US20110294835A1 - Muscarinic Agonists as Cognitive Enhancers - Google Patents

Muscarinic Agonists as Cognitive Enhancers Download PDF

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US20110294835A1
US20110294835A1 US12/992,709 US99270909A US2011294835A1 US 20110294835 A1 US20110294835 A1 US 20110294835A1 US 99270909 A US99270909 A US 99270909A US 2011294835 A1 US2011294835 A1 US 2011294835A1
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William S. Messer, Jr.
Michael Ragozzino
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University of Illinois
University of Toledo
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Assigned to NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT reassignment NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF TOLEDO
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P25/14—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
    • A61P25/28—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention is directed to methods for enhancing cognitive functions in subjects in need thereof.
  • cholinergic receptors which are proteins embedded in the cell membrane that respond to the chemical acetylcholine. Cholinergic receptors are subdivided into the nicotinic and muscarinic receptor families, and muscarinic receptors represent a family of five subtypes. Muscarinic receptors mediate a variety of physiological responses to the neurotransmitter acetylcholine in the central and peripheral nervous systems. In particular, M 1 muscarinic receptors play a role in learning and memory function in the brain and regulate gastric acid secretion in the stomach. Consequently, muscarinic receptors are being considered as important targets in the treatment of different mental conditions. While an M 1 agonist profile could provide efficacy in a broad range of symptomatic domains including enhancement of cognitive function, the development of selective muscarinic agonists has been hindered by the high degree of homology among the five receptor subtypes.
  • muscarinic agonist It is difficult to predict whether a muscarinic agonist will have a beneficial result.
  • anticholinergic drugs including the glycolate esters, produce psychotomimetic effects in humans.
  • muscarinic antagonists have been used in schizophrenic subjects to control the Parkinsonism associated with administration of antipsychotics with dopamine antagonist activity; yet at higher doses, muscarinic antagonists exacerbate the symptoms of schizophrenia, producing confusion and hallucinations.
  • Alzheimer's disease subjects treated with cholinesterase inhibitors which elevate levels of acetylcholine, exhibit improvements in neuropsychiatric symptoms such as agitation, hallucinations and psychosis.
  • the selective M 1 /M 4 muscarinic agonist xanomeline significantly improved psychiatric symptoms such as hallucinations in phase II clinical trials in Alzheimer's subjects.
  • xanomeline produced unwanted side effects associated with activation of M 3 receptors (including salivation, diarrhea and profuse sweating) that limited subject compliance.
  • the side effects seem to be associated with rapid metabolism of the alkyloxy side chain following oral administration, resulting in a nonselective, yet active compound with limited therapeutic utility.
  • the liabilities of xanomeline still outweigh its benefits.
  • M 4 receptors modulate locomotor activity produced by the stimulation of D 1 dopamine receptors.
  • M 4 knockout mice also show enhanced sensitivity to the effects of PCP on the pre-pulse inhibition model of psychosis. Since M 1 and M 2 receptors play a role in cognitive and memory function, agonists with M 1 and M 2 activity might be particularly useful in treating memory and cognitive deficits associated with schizophrenia.
  • muscarinic agonists are claimed in U.S. Pat. Nos. 5,403,845; 5,175,166; 5,726,179; 6,096,767; 6,211,204 B1; 6,369,081 B1; 6,376,675 B2; and 6,602,891 B2; and in PCT patent applications Nos. WO/2007/075397 claiming priority to U.S. Ser. No. 60/754,529); PCT/US08/003,637 (claiming priority to U.S. Ser. No. 60/919,800), which are expressly incorporated herein by reference. Also, muscarinic agonists are claimed in U.S. Pat. No. 5,618,818 which is owned by the same assignee as herein.
  • muscarinic agonists for the treatment of neurological disorders have been hampered by the high degree of amino acid homology within the binding pocket of muscarinic receptors. While many compounds have been developed with reported selectivity, relatively few compounds have been identified that selectively activate M 1 and/or M 4 receptors.
  • Cognitive function reflects the ability to process information and includes various domains of intellectual function including learning and memory, attention or vigilance, language capabilities, and executive functions. Each of these aspects of cognitive function can be further divided into multiple domains. For example, different types of memory function include episodic memory, working memory, reference memory, etc. In a similar fashion, executive function includes reasoning, problem solving, planning, organization and behavioral flexibility.
  • Errors in perseveration reflect an inability to initially inhibit a previously relevant strategy. Regressive errors reflect an inability to maintain or reliably execute a new strategy once it is selected.
  • the medial prefrontal cortex has been implicated in behavioral flexibility and the ability to shift from previously relevant strategies, while the dorsomedial striatum likely plays a role in mediating the maintenance and execution of novel strategies.
  • None-reinforced errors are associated with choices that were never reinforced previously and it is not clear which brain regions are involved.
  • muscarinic cholinergic receptor subtypes because of the complexity of muscarinic cholinergic receptor subtypes, some specific muscarinic receptor subtypes, but not all may prominently enhance cognitive flexibility. Furthermore, alterations in forebrain cholinergic systems are proposed to contribute to the cognitive deficits associated with neurological disorders including Alzheimer's disease and schizophrenia.
  • muscarinic agonists that result in the selective activation of muscarinic receptors, particularly so side effects are minimized during treatment of the conditions noted above.
  • It is another object of the present invention to provide pharmaceutical composition comprising compounds of the present invention, as active ingredients.
  • a method of treating a mental condition in a subject in need thereof comprising: administering to a subject in need thereof an effective amount of 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-102A).
  • CDD-102A 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride
  • the mental condition is selected from the group consisting of cognitive impairment, poor memory confusion, memory loss, and attentional deficits.
  • Other examples include neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, age-related cognitive decline, and attention-deficit disorder.
  • a method of modulating the progression of one or more mental conditions of claim that includes administering an effective amount of compound CDD-102A where the effective amount is sufficient to beneficially affect M 1 receptor activity.
  • composition comprising the compound CDD-102A together with pharmaceutically acceptable carriers or excipients.
  • compositions for prevention of deterioration of a cognitive function, amelioration of a cognitive function and/or enhancement of a cognitive function comprising an effective amount of a CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • the cognitive function comprises one or more of: executive functioning (such as, for example, planning and prioritizing), reasoning and problem solving, a memory function, a learning function and behavioral flexibility function.
  • the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors.
  • Cognitive function reflects the ability to process information and includes various domains of intellectual function including learning and memory, attention or vigilance, language capabilities, and executive functions. Each of these aspects of cognitive function can be further divided into multiple domains. For example, different types of memory function include episodic memory, working memory, reference memory, etc.
  • executive function includes reasoning, problem solving, planning, organization and behavioral flexibility.
  • the administration of the compound gives rise to efficacious treatment without substantially producing M 2 , M 3 , M 4 and/or M 5 receptor activity in the subject.
  • the administration of the compound gives rise to efficacious treatment without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity.
  • compositions for prevention of deterioration of a cognitive function, amelioration of a cognitive function and/or enhancement of a cognitive function comprising an effective amount of a CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof;
  • the cognitive function includes one or more of: executive functioning, reasoning and problem solving, a memory function, a learning function and behavioral flexibility function; wherein the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors; and,
  • compositions as described herein together with pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition is formulated to be administered to a subject in need thereof in a dosage ranging from about 0.001 mg/kg to about 10 mg/kg body weight.
  • the pharmaceutical composition is formulated to be administered to a subject in need thereof in a dosage ranging from about 0.01 to about 10 mg/kg of body weight.
  • the pharmaceutical composition is formulated to be administered to a subject in need thereof in a dosage ranging from about 0.01 mg/kg to about 0.1 mg/kg of body weight.
  • the pharmaceutical composition is formulated to be administered to a subject in need thereof in a daily dosage.
  • the pharmaceutical composition is formulated to be administered to a subject in need thereof in a regimen of 1 to 4 times per day.
  • kits comprising at least one pharmaceutically effective dosage unit of a CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof;
  • a continuous schedule having a dosing interval selected from one or more of: once daily dosing and/or multiple daily dosing; and, for administration for one or more of: prevention of deterioration of a cognitive function, amelioration of a cognitive function and/or enhancement of a cognitive function in a subject in need thereof;
  • the cognitive function includes one or more of: executive functioning, reasoning and problem solving, a memory function, a learning function and behavioral flexibility function;
  • the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors; and,
  • a dosage unit comprising CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier or excipient;
  • the dosage unit being efficacious for prevention of deterioration of a cognitive function, amelioration of a cognitive function and/or enhancement of a cognitive function in a subject in need thereof;
  • the cognitive function includes one or more of: executive functioning, reasoning and problem solving, a memory function, a learning function and behavioral flexibility function;
  • the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors; and,
  • a dosage unit wherein the dosage unit is a formulation comprising from about 0.001 mg/kg to about 10 mg/kg body weight CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a dosage unit wherein the dosage unit is a formulation comprising about 1.0 to about 10 mg/kg body weight CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a dosage unit wherein the dosage unit is a formulation comprising from about 0.1 to about 1.0 mg/kg of body weight CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a dosage unit wherein the dosage unit is a formulation comprising about 0.01 to about 0.1 mg/kg body weight CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a dosage unit wherein the dosage unit is a formulation comprising from about 0.01 mg/kg to about 0.1 mg/kg of body weight CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a dosage unit wherein the dosage unit is a formulation comprising about 0.001 mg/kg to about 0.01 mg/kg of body weight CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a dosage unit wherein the dosage unit is a formulation comprising about CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof formulated as a daily dosage.
  • the dosage unit is a pharmaceutical formulation.
  • the dosage unit is a solid formulation.
  • the dosage unit is a tablet or capsule formulation.
  • the dosage unit is a tablet formulation.
  • the dosage unit is an oral formulation.
  • a method of treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, thereby treating the subject.
  • the pharmaceutical composition is provided as a plurality of individual dosage forms, and
  • the pharmaceutical composition is provided with a set of instructions directing the administration of at least one of each individual dosage forms so as to improve cognitive function.
  • a method of improving the cognitive function in a subject in need thereof comprising: administering to a subject in need thereof an effective amount of CDD-102A [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound or a pharmaceutically acceptable salt or hydrate thereof,
  • the mental condition comprised one or more of: executive functioning, reasoning and problem solving, a memory function, a learning function and behavioral flexibility function.
  • the method includes wherein the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors.
  • the method included administration of the compound which gives rise to efficacious treatment without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity in the subject.
  • the mental condition is at least partially due to decreased M 1 receptor activity.
  • the subject has a mental condition selected from the group consisting of one or more of: neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, age-related cognitive decline, and attention-deficit disorder.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, to selectively activate M 1 receptors in the subject without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity in the subject.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, to selectively activate M 1 receptors in the subject without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity in the subject.
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, to selectively activate M 1 receptors in the subject without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity in the subject.
  • a method for treating a subject suffering from memory impairment comprising;
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, to selectively activate M 1 receptors in the subject without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity in the subject.
  • a method for the treatment or prophylaxis of a disease or condition resulting from dysfunction of M 1 receptor transmission in a subject comprising;
  • CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, to selectively activate M 1 receptors in the subject without substantially producing M 2 , M 3 , M 4 and/or M S subtype receptor activity in the subject.
  • the prophylaxis of the disease includes prevents the development of the disease or condition, and/or whereby the disease or condition has already developed and the subject is protected against worsening of the disease or condition.
  • the disease or condition results from defective or malfunctioning M 1 receptors in the subject.
  • the treatment disease or condition results from suppressed M 1 receptor transmission in the subject.
  • the subject is a human.
  • a method of selectively activating M 1 muscarinic receptor, without substantially activating with M 2 , M 3 , M 4 and/or M 5 receptor activity in a subject comprising:
  • CDD-102A [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • a method of ameliorating at least one symptom in a subject of a condition where it is beneficial to increase the level of activity of an M 1 muscarinic receptor comprising:
  • determining that the subject would benefit from an increased level of activity of at least one of an M 1 muscarinic receptor determining that the subject would benefit from an increased level of activity of at least one of an M 1 muscarinic receptor; and, administering an amount of a CDD-102A [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, which is therapeutically effective to increase the level of activity of M 1 muscarinic receptors in the subject without substantially producing M 2 , M 3 , M 4 and M 5 receptor activity, and to ameliorate the at least one symptom in the subject.
  • a CDD-102A [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof, which is therapeutically effective to increase the level of activity of M
  • the level of activity of M 2 , M 3 , M 4 and M 5 receptor activity is not increased to a level sufficient to cause adverse symptom in the subject.
  • FIG. 1 is a graph showing the effects of i.p. injections of CDD-0102A on delayed spontaneous alternation in a modified T-maze.
  • FIG. 2 is a graph showing the results of tests for shifting from a place cue task to a visual cue task.
  • CDD-0102A at doses of 0.03 and 0.1 mg/kg decreased the number of trials to criterion (10 consecutive correct choices).
  • FIG. 3 is a graph showing the results of tests for shifting from a visual cue task to a place cue task.
  • CDD-0102A at doses of 0.03 and 0.1 mg/kg decreased the number of trials to criterion (10 consecutive correct choices).
  • FIG. 4A-C presents graphs depicting the breakdown of the types of errors exhibited during the shift from a place cue task to a visual cue task.
  • CDD-0102A at doses of 0.03 and 0.1 mg/kg decreased the number of A) perseverative errors, B) regressive errors and C) never-reinforced errors.
  • FIG. 5A-C presents graphs depicting the breakdown of the types of errors exhibited during the shift from a visual cue task to a place cue task.
  • CDD-0102A at doses of 0.03 and 0.1 mg/kg decreased the number of A) perseverative errors and B) regressive errors with no significant impact on C) never-reinforced errors.
  • FIG. 6 presents a graph comparing the effects of CDD-0102A on memory function and salivation following i.p. injections in the rat.
  • FIG. 7 shows Table 1 which summarizes functional data for CDD-0102A with respect to activation of muscarinic receptor subtypes.
  • M 1 is also referred to as a “muscarinic acetylcholine receptor M 1 ,” “cholinergic receptor,” and/or “muscarinic 1.”
  • Such compounds can be useful in treating memory and cognitive deficits associated with neurological disorders including schizophrenia.
  • CDD-102A [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine].
  • CDD-102 has the Formula I shown below:
  • CDD102 was synthesized at The University of Toledo and characterized as a selective muscarinic agonist in a variety of binding and functional assays. (Dunbar et al. 1993). The biological data indicate that CDD-0102 is a partial M 1 muscarinic agonist with low activity at other muscarinic receptor subtypes. It exhibits a low side effect profile in vivo and reverses memory deficits in rats with impaired cholinergic function. (Messer et al. 2002). See also Dunbar, P. G. et al. (1993).
  • CDD-0102 is generally described in “Muscarinic Agonists,” Dunbar, P. G., G. J. Durant, W. Hoss and W. S. Messer, Jr., U.S. Pat. No. 5,403,845, issued Apr. 4, 1995.
  • a method of treating a subject suffering from a muscarinic receptor related disorder comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one CDD-102A analog compound.
  • the compounds of Formula I are potentiators of the M 1 subtype of muscarinic receptors. Furthermore, the compounds of Formula I selectively potentiate M 1 receptors relative to other muscarinic receptors.
  • CDD-102A By “CDD-102A”, “CDD-102A compound” and/or “CDD-102A analog compound,” it is generally meant a pharmaceutically acceptable salt or hydrate of the CDD-102 compound.
  • muscarinic related disorder it is generally meant a disorder whose symptoms are ameliorated by activating a muscarinic receptor.
  • M 1 receptors By “selectively activating M 1 receptors,” it is generally meant activating M 1 receptors in a subject without substantially affecting (e.g., by activating and/or suppressing) other M subtype receptor activity. These other M subtype receptors are generally understood to include M 2 , M 3 , M 4 and/or M 5 receptors. By “selectively activating M 1 receptors” in a subject, such subject does not substantially experience symptoms or the effects that are caused by the other M subtype receptors.
  • a method of treating a mental condition in a subject in need thereof comprising: administering to a subject in need thereof an effective amount of 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-102A).
  • CDD-102A 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride
  • the mental condition is selected from the group consisting of cognitive impairment, poor memory confusion, memory loss, and attentional deficits.
  • Other examples include neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, age-related cognitive decline, and attention-deficit disorder.
  • the cognitive function comprises one or more of: executive functioning (such as, for example, planning and prioritizing), reasoning and problem solving, a memory function, a learning function and behavioral flexibility function.
  • the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors.
  • Cognitive function reflects the ability to process information and includes various domains of intellectual function including learning and memory, attention or vigilance, language capabilities, and executive functions. Each of these aspects of cognitive function can be further divided into multiple domains. For example, different types of memory function include episodic memory, working memory, reference memory, etc. In a similar fashion, executive function includes reasoning, problem solving, planning, organization and behavioral flexibility.
  • a method of enhancing cognitive function in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one CDD-102A analog compound.
  • the method comprises treating a subject with a pharmacologically active dose of at least one CDD-102A analog compound, for the purpose of controlling the cognitive symptoms associated with loss of cognitive function.
  • the present invention relates to a method of ameliorating at least one symptom in a subject of a condition where it is beneficial to increase the level of activity of at least one of an M 1 muscarinic receptor comprising: determining that the subject would benefit from an increased level of activity of at least one of an M 1 muscarinic receptor; and administering an amount of at least one analog of the compound CDD-102A which is therapeutically effective to increase the level of activity of the at least one of an M 1 muscarinic receptor and to ameliorate the at least one symptom to the subject.
  • a method of modulating the progression of one or more mental conditions of claim that includes administering an effective amount of compound CDD-102A where the effective amount is sufficient to beneficially affect M 1 receptor activity.
  • compositions for prevention of deterioration of a cognitive function, amelioration of a cognitive function and/or enhancement of a cognitive function comprising an effective amount of a CDD-0102 [5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine] compound, or a pharmaceutically acceptable salt or hydrate thereof.
  • the cognitive function comprises one or more of: executive function, reasoning and problem solving; a memory function, a learning function and behavioral flexibility function.
  • the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors.
  • the CDD-102A compound and/or compositions comprising CDD-102A for use in treating a mental condition.
  • the mental condition is at least partially due to decreased M 1 receptor activity.
  • the CDD-102A compound and/or compositions comprising CDD-102A for use in modulating the progression of one or more mental conditions.
  • the mental condition is selected from the group consisting of one or more of: neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, age-related cognitive decline, and attention-deficit disorder.
  • CDD-102A compound and/or compositions comprising CDD-102A for use in treating and/or enhancing cognitive function.
  • CDD-102A compound and/or compositions comprising CDD-102A for use in treating loss of memory.
  • CDD-102A compound and/or compositions comprising CDD-102A for use in treating memory impairment.
  • CDD-102A compound and/or compositions comprising CDD-102A for use in treatment or prophylaxis of a disease or condition resulting from dysfunction of M 1 receptor transmission.
  • CDD-102A compound and/or compositions comprising CDD-102A wherein the prophylaxis of the disease includes preventing the development of the disease or condition, and/or whereby the disease or condition has already developed and the subject is protected against worsening of the disease or condition.
  • CDD-102A compound and/or compositions comprising CDD-102A wherein the disease or condition results from defective or malfunctioning M 1 receptors in the subject.
  • CDD-102A compound and/or compositions comprising CDD-102A wherein the treatment disease or condition results from suppressed M 1 receptor transmission in the subject.
  • CDD-102A compound and/or compositions comprising CDD-102A for use in selectively activating M 1 muscarinic receptor, without substantially producing M 2 , M 3 , M 4 and M 5 receptor activity.
  • CDD-102A compound and/or compositions comprising CDD-102A for use in ameliorating at least one symptom in a subject of a condition where it is beneficial to increase the level of activity of an M 1 muscarinic receptor.
  • CDD-102A compound or a composition comprising CDD-102A in the manufacture of a medicament for use in improving cognitive function; in the manufacture of a medicament for treating a mental condition; in the manufacture of a medicament for modulating the progression of one or more mental conditions; in the manufacture of a medicament for treating and/or enhancing cognitive function; in the manufacture of a medicament for treating loss of memory; in the manufacture of a medicament for treating memory impairment; in the manufacture of a medicament for the treatment or prophylaxis of a disease or condition resulting from dysfunction of M 1 receptor transmission; in the manufacture of a medicament for selectively activating M 1 muscarinic receptor, without substantially producing M 2 , M 3 , M 4 and M 5 receptor activity; and. in the manufacture of a medicament for ameliorating at least one symptom in a subject of a condition where it is beneficial to increase the level of activity of an M 1 muscarinic receptor.
  • CDD-102A compound or a pharmaceutically acceptable salt or hydrate thereof or a composition comprising CDD-102A compound or a pharmaceutically acceptable salt or hydrate thereof, for use in treating a mental condition.
  • the CDD102A compound selectively activates M 1 receptors without substantially producing M 2 , M 3 , M 4 and/or M 5 subtype receptor activity.
  • the CDD-102A analog compounds may be administered in a single daily dose, or the total daily dosage may be administered as a plurality of doses, (e.g., divided doses two, three or four times daily).
  • compounds for the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, or via topical use of ocular formulations, or using those forms of transdermal skin patches well known to persons skilled in the art.
  • the selective M 1 agonist CDD-0102A enhances learning and memory function in intact animals in three separate memory tasks including spontaneous alternation and two behavioral flexibility paradigms.
  • muscarinic agonists are effective in enhancing memory function in animals with brain lesions, specifically involving cholinergic pathways that release acetylcholine.
  • One novel and unexpected aspect of the present invention is that muscarinic agonists enhance learning and memory function in normal animals.
  • CDD-0102A improves behavioral flexibility by decreasing perseverative errors, regressive errors and never-reinforced errors—an unusual and unexpected combination of behavioral effects that has not been observed with other compounds.
  • CDD-102A is a functionally-selective M 1 agonist with lower activity at other muscarinic receptor subtypes.
  • the present experiment investigated the effects of systemic treatment with CDD-102A on working memory and/or attentional set-shifting in rats. All testing occurred in a four-arm cross maze. Delayed (30 sec) spontaneous alternation in Long Evans rats was used as a test for working memory.
  • CDD-102A which is a selective M 1 muscarinic cholinergic agonist
  • mice were tested on a delayed spontaneous alternation task in a modified T-maze.
  • the task takes advantage of rats' natural tendency to alternate. Animals were placed in a 4-arm maze shaped like a “+”. If a rat chose four different arms in four consecutive choices it was scored as an alternation. A delay was inserted between arm choices to help assess memory function.
  • CDD-0102A a functionally selective M 1 agonist
  • improved memory function in a dose dependent manner see FIG. 1 ).
  • Rats had to inhibit using a place strategy and learn a visual cue strategy. That is, a rat had to choose the arm that contained a particular color cue (e.g., black).
  • CDD-0102A at doses of 0.03 and 0.1 mg/kg decreased the number of A) perseverative errors, B) regressive errors and C) never-reinforced errors.
  • FIG. 5 A similar analysis of the types of errors exhibited during the shift from a visual cue task to a place cue task is shown in FIG. 5 .
  • CDD-0102A at doses of 0.03 and 0.1 mg/kg decreased the number of A) perseverative errors and B) regressive errors with no significant impact on C) never-reinforced errors.
  • FIG. 6 A comparison of the effects on memory function (adapted from FIG. 2 ) with effects on salivation is shown in FIG. 6 .
  • Significant effects on memory function as measured by spontaneous alternation were observed with CDD-0102A at 0.1, 0.3 and 1.0 mg/kg i.p., while salivation was not observed until 0.3 mg/kg.
  • CDD-0102A was effective in enhancing learning of a place-visual cue task at a dose of 0.03 mg/kg i.p., a dose ten-fold lower than the lowest dose producing salivation.
  • CDD-0102A The observed functional selectivity of CDD-0102A is unique among compounds purported to be selective M 1 agonists. Recent studies have indicated that a variety of compounds claimed to exhibit selective M 1 agonist activity activate multiple muscarinic receptors (Heinrich et al., 2008). The lack of selectivity likely contributes to the high incidence of adverse effects observed when the compounds are administered to humans. To assess selectivity for muscarinic receptors, the ability of CDD-0102A to activate responses was compared with the nonselective, full agonist carbachol at each muscarinic receptor subtype. In cultured cell lines expressing individual muscarinic receptor subtypes, phosphoinositide (PI) metabolism studies assessed activity at M 1 , M 3 and M 5 receptors, while measures of cAMP levels examined M 2 and M 4 receptor activity.
  • PI phosphoinositide
  • CDD-0102 stimulated PI metabolism to 46% of the carbachol response with an EC 50 of 13 ⁇ M.
  • CDD-0102 stimulated PI metabolism to 6.6% of the carbachol response with an EC 50 of 10 ⁇ M.
  • CDD-0102 was not active when M 5 receptors were expressed at low levels in A9 L cells.
  • CDD-0102 stimulated PI metabolism to 28% of the carbachol response with an EC 50 of 7.5 ⁇ M.
  • CDD-0102 was inactive in assays assessing the inhibition of adenylyl cyclase activity in A9 L cells expressing M 2 receptors and in CHO cells expressing M 4 receptors.
  • CDD-0102 is a functionally-selective M 1 agonist with weaker activity at M 5 receptors, very weak activity at M 3 receptor and no activity at M 2 or M 4 receptors.
  • the maze was placed on a table that was 72 cm above the floor. Each arm was 55 cm long 10 cm wide. The height of the arm walls was 15.0 cm.
  • Each arm contained a food well (3.2 cm diameter ⁇ 1.6 cm high) that was 3 cm away from the end wall. Each food-well hole was 2.3 cm in diameter and 1.6 cm deep.
  • each rat received a single intraperitoneal injection of one of the following treatments: 1) saline; 2) CDD-102A 0.03 mg/kg; 3) CDD-102A 0.1 mg/kg; 4) CDD-102A 0.3 mg/kg; 5) CDD-102A 1 mg/kg.
  • the drug was mixed in saline.
  • compositions comprising a CDD-102A compound of the Formula I and a pharmaceutically acceptable diluent.
  • the compounds of Formula I can be administered by a variety of routes.
  • a CDD-102A compound of Formula I can be administered in any form or mode that makes the compound bioavailable in an effective amount, including oral and parenteral routes.
  • CDD-102A compounds of Formula I can be administered orally, by inhalation, or by the subcutaneous, intramuscular, intravenous, transdermal, intranasal, rectal, occular, topical, sublingual, buccal, or other routes.
  • Oral administration is generally preferred for treatment of the neurological and psychiatric disorders described herein.
  • the pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semi-solid, or liquid material that can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the subject in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions, suspensions, or the like.
  • the compounds of the present invention may be administered orally, for example, with an inert diluent or capsules or compressed into tablets.
  • the compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 4% of the compound of the present invention, the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit.
  • the amount of the compound present in compositions is such that a suitable dosage will be obtained.
  • Preferred compositions and preparations according to the present invention may be determined by a person skilled in the art.
  • the tablets, pills, capsules, troches, and the like may also contain one or more of the following adjuvants: binders such as povidone, hydroxypropyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as dicalcium phosphate, starch, or lactose; disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as talc, magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents, such as sucrose, aspartame, or saccharin, or a flavoring agent, such as peppermint, methyl salicylate or orange flavoring, may be added.
  • binders such as povidone, hydroxypropyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin
  • excipients such as dicalcium phosphate, starch, or lactose
  • disintegrating agents such as alginic acid, Primo
  • the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
  • a liquid carrier such as polyethylene glycol or a fatty oil.
  • Other dosage unit forms may contain other various materials that modify the physical form of the dosage unit, for example, coatings.
  • tablets or pills may be coated with sugar, shellac, or other coating agents.
  • a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the compounds of the present invention may be incorporated into a solution or suspension. These preparations typically contain at least 0.001% of a compound of the invention, but may be varied to be between 0.001 and about 90% of the weight thereof.
  • the amount of the CDD-102A compound of Formula I present in such compositions is such that a suitable dosage will be obtained.
  • the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylene diaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for the adjustment of tonicity, such as sodium chloride or dextrose.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. Preferred compositions and preparations are able to be determined by one skilled in the art.
  • the compounds of the present invention may also be administered topically, and when done so, the carrier may suitably comprise a solution, ointment, or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bees wax, mineral oil, diluents such as water and alcohol, and emulsifiers, and stabilizers.
  • Topical formulations may contain a concentration of a CDD-102A compound of Formula I or its pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume).
  • the CDD-102A compound of Formula I is useful in the treatment of memory function symptoms, particularly a memory function, a learning function, and behavioral flexibility function; and more particularly, where the behavioral flexibility function includes one or more of: perseveration errors, regressive errors and never-reinforced errors.
  • the CDD-102A compounds are employed in a subject who has suffered at least one symptom event.
  • the CDD-102A compounds invention are most typically employed to reduce the likelihood that the subject will further incur such symptoms.
  • the disorders associated with M 1 muscarinic receptors are treated by administering an effective amount of a CDD-102A compound or pharmaceutical composition of Formula I.
  • An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • the dose of a CDD-102A compound of Formula I a number of factors are considered by the attending diagnostician, including, but not limited to: the CDD-102A compound of Formula I to be administered; the species of mammal—its size, age, and general health; the specific disorder involved; the degree of involvement or the severity of the disorder; the response of the individual subject; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.
  • the specific dose administered is determined by the particular circumstances surrounding each situation. These circumstances can include: the route of administration, the prior medical history of the recipient, the symptom being treated, the severity of the symptom being treated, and the age of the recipient. The recipient subject's attending physician should determine the therapeutic dose administered in light of the relevant circumstances.
  • dose titrating the recipient; that is, initially administering a low dose of the compound, and gradually increasing the dose until the desired therapeutic effect is observed.
  • the dosage regimen can be selected in accordance with a variety of factors. These include type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the kidney and liver functions of the subject; and the particular compounds employed. A physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder that is being treated.
  • CDD102A compounds are effective in enhancing cognitive function at dosages much lower than previously thought possible or achieved by other types of muscarinic agonists.
  • the daily dosage of the products may be varied over a wide range from about 0.0001 to about 10 mg per adult human per day.
  • An effective amount of the drug can be supplied at a dosage level of about 0.001 mg/kg to about 10 mg/kg body weight per day.
  • the range can be from about 0.1 to about 10 mg/kg of body weight per day; and in certain embodiments, from about 0.01 mg/kg to about 0.1 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • CDD-102A analog compounds may be used alone at appropriate dosages defined by routine testing in order to obtain optimal pharmacological effect, while minimizing any potential toxic or otherwise unwanted effects.
  • the CDD-102A compounds may be used as adjunctive therapy with known drugs to reduce the dosage required of these traditional drugs, and thereby reduce their side effects.
  • terapéuticaally effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes alleviation of the symptoms of the disease being treated.
  • pharmaceutically acceptable addition salts refers to salts known in the art to be acceptable in pharmaceutical practice, for example acid addition salts such as hydrochloric acid salts, maleic acid salts, and citric acid salts.
  • Pharmaceutically acceptable acid addition salts include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like.
  • metabolite refers to a form of a compound obtained in a human or animal body by action of the body on the administered form of the compound, for example a de-methylated analogue of a compound bearing a methyl group which is obtained in the body after administration of the methylated compound as a result of action by the body on the methylated compound. Metabolites may themselves have biological activity.
  • prodrug refers to a form a compound which after administration to a human or animal body is converted chemically or biochemically to a different compound in the body having biological activity.
  • a prodrug form of a compound may itself have biological activity.

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Family Cites Families (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE788151A (fr) 1971-08-31 1973-02-28 Ciba Geigy Thiadiazoles pouvant servir de fongicides pour le traitement des semences et des terres et de substances actives pour medicaments
DE3069956D1 (en) 1980-09-11 1985-02-21 Caterpillar Tractor Co Rotation sensitive pressure regulator
JPS58193318U (ja) 1982-06-17 1983-12-22 株式会社ケンウッド 信号切替装置
US4652641A (en) 1984-06-26 1987-03-24 S. C. Mitri Benzofused lactams useful as antihypertensive agents and as cholecystokinin antagonists
NZ219646A (en) 1986-03-27 1990-10-26 Merck Sharp & Dohme Oxadiazole derivatives of azacyclics for treating cns disorders
GB8610432D0 (en) 1986-04-29 1986-06-04 Akzo Nv Amino-thiazole & oxazole derivatives
IL83275A (en) 1986-09-08 1994-02-27 Novo Nordisk As Compounds 1,2, 4-Oxadiazolyl Pipridine Transformed, their preparation and pharmaceutical preparations containing them
US4710508A (en) 1986-12-08 1987-12-01 Warner-Lambert Company O-substituted tetrahydropyridine oxime cholinergic agents
US4786648A (en) 1986-12-08 1988-11-22 Warner-Lambert Company O-substituted tetrahydropyridine oxime cholinergic agents
GB8714789D0 (en) 1987-06-24 1987-07-29 Lundbeck & Co As H Heterocyclic compounds
NZ225999A (en) 1987-09-10 1992-04-28 Merck Sharp & Dohme Azacyclic- or azabicyclic-substituted thiadiazole derivatives and pharmaceutical compositions
IE63906B1 (en) 1987-11-13 1995-06-14 Novo Nordisk As Azabicyclic compounds and their preparation and use
DK162892C (da) 1988-07-04 1992-05-11 Novo Nordisk As 1,2,5,6-tetrahydropyridinforbindelser, deres fremstilling og farmaceutiske praeparater indeholdende disse
FR2636628B1 (fr) 1988-08-25 1990-12-28 Sanofi Sa Derives du thiadiazole-1,3,4, leur procede d'obtention et compositions pharmaceutiques en contenant
US5043345A (en) 1989-02-22 1991-08-27 Novo Nordisk A/S Piperidine compounds and their preparation and use
EP0459568A3 (en) 1990-05-31 1992-09-30 Merck Sharp & Dohme Ltd. Substituted oxadiazoles and thiadiazoles for use in the treatment of glaucoma and novel compounds having such use
DK198390D0 (da) 1990-08-21 1990-08-21 Novo Nordisk As Heterocykliske forbindelser, deres fremstilling og anvendelse
US5376668A (en) 1990-08-21 1994-12-27 Novo Nordisk A/S Heterocyclic compounds
US5418240A (en) 1990-08-21 1995-05-23 Novo Nordisk A/S Heterocyclic compounds and their preparation and use
US5175166A (en) 1991-08-27 1992-12-29 The University Of Toledo Muscarinic agonists
JPH05140135A (ja) 1991-11-13 1993-06-08 Tosoh Corp ３−クロロ−４−ヒドロキシ−１，２，５−チアジアゾールの製造法
WO1993014089A1 (fr) 1992-01-13 1993-07-22 Novo Nordisk A/S Composes heterocycliques, leur preparation et leur utilisation
EP0644759A4 (fr) 1992-06-19 1998-04-01 Univ Toledo Production et utilisation d'imines de porphyrines.
US5744598A (en) 1992-06-19 1998-04-28 University Of Toledo Imines of porphyrins, of porphyrin derivatives, and of related compounds, and pharmaceutical compositions containing such imines
PT714394E (pt) 1993-08-19 2001-12-28 Novo Nordisk As Metodo antipsicotico com derivados de tiadiazol e oxadiazol
DK0709094T3 (da) 1994-10-31 2000-07-10 Lilly Co Eli Tetrahydropyridinoxadiazol- eller thiadiazolforbindelse til behandling af angst
US6040442A (en) 1995-06-01 2000-03-21 Eli Lilly And Company Process for preparing 1,2,5-thiadiazole containing ethers
US5852037A (en) 1995-11-13 1998-12-22 Eli Lilly And Company Method for treating anxiety
US5618818A (en) 1996-03-20 1997-04-08 The University Of Toledo Muscarinic agonist compounds
US5726179A (en) 1996-04-01 1998-03-10 The University Of Toledo Muscarinic agonists
US5718912A (en) 1996-10-28 1998-02-17 Merck & Co., Inc. Muscarine agonists
US6162791A (en) 1998-03-02 2000-12-19 Apotex Inc. Thiadiazole compounds useful as inhibitors of cysteine activity dependent enzymes
US6528529B1 (en) * 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
US6096767A (en) 1999-01-22 2000-08-01 The University Of Toledo Muscarinic receptor agonists
US6211204B1 (en) 1999-01-22 2001-04-03 University Of Toledo Muscarinic receptor agonists
US6376675B2 (en) 1999-01-22 2002-04-23 The University Of Toledo Muscarinic receptor agonists
US6255540B1 (en) 1999-06-30 2001-07-03 The University Of Toledo Methods for producing two-substituted glycerols having various levels of protection
EP1419161A1 (fr) 2001-08-24 2004-05-19 PHARMACIA & UPJOHN COMPANY Heteroaryl-7-aza 2.2.1]bicycloheptanes substitues destines au traitement de maladies
US7326731B2 (en) 2001-09-21 2008-02-05 Eli Lilly And Company Muscarinic agonists
CN1561212A (zh) 2001-10-02 2005-01-05 阿卡蒂亚药品公司 作为毒蕈碱试剂的苯并咪唑啉酮衍生物
US6951849B2 (en) 2001-10-02 2005-10-04 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
BR0212983A (pt) 2001-10-17 2004-10-13 Ucb Sa Composto, uso do composto, e, intermediários de sìntese
EP1644320B1 (fr) 2003-07-03 2008-01-16 Eli Lilly And Company Derives d'indane utilises comme agonistes du recepteur muscarinique
JP2009506069A (ja) 2005-08-26 2009-02-12 ブレインセルス，インコーポレイティド ムスカリン性受容体調節による神経発生
JP2009521531A (ja) 2005-12-27 2009-06-04 ザ・ユニバーシティ・オブ・トレド ムスカリンアゴニスト及びその使用方法
KR20090013815A (ko) * 2006-05-04 2009-02-05 솔베이 파마슈티칼스 비. 브이 충동 조절 장애의 치료를 위한 무스카린 작용제
CN101466365A (zh) * 2006-06-09 2009-06-24 惠氏公司 增强认知功能的方法
WO2008118326A1 (fr) 2007-03-23 2008-10-02 University Of Toledo Agonistes muscariniques et procédés d'utilisation de ceux-ci
JP6501682B2 (ja) 2015-09-14 2019-04-17 リンテック株式会社 シート貼付装置およびシート貼付方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012149524A1 (fr) * 2011-04-29 2012-11-01 The University Of Toledo Agonistes muscariniques en tant qu'agents d'amélioration de la mémoire de travail et de la flexibilité cognitive

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US20140045863A1 (en) 2014-02-13
JP2011520905A (ja) 2011-07-21

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