Deuterated Compounds

Abstract

The present disclosure provides deuterated compounds and their use as agonists of the M4 muscarinic acetylcholine receptor in the treatment or prevention of various diseases or disorders associated with the M4 receptor. The present invention further provides a method for treating a disease or disorder associated with the muscarinic M4 receptor in a patient, comprising administering to the patient a compound described herein, or a pharmaceutically acceptable salt thereof. The present invention further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

Description

[Technical Field]

[0001] Technical Field The present invention relates to deuterated compounds and their use as selective agonists of the M4 muscarinic acetylcholine receptor, which deuterated compounds are useful in the treatment or prevention of various diseases or disorders associated with the M4 receptor. [Background technology]

[0002] background Muscarinic acetylcholine receptors (mAChRs) are members of the G protein-coupled receptor superfamily that mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous systems. Five mAChR subtypes, M1–M5, have been cloned. M1 mAChRs are primarily expressed postsynaptically in the cortex, hippocampus, striatum, and thalamus; M2 mAChRs are primarily present in the brainstem and thalamus, but also in the cortex, hippocampus, and striatum, where they are located at cholinergic synaptic terminals (Langmead et al. 2008 Br J Pharmacol). However, M2 mAChRs are also peripherally expressed on cardiac tissue (mediating vagus nerve innervation of the heart) and in smooth muscle and exocrine glands. M3mAChRs are expressed at relatively low levels in the CNS, but are widely expressed in smooth muscle and glandular tissues, such as sweat and salivary glands (Langmead et al., 2008 Br J Pharmacol). Muscarinic receptors in the central nervous system (especially M1 mAChRs) play a crucial role in mediating higher-level cognitive processing. Diseases associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a loss of cholinergic neurons in the basal forebrain (Whitehouse et al., 1982 Science). In schizophrenia, which also has cognitive dysfunction as an important component of the clinical picture, mAChR density is reduced in the prefrontal cortex, hippocampus, and caudate-putamen of schizophrenic subjects (Dean et al., 2002 Mol Psychiatry). Furthermore, animal models have shown that blockade or damage to central cholinergic pathways causes significant cognitive deficits, and nonselective mAChR antagonists induce psychotomimetic effects in psychiatric patients. Cholinergic replacement therapy is primarily based on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. Although these compounds have demonstrated efficacy against symptomatic cognitive decline in clinical settings, they also cause dose-limiting adverse events (including impaired gastrointestinal motility, bradycardia, nausea, and vomiting) due to stimulation of peripheral M2 and M3 mAChRs. Muscarinic receptors are also involved in the neurobiology of addiction. The reinforcing effects of cocaine and other addictive substances are mediated by the mesolimbic dopamine system, and in this system, behavioral and neurochemical studies have shown that cholinergic muscarinic receptor subtypes play a critical role in regulating dopaminergic neurotransmission. For example, M4(- / -) mice demonstrated significantly enhanced reward-driven behavior as a result of cocaine exposure (Schmidt et al., Psychopharmacology, 2011, Aug;216(3):367-78). Furthermore, xanomeline has been demonstrated to block the effects of cocaine in these models. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Schmidt et al.,Psychopharmacology,2011,Aug;216(3):367-78 Summary of the Invention [Means for solving the problem]

[0004] overview The present application relates inter alia to compounds of formula I: [ka] wherein the constituent members are defined herein, or a pharmaceutically acceptable salt thereof.

[0005] The present invention further provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0006] The present invention further provides a method of agonizing a muscarinic M4 receptor, comprising contacting the M4 receptor with a compound described herein or a pharmaceutically acceptable salt thereof.

[0007] The present invention further provides a method of agonizing muscarinic M4 receptors in a patient, comprising contacting the M4 receptor with a compound described herein or a pharmaceutically acceptable salt thereof.

[0008] The present invention further provides a method of treating a disease or disorder associated with the muscarinic M4 receptor in a patient, comprising administering to said patient a compound described herein, or a pharmaceutically acceptable salt thereof.

[0009] The present invention further provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in any of the methods described herein.

[0010] The present invention further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in any of the methods described herein. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows proposed metabolic pathways for observed Compound 1 metabolites from the in vitro studies described in Example 1.

[0012] [Figure 2] FIG. 2 shows the proposed metabolites of Compound 1 detected in human plasma and urine from the study described in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description Compound 1 (i.e., cisethyl 2-[4-(1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate) is a muscarinic receptor agonist selective for the M4 muscarinic acetylcholine receptor (e.g., over any of the M1 receptor, M2 receptor, and / or M3 receptor); see, e.g., U.S. Pat. Nos. 9,670,183; 9,926,297; 10,196,380; 10,385,039; 10,689,368; and 10,961,225; the entire disclosures of each of which are incorporated herein by reference). [ka]

[0014] The present application provides deuterated analogs of Compound 1 and pharmaceutically acceptable salts thereof. Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to higher metabolic stability and may therefore be preferable in some circumstances. (See, for example, A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312.) In particular, substitution of hydrogen with deuterium at one or more metabolic sites may provide one or more therapeutic advantages.

[0015] In some embodiments, the present application provides a compound of formula I: [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from hydrogen and deuterium), or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 0 to 7 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 1 to 7 of R 1 , R 2 , R 3 , R 4, R 5 , R 6 , and R 7 In some embodiments, 2 to 7 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 3 to 7 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 4 to 7 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 5 to 7 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Of these, 6-7 are deuterium.

[0017] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 0 to 6 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 1 to 6 of R 1 , R 2 , R 3 , R4 , R 5 , R 6 , and R 7 In some embodiments, 2 to 6 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 3 to 6 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 4 to 6 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Five or six of these are deuterium.

[0018] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 0 to 5 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 1 to 5 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 2 to 5 of R 1 , R 2 , R3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 3 to 5 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Of these, 4-5 are deuterium.

[0019] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 0 to 4 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, 1 to 4 of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, two to four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Of these, 3-4 are deuterium.

[0020] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7In some embodiments, one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, three of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, four of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, five of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In some embodiments, six of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each deuterium.

[0021] In some embodiments, the compound of formula I has formula II: [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of formula I has formula III: [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound of Formula I has Formula IIIa: [ka] or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound of formula I has formula IV: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of formula I has formula IVa: [ka] or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compounds provided herein are [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compounds provided herein are [ka] or a pharmaceutically acceptable salt thereof.

[0028] The compounds disclosed and described herein, unless the context clearly dictates otherwise, allow atoms at each position of the compound to independently have: 1) an isotopic distribution in the proportional amount normally found in nature for that chemical element, or 2) an isotopic distribution in a proportional amount different from that normally found in nature. A particular chemical element has an atomic number defined by the number of protons in the nucleus. Each atomic number identifies a particular element, but not an isotope; atoms of a given element can have a wide range of neutron numbers. The number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number. Compounds in which one or more atoms of a chemical element have an isotopic distribution in a proportional amount different from that normally found in nature are generally referred to as isotopically labeled compounds. Each chemical element represented in a compound structure can include any isotopic distribution of the aforementioned element. For example, in a compound structure, hydrogen atoms can be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom can be present, the hydrogen atom may be present in the proportionate amounts normally found in nature and in proportionate amounts different from the proportionate amounts normally found in nature (protium ( 1 H) and deuterium ( 2 H). Thus, unless the context clearly dictates otherwise, reference to a compound herein encompasses all possible isotopic distributions of each atom. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be appreciated by those of skill in the art, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, one or more atoms may have an isotopic distribution that differs from that normally found in nature (e.g., at a higher percentage than that normally found in nature). 2 H or 3 With or at a higher rate of H 11 C. 13 C, or 14The use of compounds disclosed and described herein having (C) is also contemplated. By way of general example and without limitation, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H). Carbon isotopes include carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C), and carbon-14 ( 14 C). The nitrogen isotope is nitrogen-13( 13 N), nitrogen-14( 14 N), and nitrogen-15( 15 N). The isotope of oxygen is oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), and oxygen-18( 18 O). The isotopes of fluorine include fluorine-17( 17 F), fluorine-18( 18 F), and fluorine-19( 19 The phosphorus isotope is phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), phosphorus-34( 34 P), phosphorus-35( 35 P), and phosphorus-36( 36 P). The sulfur isotopes include sulfur-32 ( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), and sulfur-38( 38 S). The chlorine isotope is chlorine-35 ( 35 Cl), chlorine-36( 36 Cl), and chlorine-37( 37 The isotope of bromine is bromine-75( 75 Br), Bromine-76( 76 Br), Bromine-77( 77 Br), Bromine-79( 79Br), Bromine-81( 81 Br), and bromine-82( 82 Br). The isotopes of iodine are iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I), and iodine-135( 135 I). In some embodiments, atoms at every position of the compound have an isotope distribution for each chemical element in the proportional amounts normally found in nature. In some embodiments, atoms at one position of the compound have an isotope distribution for the chemical element that is different from the proportional amount normally found in nature (the remaining atoms have an isotope distribution for the chemical element in the proportional amount normally found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotope distribution for the chemical element that is different from the proportional amount normally found in nature (the remaining atoms have an isotope distribution for the chemical element in the proportional amount normally found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotope distribution for the chemical element that is different from the proportional amount normally found in nature (the remaining atoms have an isotope distribution for the chemical element in the proportional amount normally found in nature). In some embodiments, atoms at at least four positions of the compound independently have an isotopic distribution of the chemical element in a proportionate amount different from that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportionate amount normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have an isotopic distribution of the chemical element in a proportionate amount different from that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportionate amount normally found in nature). In some embodiments, atoms at at least six positions of the compound independently have an isotopic distribution of the chemical element in a proportionate amount different from that normally found in nature (the remaining atoms have an isotopic distribution of the chemical element in a proportionate amount normally found in nature).

[0029] In addition, certain compounds (e.g., 3 H and 14 Compounds into which a radioactive isotope, such as C, has been incorporated are useful in drug or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred because they are easy to prepare and detect. 2 Compounds bearing isotopes such as H may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to greater metabolic stability. Isotopically labeled compounds can generally be prepared by routine procedures in the chemical arts. Methods for measuring such isotopic perturbations or enrichments are readily available, such as mass spectrometry, and for isotopes that are radioisotopes, additional methods are available, such as radiation detectors used in conjunction with HPLC or GC.

[0030] As used herein, "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute the compound. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, such as protium ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 I). In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes (hydrogen ( 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), and oxygen-18( 18 In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound of the invention contains unnatural proportions of one or more isotopes, such as tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), and oxygen-15( 15In the compounds provided herein, any hydrogen may be, for example, in the major isotopic form. 2 H, or any carbon, for example, containing 13C as the major isotopic form, or any nitrogen, for example, containing 13C as the major isotopic form. 15 Any oxygen can include N as the major isotopic form, for example 18 It is understood that the compound may contain unnatural proportions of deuterium ( 2 H).

[0031] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d", it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position, in certain embodiments.

[0032] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0033] The present disclosure further provides synthetic methods for incorporating radioisotopes into the compounds of the present disclosure. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and those skilled in the art will readily recognize methods that are applicable to the compounds of the present disclosure.

[0034] How to use The compounds of the present disclosure have activity as selective muscarinic M4 receptor agonists (e.g., more selective than any of M1, M2, and / or M3). The muscarinic activity of Compound 1 has been previously reported in, for example, U.S. Patent Nos. 9,670,183; 9,926,297; 10,196,380; 10,385,039; 10,689,368; and 10,961,225 (the entire disclosures of which are each incorporated herein by reference).

[0035] In some embodiments, the present application provides a method for treating a disease or disorder associated with the muscarinic M4 receptor. In some embodiments, the method includes administering to a subject (e.g., a subject in need thereof) a compound provided herein (e.g., a therapeutically effective amount of a compound provided herein) or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the present application provides a method for treating a cognitive disorder, a psychotic disorder, a movement disorder, an addiction, or for treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain in a subject in need thereof, comprising administering to said subject a compound provided herein or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the present application provides methods of treating a cognitive or psychotic disorder in a subject in need thereof.

[0038] In some embodiments, the cognitive or psychotic disorder is cognitive impairment, mild cognitive impairment, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, presenile dementia, senile dementia, Friedreich's ataxia, ataxia, Down syndrome, Huntington's chorea, hyperkinesia, mania, Tourette's syndrome, Alzheimer's disease, progressive supranuclear palsy, deficits in cognitive function (including attention, orientation, learning disabilities, memory (i.e., memory impairment, amnesia, amnesia, transient global amnesia syndrome, and age-related memory deficits), and language function); cognitive impairment as a result of stroke, Huntington's disease, Pick's disease, AIDS-related dementia, or other dementia conditions, e.g., multi-infarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated with other degenerative disorders (such as cerebellar atrophy and amyotropic lateral sclerosis); other acute or subacute conditions that may cause cognitive decline, e.g., delirium or depression (pseudodementia state), trauma, head injury, age-related cognitive decline, stroke, neurodegeneration, drug-induced states, neurological disorders, cognitive deficits associated with toxic factors, age-related cognitive impairment, autism-related cognitive impairment, Down's syndrome, psychiatric disorders (such as dementia-related psychiatric disorders), and post-electroconvulsive procedure-related cognitive impairment; cognitive impairment due to substance abuse or withdrawal (including nicotine, cannabis, amphetamine, cocaine), attention deficit hyperactivity disorder (ADHD) and dyskinetic disorders (such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesia), schizophrenia, schizophreniform disorders, psychotic depression, mania, acute mania, paranoid disorder, hallucinogenic disorder, and delusional disorder, personality disorder, obsessive-compulsive disorder, schizotypal disorder, delusional disorder, mental disorders due to malignant disease, metabolic disorders, endocrine disorders, or narcolepsy, mental disorders due to substance abuse or withdrawal, bipolar disorder, epilepsy, and schizoaffective disorder.

[0039] In some embodiments, the psychotic disorder is schizophrenia.

[0040] In some embodiments, the present application provides a method of treating Alzheimer's disease or dementia with Lewy bodies in a subject in need thereof, comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the method is a method of treating Alzheimer's disease. In some embodiments, the method is a method of treating dementia with Lewy bodies.

[0041] In some embodiments, the present application provides a method for treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain in a subject in need of treatment or reduction in severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-operative pain, or cancer pain. Provided are methods for treating or lessening the severity of inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, post-surgical pain, or cancer pain, comprising administering to said subject a compound provided herein or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the present application provides a method of treating a peripheral disorder, such as reducing intraocular pressure in glaucoma, in a subject in need thereof, comprising administering to said subject a compound provided herein or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the present application provides a method of treating dry eye disease in a subject in need thereof, comprising administering to said subject a compound provided herein or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the present application provides a method of treating dry mouth (including Sjogren's syndrome) in a subject in need thereof, comprising administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, the present application provides a method of treating an addiction in a subject in need thereof, comprising administering to said subject a compound provided herein or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, the present application provides a method of treating a movement disorder in a subject in need thereof, comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the movement disorder is selected from Parkinson's disease, ADHD, Huntingdon's disease, Tourette's syndrome, and other syndromes associated with dopaminergic dysfunction as the underlying pathogenic factor causing the disease, such as.

[0047] As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or an in vivo system.

[0048] As used herein, the terms "patient" or "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0049] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent, such as an amount of any of the solid forms disclosed herein or salts thereof, that elicits the biological or medical response in a tissue, system, animal, subject, or human that is desired by a researcher, veterinarian, physician, or other clinician. An appropriate "effective" amount in any individual case can be determined using techniques known to those of ordinary skill in the art.

[0050] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0051] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition, or vehicle (such as a liquid or solid filler, diluent, solvent, or encapsulating material). Excipients or carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In some embodiments, each component is "pharmaceutically acceptable" as defined herein. For example, Remington:The Science and Practice of Pharmacy,21st ed.;Lippincott Williams&Wilkins:Philadelphia,Pa.,2005;Handbook of Pharmaceutical Excipients,6th ed.;Rowe et al.,Eds.;The Pharmaceutical Press and the American Pharmaceutical Association:2009;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company:2007;Pharmaceutical Preformulation and Formulation, 2nd ed.;Gibson Ed.;CRC Press LLC:Boca Raton,Fla.,2009.

[0052] As used herein, the term "treating" or "treatment" refers to the inhibition of a disease; e.g., the inhibition of a disease, condition, or disorder (i.e., the arrest of further development of the pathology and / or symptomatology) or the amelioration of a disease in a subject experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder; e.g., the amelioration of a disease, condition, or disorder (i.e., the reversal of the pathology and / or symptomatology) in a subject experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder, such as the reduction of the severity of the disease.

[0053] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases mentioned herein (e.g., preventing or reducing the risk of developing a disease, condition, or disorder in a subject who may be predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptomology of the disease).

[0054] It will be appreciated that certain features of the present disclosure, which are, for clarity, described in separate embodiments, may also be provided in combination in a single embodiment (provided that the embodiments are intended to be combined as if set forth in a multiple dependent form). Conversely, various features of the present disclosure, which are, for brevity, described in a single embodiment, may also be provided separately or in any suitable subcombination.

[0055] Pharmaceutical preparations The present application further provides pharmaceutical compositions comprising the compounds provided herein. In some embodiments, the present application provides compositions (e.g., pharmaceutical compositions) comprising a compound provided herein (e.g., a compound of any of Formulas I-IVa) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier, excipient, or diluent.

[0056] The compounds of the present invention or their pharmaceutically acceptable salts in pure form or in suitable pharmaceutical compositions can be administered via any of the accepted modes of administration for similar purposes.The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents, or additives, and can be formulated into solid, semi-solid, liquid, or gaseous preparations (tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc.).Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.The term "parenteral" as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques.The pharmaceutical compositions of the present invention are formulated so that the active ingredients contained in the compositions are bioavailable when administered to a patient. The composition administered to a subject or patient may take the form of one or more dosage units, where, for example, a tablet may be a single dosage unit, and a container of the compound of the present invention in aerosol form may hold multiple dosage units. The actual preparation of such dosage forms is known or apparent to those skilled in the art; see, for example, The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for treating the disease or condition of interest in accordance with the teachings of the present invention.

[0057] The pharmaceutical compositions provided herein further comprise a pharmaceutically acceptable carrier, including any suitable diluent or additive (including any pharmaceutical agent that does not itself induce antibody production harmful to the individual receiving the composition and that can be administered without undue toxicity). Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol, and ethanol. A comprehensive discussion of pharmaceutically acceptable carriers, diluents, and other additives is provided in Remington's Pharmaceutical Sciences (Mack Pub. Co., NJ, current edition).

[0058] The pharmaceutical composition of the present invention can be in solid or liquid form.In one embodiment, carrier(s) are particulate, so that the composition is, for example, in the form of tablet or powder.Carrier(s) can be liquid, so that the composition is, for example, oral syrup, injection solution or aerosol that is useful for, for example, inhalation administration.

[0059] The pharmaceutical composition of the present invention can be prepared by the methodology well known in the pharmaceutical field.For example, the pharmaceutical composition intended to be administered by injection can be prepared by combining the compound of the present invention with sterile distilled water to form a solution.Surfactant can be added to facilitate the formation of a uniform solution or suspension.Surfactant is a compound that interacts non-covalently with the compound of the present invention to facilitate the dissolution or uniform suspension of the compound in aqueous delivery system.

[0060] The most suitable route will depend on the nature and severity of the condition being treated, and one of skill in the art will be familiar with determining the mode of administration (e.g., oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, suitable pharmaceutical excipients, and other considerations related to delivery of the compound to a subject in need thereof.

[0061] kit The present invention also provides kits containing pharmaceutical compositions comprising one or more compounds of the present invention. The kits also include instructions for using the pharmaceutical compositions for the treatment of any of the diseases and disorders described herein, as well as other uses disclosed herein. In some embodiments, the commercial packaging contains one or more unit doses of the pharmaceutical composition. For example, such a unit dose may be sufficient for the preparation of an intravenous injection. It will be apparent to those skilled in the art that light- and / or air-sensitive compounds may require special packaging and / or formulation. For example, packaging may be used that is light-opaque and / or sealed from contact with ambient air and / or formulated with suitable coatings or additives. [Example]

[0062] Example The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed or modified to achieve essentially the same results.

[0063] Example 1. In vitro metabolic profile and metabolite identification of Compound 1 The metabolic profile and metabolite identification of Compound 1 were studied in cryopreserved SD rat, beagle, and human hepatocytes. Incubations were performed with an initial test substance concentration of 10 μM and sampled at 0, 60, and 120 min. Samples were analyzed using UPLC / Q-TOF-MS. The incubation materials and procedures are provided in Table 1. Samples were thawed at room temperature (RT), centrifuged at 13,000 × g for 10 min (Heraeus Pico 17 centrifuge), and the supernatant was pipetted into glass vials for analysis. Analysis was performed using liquid chromatography-mass spectrometry (LC-MS) according to the parameters listed in Table 2. Samples were thawed at room temperature (RT), centrifuged at 13,000 × g for 10 min (Heraeus Pico 17 centrifuge), and the supernatant was pipetted into glass vials for analysis.

[0064] [Table 1]

[0065] [Table 2]

[0066] Compound 1 showed low turnover in incubations with hepatocytes; 79-93% remained after 120 minutes of incubation in all species. Virtually no loss was observed in control incubations without cells. Results for the positive control compound verapamil indicated acceptable levels of enzyme activity.

[0067] The metabolite profile upon incubation with hepatocytes is provided in Table 3. A total of 11 metabolites (M1-M11) were observed for compound 1. The metabolites were mainly formed by various dealkylation reactions and their further hydroxylation; i.e., CH 13N3 loss (in M1 and M3), N-demethylation (in M2, M5, and M7), and C3H4O2 loss (in M4, M5, and M10) were also observed. Hydroxylation / oxidation without dealkylation (M9), dehydrogenation (ketogenesis, M6), and S-glutathione and glucuronide conjugation (M8 and M11) were also observed. Acetylation was observed in M7. Eight of these metabolites (M1–M8) were observed in human hepatocytes. The minor metabolite M8 was unique to humans. M4 appeared to be the major metabolite in rat and dog hepatocytes. Proposed metabolic pathways for the observed compound 1 metabolites are shown in Figure 1.

[0068] [Table 3]

[0069] The metabolism of compound 1 was qualitatively similar in all species. Two major pathways were identified in human hepatocytes: 1. Decarboethoxylation to form metabolite M4 2. N-demethylation to form metabolite M2

[0070] The proposed structures of these metabolites are shown below. [ka]

[0071] Metabolites M4 and M2 were formed via oxidative and / or hydrolytic mechanisms; direct phase II conjugation of the parent compound 1 was not observed. Both metabolites were observed in all species evaluated, supporting the use of these species for the toxicity assessment of compound 1. Several other metabolites were observed at trace levels. The metabolic pathways involved in the formation of these minor metabolites include oxidation, desaturation, dealkylation, and secondary phase II conjugations (acetylation, formylation, glucuronidation, glycosylation, and glutathione conjugation).

[0072] Example 2. In vivo metabolic profile and metabolite identification of Compound 1 The in vivo metabolism of Compound 1 was investigated in studies using rat, dog, rabbit, and human plasma and human urine samples from toxicity studies, embryo-fetal development studies, and human clinical studies.

[0073] Human samples Human plasma and urine samples were derived from a human clinical study using subjects aged 65 years or older who received 15 mg daily and reached steady state before day 7. Samples were stored at or below -75°C from collection until analysis.

[0074] Human plasma samples from each Compound 1-treated subject (15 mg; n=8) were collected at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours on Day 7 after multiple daily oral doses and pooled for analysis. Plasma from placebo-treated subjects (n=2) obtained at the same time points and pre-dose plasma collected on Day 1 from Compound 1-treated subjects were used as controls for metabolite identification.

[0075] Human urine samples from subjects receiving Compound 1 (15 mg; n=8) were also collected at 0-4 hours, 4-8 hours, 8-12 hours, and 12-24 hours on Day 7 after multiple daily oral doses and pooled for analysis. Urine from subjects receiving placebo (n=2) collected over the same time period on Day 7 was used as a control for metabolite identification.

[0076] Pooling and preparation of plasma samples for metabolite identification Time-normalized pooled plasma samples (day 7; 0-24 hours) were prepared for each human subject treated with Compound 1 (15 mg; n = 8) or placebo (n = 2) (see, e.g., Hamilton et al., Clin. Pharmacol. Ther. 1983, 29(3):408-13). Composite time-normalized pooled plasma samples for human subjects administered Compound 1 or placebo were then prepared by combining equal volumes from the pooled samples prepared for each subject. Composite control plasma samples were prepared by combining equal volumes of pre-dose plasma from human subjects (n = 8) treated with Compound 1.

[0077] Aliquots (100 μL) of pooled plasma samples prepared for metabolite identification were treated with ice-cold acetonitrile (500 μL), mixed, and centrifuged (2000 g; 4°C; 10 min). The supernatant (550 μL) was removed and dried under a stream of nitrogen (35°C), and the dried extract was redissolved in 200 μL of 90:10 (v / v) water:acetonitrile prior to analysis. Excess sample aliquots were stored at −80°C.

[0078] Pooling and preparation of human urine samples for metabolite identification Composite urine samples (day 7; 0-24 hours) were prepared by combining proportional amounts of samples collected over each period for each human subject treated with Compound 1 (15 mg; n=8) or placebo (n=2). Composite intersubject urine samples for human subjects administered Compound 1 or placebo were then prepared by combining proportional amounts of pooled urine from each subject. All urine pools were mixed and centrifuged (2000 g; 4°C; 10 minutes) before analysis. Excess sample aliquots were stored at -80°C.

[0079] LC-MS identification of metabolites of compound 1 Samples were analyzed by LC-MS utilizing a Vion Q-ToF mass spectrometer (Waters), Acquity I-class LC pump, column heater, sample manager, and photodiode array detector (Waters). The mass spectrometer was configured to operate in positive ion mode, and several experiments were performed to allow for the acquisition of full scan and product ion data. Metabolite "identification" refers to putative metabolites deemed related to compound 1 by comparison of predicted and observed accurate masses and other appropriate LC-MS techniques. Metabolite abundance was calculated as a percentage of the total drug-related material in a given sample; MS peak areas were collated and summed, and the abundance of each metabolite was calculated as a percentage of the total in each sample. Based on apparent abundance, metabolites were classified as "major" if present at 10% or more of the total drug-related material, "trace" if present between 1% and less than 10%, and "trace" if present at less than 1%. [Table 5]

[0080] [Table 6]

[0081] Identification of metabolites of compound 1 in human plasma from intersubject pools LC-MS analysis of intersubject human plasma (n = 8; day 7, 0–24 h pool) showed that unchanged compound 1 (m / z 347; P [parent]) was the predominant drug-related component in intersubject human plasma, accounting for 82.0% of the total drug-related material. The major product resulting from hydrolysis of the ethyl carbamate moiety (m / z 275; P-72; metabolite M4; product of decarboethoxylation) appeared to be the most abundant metabolite in intersubject human plasma, accounting for 11.4% of the total drug-related material. The product of mono-oxidation of the ethyl group of the ethyl carbamate moiety (m / z 363; P+16; metabolite M7) and the product of N-demethylation (m / z 333; P-14; metabolite M2) were detected as minor metabolites, accounting for 1.0% and 2.3% of the total drug-related material, respectively. Several trace metabolites (each estimated to account for less than 1% of the total drug-related material) were detected in human plasma: a product consistent with hydrolysis of the ethyl carbamate moiety in combination with glucose conjugation (m / z 437; P+90M4+glucose), a product assumed to result from hydrolysis of the ethyl carbamate moiety in combination with formylation (m / z 303; P-44; metabolite M5), a product of hydration (i.e., addition of HO) at the azaspiro moiety (m / z 365; P+18; metabolite M8), a product of mono-oxidation at the azaspiro moiety (m / z 363; P+16; metabolite M10), and a product of mono-oxidation at the azaspiro ring, piperidine ring, or pyrazole ring (m / z 363; P+16; metabolite M10). The following products were detected: a product of mono-oxidation at either the piperidine or pyrazole ring (m / z 363; P+16; metabolite M11), a product of mono-oxidation at either the piperidine or pyrazole ring (m / z 363; P+16; metabolite M13), a product assumed to result from hydrolysis of the ethyl carbamate moiety in combination with acetylation (m / z 317; P-30; metabolite M14), a product resulting from N-demethylation in combination with mono-oxidation (m / z 349, P+2; metabolite M17), a product consistent with hydrolysis of the ethyl carbamate moiety in combination with N-demethylation (m / z 261, P-86; metabolite M18), and a product of mono-oxidation (m / z 363; P+16; metabolite M19). Additional low-abundance secondary metabolites involved in the hydrolysis and / or oxidation of the ethyl carbamate group were also detected.

[0082] Identification of metabolites of compound 1 in human urine from intersubject pools LC-MS analysis of intersubject human urine (n = 8; day 7, 0–24 h pool) showed that unchanged compound 1 (m / z 347; P [parent]) was the predominant drug-related component in intersubject human urine, accounting for 63.3% of the total drug-related material. The product resulting from hydrolysis of the ethyl carbamate moiety (m / z 275; P-72; metabolite M4) appeared to be the major metabolite in intersubject human urine, accounting for 26.4% of the total drug-related material. Several minor metabolites (estimated to account for between 1.2% and 3.3% of the total drug-related material) were observed in human urine: a product of monooxidation of the ethyl group of the ethyl carbamate moiety (m / z 363; P+16; metabolite M7), a product of hydration (i.e., addition of HO) at the azaspiro moiety (m / z 365; P+18; metabolite M8), a product of N-demethylation (m / z 333; P-14; metabolite M2), and a product consistent with hydrolysis of the ethyl carbamate moiety in combination with N-demethylation (m / z 261; P-86; metabolite M18). In addition, several trace metabolites (each estimated to account for less than 1% of the total drug-related material) were detected in human urine: a product postulated to result from hydrolysis of the ethyl carbamate moiety in combination with formylation (m / z 303; P-44; metabolite M5), a product of mono-oxidation in the azaspiro moiety (m / z 363; P+16; metabolite M10), a product of mono-oxidation at either the azaspiro, piperidine, or pyrazole ring (m / z 363; P+16; metabolite M11), a product postulated to result from hydrolysis of the ethyl carbamate moiety in combination with acetylation (m / z 317; P-30; metabolite M14), a product resulting from N-demethylation in combination with mono-oxidation (m / z 349, P+2; metabolite M17), and a product of mono-oxidation (m / z 363; P+16; metabolite M19). A summary of proposed metabolites of Compound 1 in human plasma and urine after multiple daily oral doses is provided in Table 4 and Figure 2.

[0083] [Table 4]

[0084] Analysis of rat, dog, rabbit, and human plasma samples showed that unchanged Compound 1 was the major circulating component. Consistent with the in vitro data (Example 1), metabolites M4 and M2 were the two most abundant human circulating metabolites of Compound 1, accounting for an estimated 11.4% (M4) and 2.3% (M2), respectively, of the total drug-related material in plasma collected after multiple oral doses of 15 mg of Compound 1. These metabolites were also observed in rat, dog, and rabbit plasma. Other human circulating metabolites were observed at trace levels.

[0085] In general, metabolites detected in human urine were qualitatively similar to those in human plasma. In urine samples collected after multiple oral doses of 15 mg of compound 1, the parent drug was the predominant drug-related component, accounting for an estimated 63.3% of the total drug-related material. Metabolite M4 was identified as the most abundant metabolite in human urine, accounting for 26.4% of the total drug-related material.

[0086] A preliminary comparison of Compound 1 metabolite exposure in rat, dog, and rabbit plasma compared with humans was also performed. Pooled rat and dog plasma from a 13-week toxicity study, pooled rabbit plasma from an embryo-fetal development study, and pooled human plasma from a clinical study were analyzed by LC-MS / MS. Metabolite exposure in pooled animal plasma samples was compared to exposure in the human pool by comparison of relative LC-MS-MS peak areas. Metabolites evaluated included metabolite M4, metabolite M2, and trace levels of additional human metabolites. The relative abundance of metabolites measured using LC-MS / MS was higher in rat, rabbit, dog, and monkey plasma than in humans. These data suggest that the safety of these human metabolites has been adequately assessed in nonclinical species.

[0087] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety.

Claims

1. Formula I: 【Chemistry 13】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ are each independently selected from hydrogen and deuterium, or a pharmaceutically acceptable salt thereof.

2. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one of is deuterium.

3. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein two of are each deuterium.

4. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein three of are each deuterium.

5. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein four of are each deuterium.

6. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein five of are each deuterium.

7. R １ , R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each is deuterium.

8. Formula II: 【Chemistry 14】 2. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

9. Formula III: 【Chemistry 15】 2. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

10. Formula IIIa: 【Chemistry 16】 2. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

11. Formula IV: 【Chemistry 17】 2. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

12. Formula IVa: [Chemistry 18] 2. The compound of claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 【Request Item 13】 【Chemistry 19】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 20】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. 15. A method for treating a cognitive disorder, a psychotic disorder, a movement disorder, an addiction, or for treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

17. 17. The method of claim 16, wherein the psychotic disorder is schizophrenia.

18. 15. A method of treating Alzheimer's disease or dementia with Lewy bodies in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

19. 19. The method of claim 18, which is a method for treating Alzheimer's disease.

20. 19. The method of claim 18, which is a method for treating dementia with Lewy bodies.

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