-16 北京大学 2-indolizine formylamine compound as well as preparation method and application thereof
WO2018066718A1 (en) 2016-10-04 2018-04-12 Takeda Pharmaceutical Company Limited Therapeutic compounds
WO2018092921A1 (en) 2016-11-18 2018-05-24 Takeda Pharmaceutical Company Limited Mglur7 agonist compounds for treating mglur7- regulated diseases, disorders, or conditions
US11465994B2 (en) 2016-11-18 2022-10-11 Takeda Pharmaceutical Company Limited MGluR7 agonist compounds for treating mGluR7-regulated diseases, disorders, or conditions
WO2021176273A1 (en) 2020-03-04 2021-09-10 Takeda Pharmaceutical Company Limited Oral solid preparations

Also Published As

Publication number Publication date
US20050256146A1 (en) 2005-11-17
EP1545537B1 (en) 2007-04-04
PT1545537E (en) 2007-06-20
ATE358485T1 (en) 2007-04-15
DK1545537T3 (en) 2007-07-02
ES2283860T3 (en) 2007-11-01
DE60313004T2 (en) 2008-01-03
US20090192180A1 (en) 2009-07-30
JP2006505530A (en) 2006-02-16
HK1077193A1 (en) 2006-02-10
SE0202598D0 (en) 2002-09-02
DE60313004D1 (en) 2007-05-16
EP1545537A1 (en) 2005-06-29
EP1545537B9 (en) 2008-08-20
SI1545537T1 (en) 2007-08-31
AU2003256203A1 (en) 2004-03-19

Similar Documents

Publication Publication Date Title
US20090192180A1 (en) Alpha-7 Nicotinic Receptor Agonists and Statins In Combination
Hayley et al. Neuroplasticity and the next wave of antidepressant strategies
AU2007271186C1 (en) Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases
Ge et al. Ginkgolide B attenuates myocardial infarction-induced depression-like behaviors via repressing IL-1β in central nervous system
EA038531B1 (en) Method for treatment of an amyotrophic lateral sclerosis, use of a pharmaceutical composition comprising masitinib
JP2006505530A5 (en)
WO2006007312A2 (en) Co-administration of dehydroepiandrosterone (dhea) congener with pharmaceutically active agents for treating inflammation
JP2012505257A (en) Compositions and methods for the treatment of multiple sclerosis
Dass et al. Behavioural and immunohistochemical changes following supranigral administration of sonic hedgehog in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-treated common marmosets
US10576076B2 (en) Pharmaceutical combination of everolimus with dactolisib
KR20150011379A (en) Methods and compositions for administration of oxybutynin
US20210393595A1 (en) Anti-neurodegenerative combinations and use for treatment of neurodegenerative diseases
US20020107193A1 (en) Therapeutic uses for IP3 receptor-mediated calcium channel modulators
JP2002518448A (en) Compositions and methods for treating high blood cholesterol
JP6261048B2 (en) Preventive or therapeutic agent for diseases involving osteoclasts
US20200054646A1 (en) Use of phenothiazine derivative in the treatment of infectious purpura or purpura fulminans
JPWO2019237054A5 (en)
Yıldırım et al. Effect of Antidepressants and its Orthodontic Implications
WO2002038140A2 (en) Therapeutic uses for ip3 receptor-mediated calcium channel modulators
AU2013203070B2 (en) Combination of HMG-CoA reductase inhibitors with phosphodiesterase 4 inhibitors for the treatment of inflammatory pulmonary diseases

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003791540

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10525783

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2004532517

Country of ref document: JP

WWP Wipo information: published in national office

Ref document number: 2003791540

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2003791540

Country of ref document: EP