Enantiomers of tetrahydro-n,n-dimethyl-2,2-diphenyl-3-furanmethanamine (anavex2-73) and use thereof in the treatment of alzheimer's disease and other disorders modulated by the sigma 1 receptor

Abstract

To provide enantiomers of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine (ANAVEX2-73) and use thereof in the treatment of Alzheimer's disease and other disorders modulated by the sigma 1 receptor.SOLUTION: The compound (-)-tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride ((-)-ANAVEX2-73, (-)A2-73, (-)AE 37) has been found to exhibit selectivity for sigma-1 (σ1) receptors and stronger agonist activity at the muscarinic M1 acetylcholine receptor than the (+) enantiomer of the compound. Pharmaceutical compositions comprising the (-) enantiomer are disclosed, as are methods of using the (-) enantiomer in the treatment of disorders associated with σ-1 receptors and the treatment of Alzheimer's disease.SELECTED DRAWING: None

Description

[Technical field]

[0001] FIELD OF THEINVENTION [ka] Substantially free of [ka] The present invention relates to a pharmaceutical preparation comprising: [ka] A therapeutically effective amount substantially free of [ka] The present invention further includes a method for treating Alzheimer's disease in a subject in need of such treatment by administering

[0002] The present invention also provides a method for classifying a cell with respect to sigma receptor type, comprising: [ka] Substantially free of detectable amounts of [ka] and determining the level of sigma receptor binding. [Background technology]

[0003] 2. Background of the Invention Two sigma receptor subtypes have been identified based on their pharmacological profiles. The sigma-1 (sigma-1) receptor was cloned (Hanner et al., 1996). The sigma-2 receptor was reported as a separate molecular entity (Langa et al., 2003). The sigma-1 receptor was reported to have high affinity for the positive isomers of bezomorphas (e.g., (+)-pentazocine and (+)-SKF-10,047). The sigma-2 receptor was reported to have high affinity for ibogaine (Vilner and Bowen, 2000). Notably, sigma-1 receptor agonists were also reported to have antidepressant effects. In this regard, sigma-1 receptor ligands show clear antidepressant effects in several animal models. For example, the selective sigma 1 receptor agonists (+)-pentazocine, (+)-SKF-10,047, igmesine, OPC14523, DTG or SA4503 shorten the immobility time in the forced swimming test or are active in the tail suspension test (Ukai et al. 1998, Matsuno et al., 1996, Tottori et al. 1997, Kinsora et al. 1998). US Patent No. 5,034,419 describes N-cycloalkylalkylamines, which are also reportedly sigma 1 receptor agonists.

[0004] The sigma-1 receptor, first reported and cloned in 1996, is a single polypeptide transmembrane protein containing 223 amino acids. It is located primarily on the endoplasmic reticulum membrane. The sigma-1 receptor has been reported to be expressed in ocular tissues, including the cornea, lens, and retina. It has also been reported to play a role in cell survival (Wang et al., Exp Cell Research, Vol. 312(8):1439-1446, 2006; Hayashi et al., Cell, Vol. 131(3):596-610, November 2007; Jiang et al., IOVS, Vol. 47(12):5576-5582, 2006).

[0005] Sigma receptor ligands have been reported to be neuroprotective. The Sigma receptor ligand, opipramol, has been reported to be protective against ischemia in gerbils. Still other Sigma ligands, including BMY-14802, caramiphen, and haloperidol, have shown properties consistent with a protective effect in in vivo models (Pontecorvo et al., Brain Research Bulletin, Vol. 26:461-465, 1991). Several Sigma ligands have been reported to inhibit ischemia-induced glutamate release from in vitro hippocampal slice preparations (Lobner et al., Neuroscience Letters, Vol. 117:169-174, 1990). It has also been reported that the σ-1 receptor agonist (+)-pentazocine can protect retinal cells against stress (Dun et al., IOVS, Vol. 48(10):4785-4794, 2007; Smith et al., IOVS, Vol. 49(9):4154-4161, 2008).

[0006] Iniguez et al. reported that treatment of Jurkat T cells with sigma-2 (σ-2) agonists reduced the induction of interleukin (IL)-2, tumor necrosis factor (TNF)-α, and cyclooxygenase (COX)-2 expression by activated T cells in a dose-dependent manner ("Inhibitory effects of σ-2 receptor agonists on T lymphocyte activation", Front. Pharmacology , 13 March 2013 | doi: 10.3389 / fphar.2013.00023.) The reported effects occur at the transcriptional level, since the sigma-2 agonists BD-737 and CB-184 decreased the activity of the promoters of those genes. Their immunosuppressive effects could be attributed to interference with transcription factor activation. Induced transcription mediated by nuclear factor (NF)-κB or Nuclear Factor of Activated T cells (NFAT) was inhibited by sigma-2 agonists. The authors suggested that these effects were specific for sigma-2 agonists, since no significant effect on T cell activation by the sigma-1 ligands PRE-084 [2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate] and BD-1063 was found. By way of non-limiting examples, reported sigma-2 agonists include CB-64D, CB-184, BD-737, and haloperidol.

[0007] A receptor antagonist is a type of receptor ligand or drug that blocks or reduces agonist-mediated responses upon binding to a receptor, rather than inducing a biological response itself. In pharmacology, antagonists have affinity but no potency for their cognate receptors, and binding interferes with the interaction and inhibits the function of agonists or inverse agonists at the receptor. Antagonists mediate their effects by binding to the active site (orthosteric = right place) or allosteric site (= other place) on the receptor, or they may interact at a unique binding site that is not normally involved in the biological regulation of the activity of that receptor. Antagonist activity may be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, which in turn depends on the nature of the antagonist-receptor binding. Most drug antagonists achieve their effectiveness by competing with endogenous ligands or substrates for structurally defined binding sites on receptors.

[0008] A competitive (also known as surmountable) agonist or antagonist binds reversibly to the receptor at the same binding site (active site) as the endogenous ligand or agonist / antagonist, but does not activate the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Once bound, the antagonist blocks the oppositely functioning molecule from binding. The level of receptor activity is determined by the relative affinity of each molecule for the site and their relative concentrations. Higher concentrations of competitive agonist or antagonist increase the proportion of the receptor that the molecule occupies, and higher concentrations of the molecule are required to obtain the same degree of binding site occupancy. In functional assays using competitive antagonists, a parallel shift to the right of the agonist dose-response curve is observed without any change in the maximum response.

[0009] The term "noncompetitive" (sometimes referred to as insurmountable antagonist) can be used to describe two separate phenomena: agonists or antagonists binding to the active site of a receptor and agonists / antagonists binding to the allosteric site of a receptor. While the mechanisms are different in both of these phenomena, they are both said to be "noncompetitive" because the outcome of each is functionally very similar. Unlike competitive, which affects the amount of agonist or antagonist required to achieve a maximal response but does not affect the magnitude of that maximal response, noncompetitive agonists or antagonists reduce the magnitude of the maximal response that can be obtained with a given amount of agonist or antagonist.

[0010] Sigma 1--Without being bound by any particular theory, it is believed that Sigma 1 receptors regulate neurotransmission through NMDA receptors and the release of neurotransmitters such as dopamine and acetylcholine. Thus, it has been proposed that Sigma 1 receptors play a role in learning and memory, as well as in certain neuropsychiatric disorders.

[0011] Antagonists-Sigma 1 antagonists are believed to be useful in treating schizophrenia-related symptoms of blunted affect, anhedonia, lack of motivation or apathy, and alogia.Sigma 1 antagonists are also believed to be useful in relieving the orofacial dyskinesia and dystonic reactions associated with psychotropic drugs as side effects.Sigma 1 antagonists are also believed to be useful as cancer anti-proliferatives.

[0012] Agonists - σ1 agonists are useful as antidepressants. In treating ischemic brain / neural damage (e.g., resulting from focal ischemia), σ1 agonists with low σ2 affinity are useful. Particularly mentioned is the usefulness of sigma 1 agonists. Sigma 1 agonists are also believed to be useful in improving cognitive dysfunction such as that exhibited with impaired neurotransmitter function (e.g., acetylcholine) and age-associated cognitive impairment, and anxiety-associated impairment (including pregnancy stress resulting in learning disabilities in offspring).

[0013] σ2--σ2 receptors are believed to be useful targets for motor function and cancer treatment. σ2 receptors are highly expressed in rapidly proliferating cancer cells.

[0014] Antagonists--Sigma 2 antagonists are useful in treating irreversible motor side effects such as those reported after chronic administration of typical antipsychotics. Sigma Receptors: Chemistry, Cell Biology and Clinical Implications Reference is made to "Publication of the Organisms ... Nguyen et al., “Role of sigma-1 receptors in neurodegenerative diseases”, J Pharmacol Sci. 2015 Jan;127(1):17-29; Guo et al., “Sigma-2 receptor ligands: neurobiological effects”, Curr Med Chem. 2015;22(8):989-1003; USSN 62 / 065,833 (entitled "A19-144, A2-73 and Certain Anticholinesterase Inhibitor Compositions and Method for Anti-Seizure Therapy" filed October 20, 2014); Crawford et al., “Sigma-2 Receptor Agonists Activate a Novel Apoptotic Pathway and Potentiate Antineoplastic Drugs in Breast Tumor Cell Lines,” Cancer Research, 62, 313-322, January 1, 2002; Rossi et al., “A step forward in the sigma enigma: a role for chirality in the sigma1 receptor-ligand interaction?” Medicinal Chemistry Communication (Impact Factor: 2.63). 09 / 2014; 6(1); U.S. Publication No. 20110206780 (titled "Morphinan modulators of nmda receptors, sigma1 receptors, sigma2 receptors, and / or a3b4 nicotinic receptors", (Gant et al., priority date: January 6, 2010) WO2013008044 (Vamvakides et al., entitled “SYNTHESIS OF (+) AND (-) 1-(5,5-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N-DIMETHYLMETHANAMINE, (+) AND (-) 1-(2,2-DIPHENYLTETRAHYDROFURAN-3-YL)-N,N-DIMETHYLMETHANAMINE AND (+) AND (-) 1-(2,2-DFFHENYLTETRAHYDROFURAN-3-YL)-N-METHIHYLMETHANAMINE" shows the chiral separation methodology. U.S. Patent Application (Entitled "ANAVEX2-73 FOR THE TREATMENT OF ALZHEIMER'S DISEASE" and previously filed applications) U.S. patent application (entitled "CRYSTAL FORMS OF tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethaneamine hydrochloride, PROCESSES OF MAKING SUCH FORMS, AND THEIR PHARMACEUTICAL COMPOSITIONS") and previously filed. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Hanner et al., 1996 [Non-Patent Document 2] Langa et al., 2003 [Non-Patent Document 3] Vilner and Bowen, 2000 [Non-Patent Document 4] Ukai et al. 1998, Matsuno et al. 1996 [Non-Patent Document 5] Tottori et al. 1997, Kinsora et al. 1998 Summary of the Invention [Means for solving the problem]

[0016] Summary of the Invention [ka] Substantially free of [ka] 13. A pharmaceutical preparation comprising:

[0017] The present invention relates to [ka] Substantially free of [ka] The present invention further includes a method of therapeutically treating a subject in need of enhanced stimulation of σ1 receptors by administering a therapeutically effective dose of a pharmaceutical preparation comprising about 0.5 to about 100 mg. [ka] (and especially, 1-20 mg) [ka] Substantially free of [ka] Of particular mention are pharmaceutical preparations of

[0018] [ka] A therapeutically effective amount substantially free of [ka] 23. A method for treating Alzheimer's disease in a subject in need thereof by administering

[0019] A method for classifying cells with respect to sigma receptor type, comprising: [ka] Substantially free of detectable amounts of [ka] Further reference is made to a method in which the subject is exposed to and the level of sigma receptor binding determined. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description of the Invention The invention will be better understood with reference to the following definitions: A. ANAVEX 2-73, or A2-73, is intended to mean tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride. It is listed as AE 37 in some of the test data. A2-73 is a compound believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinity in the low micromolar range. B. ANAVEX 19-144 or A19-144 shall mean 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride. A19-144 is a compound believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinity in the low micromolar range. C. ANAVEX1-41 or A1-41 shall mean Tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride. It is listed as AE 14 in some of the test data. A1-41 is described in Villard et al., "Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid b25-35-Induced Toxicity in Mice", Neuropsychopharmacology , 1-15 (2008). D. The terms "enantiomer" or "enantiomeric" refer to a molecule which is not superimposable upon its minor image and is therefore optically active, where an enantiomer rotates the plane of polarized light in one direction and its minor image rotates the plane of polarized light in the opposite direction. E. [ka] Formless [ka] Form, or [ka] Formless [ka] "Substantially free" with respect to defining the enantiomer of a form shall mean less than about 2% (w / w), and preferably less than about 1%, and more preferably less than about 0.5%, and in some cases less than about 0.1%, of the form removed. F. "Classifying" cells for σ1 or σ2 receptor populations shall mean determining the presence and / or density of either σ1 or σ2 receptors on the cell surface in a given cell population. Classifying utilizes differential populations of σ receptors to be used as biomarkers. Biomarkers are useful as a means of defining the propensity of cell populations (e.g., proliferative likelihood for breast cancer). The test methodology is more fully presented below: Hashimoto et al., “Sigma receotor ligands: possible application as therapeutic drugs and as radiopharmaceuticals”, Curr Pharm Des. 2006;12(30):3857-76; Mach RH et al. , “Sigma 2 receptors as potential biomarkers of proliferation in breast "cancer", Cancer Res 1997;57:156-61; Al-Nabulsi, I et al., “Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of σ-2 "receptors in proliferating and quiescent tumor cells", Br J Cancer 1999; 81: 925-33; and Wheeler KT et al., “Sigma-2 receptors as a biomarker of proliferation in solid tumors”, Br J Cancer 2000;82:1223-32. [ka] is a selective noncompetitive agonist of the σ1 receptor and [ka] It is a significantly more potent agonist.

[0021] The pharmacologically active compositions of the present invention may be processed in accordance with conventional methods of Galenic pharmacy to produce medicinal agents for administration to subjects, e.g., mammals, including humans.

[0022] Studies were conducted regarding the effects of several compounds in a variety of in vitro receptor binding and isolated organ assays. 1. Materials and Methods 1.1. In vitro pharmacology: binding assays 1.1.1. General Procedure [Table A] Experimental conditions [Table B]

[0023] As a general statement, in vitro results showing greater than 50% inhibition (or stimulation in terms of assays performed under basal conditions) are considered to represent a significant effect of the test compound. 50% is the most common cut-off value for further investigation (IC from concentration-response curves). 50 Value or EC 50 value determination).

[0024] Results showing between 20% and 50% inhibition (or stimulation) indicate a weak to moderate effect (in some assays, these can be confirmed by further testing because they are within the range where more inter-experimental variability is likely).

[0025] Results showing less than 20% inhibition (or stimulation) were not considered significant and can mostly be attributed to variability in the signal around the control level.

[0026] Low to moderate negative values ​​are virtually meaningless and can be attributed to variability in the signal around the control level. Highly negative values ​​(≧50%) occasionally obtained at high concentrations of test compound can generally be attributed to non-specific effects of the test compound in the assay.

[0027] 1.1.3. Analysis and presentation of results Specific ligand binding to the receptor is defined as the difference between total binding and nonspecific binding, which is determined in the presence of an excess of unlabeled ligand.

[0028] The results are expressed as a percentage of control specific binding obtained in the presence of test compound and as % inhibition of control specific binding. Individual and mean values ​​are presented in the Results section.

[0029] I C 50 value (the concentration causing half-maximal inhibition of control specific binding) and Hill coefficient (n H ) was determined by nonlinear regression analysis of the competition curves using curve fitting of the Hill equation. i ) by Cheng Prusoff's formula (Ki =IC 50 / (1+(L / K D )) (where L = concentration of radioligand in the assay and K D = affinity of the radioligand for the receptor).

[0030] 1.2. In vitro pharmacology: isolated organ bioassays 1.2.1. General Procedure [Table C]

[0031] Experimental conditions Prostatic segments of rabbit vas deferens were placed in an oxygenated (95% O2 and 5% CO2) and prewarmed (30°C) saline solution with the following composition (in mM): NaCl 118.0, KCl 4.7, MgSO4 0.6, CaCl2 2.5, KH2PO4 0.6, CaCl2 0.5, KH2PO4 0.5, CaCl2 0 ... The animals were then suspended in a 20 ml organ bath containing 1.2, 25% NaHCO3 and 11.0% glucose (pH 7.4).

[0032] Yohimbine (1 μM) and naloxone (1 μM) were also present throughout the experiment to block α2-adrenergic and opioid receptors, respectively.

[0033] The tissues were connected to force transducers for isometric tension recording. They were pulled to a resting tension of 1 g and then equilibrated for 60 min, during which time they were repeatedly washed and the tension readjusted. They were then electrically stimulated with square-wave pulses (submaximal intensity, 1 ms duration, 0.1 Hz) delivered by a constant current stimulator.

[0034] Experiments were performed using a semi-automated isolated organ system with eight organ baths, with multi-channel data acquisition.

[0035] Experimental protocol Testing for agonist activity Tissues were exposed to a submaximal concentration of the reference agonist McN-A-343 (1 μM) to verify the response and to obtain a control response. Washout and initial twitch contraction After recovery, the tissue was exposed to a test compound or the same agonist, which was left in contact with the tissue until a stable response was obtained or for a maximum of 15 minutes.

[0036] If an agonist-like response (inhibition of twitch contractions) was obtained, the reference antagonist pirenzepine (0.1 μM) was tested against the test compounds to confirm the involvement of M1 receptors in this response.

[0037] Testing for antagonist activity Tissues were exposed to a submaximal concentration of the reference agonist, McN-A-343 (1 μM), to obtain control responses.

[0038] After stabilization of the McN-A-343-induced response, the tissue was exposed to test compounds or the reference antagonist pirenzepine, which were left in contact with the tissue until a stable response was obtained or for a maximum of 15 minutes. If this occurred, restoration of twitch amplitude by the test compound indicated antagonist activity at the M1 receptor.

[0039] 1.2.4. Analysis and presentation of results The parameter measured was the maximum change in electrically evoked contraction amplitude induced by the compound.

[0040] Results are expressed as % of control response to McN-A-343 (mean value).

[0041] compound 1.3. Test Compounds Manufactured by: EURO GENET Lab AE [Table D-1] [Table D-2] FW: formula weight *: About isolated organ bioassay

[0042] result 1.4. In vitro pharmacology: binding assays Mean values ​​for the effects of the test compounds are summarized in Table 1-1. Individual data obtained with the test compounds are reported in Table 1-2.

[0043] IC for each reference compound 50 and K. i The values ​​are shown in Tables 1-3, each within the accepted limits of the historical average ±0.5 log units.

[0044] 1.5. Reference compounds In each experiment, each reference compound was tested simultaneously with the test compound to evaluate assay suitability. It was tested at several concentrations and the data were compared with historical values. The assay was validated if it met the suitability criteria according to the corresponding standard operating procedures. [Table 1-1-1] [Table 1-1-2] [Table 1-2-1] [Table 1-2-2] [Table 1-3]

[0045] 1.6. In vitro pharmacology: isolated organ bioassays The effects of (+)A1-41, (-)A1-41 and (-)A2-73 investigated for agonist and antagonist activity at the muscarinic M1 receptors of rabbit vas deferens are shown in Table 2-1, in which the effects of the reference compounds are also reported.

[0046] In electric-field-stimulated rabbit vas deferens, the M1 receptor agonist McN-A-343 induced a concentration-dependent decrease in twitch contraction amplitude that was reversed by the antagonist pirenzepine in a concentration-dependent manner.

[0047] In untreated tissue, (+)A1-41, (-)A1-41 and (-)A2-73 did not decrease twitch contraction amplitude but caused a slight to moderate increase.

[0048] In tissues pre-depressed with McN-A-343, (+)A1-41, (-)A1-41 and (-)A2-73 caused a concentration-dependent and nearly complete restoration of twitch contraction amplitude.

[0049] These results indicate that (+)A1-41, (-)A1-41 and (-)A2-73 behave as antagonists at the M1 receptor. [Table 2-1-1] [Table 2-1-2]

[0050] [Table 2-2]

[0051] Results are expressed as % of control response to McN-A-343 (reduction in twitch amplitude) (mean; n=2). EXAMPLES

[0052] Example 1 Neuroprotection against beta-amyloid A 67-year-old man diagnosed with early Alzheimer's disease was given the [ka] 10 mg of substantially free [ka] He is treated with 100 mg / kg / day of ...

[0053] Example 2 Neuroprotection against oxidative stress A 29-year-old female balloonist, who was expecting hypoxic stress, was given 100 mg of oxygen every day for five days before ascending in a balloon. [ka] 10 mg of substantially free Oral [ka] The balloonist is able to ascend to 6,000 meters without oxygen support and suffer no hypoxic injury.

[0054] Example 3 Neuroprotection against neurotoxicity A 37-year-old male hazardous materials worker anticipating neurotoxic stress was given tetanus toxin daily for 5 days before exposure to the drug. [ka] 1 mg of substantially free [ka] The handler is exposed to 0.1 ng / kg of the neurotoxin and suffers no injury.

[0055] Example 4 Neuroprotection in stroke patients A 57 year old male was admitted to the emergency room and diagnosed with an ischemic event involving the middle cerebral artery, with onset of symptoms lasting less than an hour. The patient was immediately treated with [ka] 1 mg of substantially free [ka] iv supplementation is administered. Daily tests of the cognitive and motor systems show no impairment of physical or mental performance. Furthermore, CT / MRI imaging shows no signs of disease changes in the affected areas immediately after recovery, which is maintained and confirmed by follow-up imaging and behavioral testing.

[0056] Example 5 Neuroprotection against amyloid An 80-year-old female patient was diagnosed with AD and had been taking [ka] 10 mg of substantially free [ka] The patient's cognitive scores stabilize and increase slowly and regularly over the following months.

[0057] Dosage information / administration form: [ka] Substantially free of [ka] With respect to AD, reference is made to a dosage of about 0.01-100 mg / day, preferably 0.5-10 mg / day, more preferably 0.5-2 mg / day. Reference is made to administration once every two days (three times a week). Since AD ​​is a chronic disease, it is preferable to receive a diagnosis and begin treatment promptly.

[0058] [ka] Substantially free of [ka] Particular attention is directed to methods of the invention that include administration of at least one cooperating acetylcholinesterase inhibitor (donepezil, galantamine, rivastigmine, or memantine), where at least one of said therapeutically effective amounts or doses of the cooperating acetylcholinesterase inhibitor is sub-therapeutic (sub-MAD) compared to the active dose when used alone. [ka] Substantially free of [ka] or a cooperating acetylcholinesterase inhibitor is used. In this regard, reference is made to USSN 13 / 940,352 (Vamvakides et al., entitled "ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORS COMPOSITION AND METHOD FOR NEUROPROTECTION", the teachings of which are incorporated herein by reference).

[0059] The compositions of the present invention are used individually or in combination with conventional excipients (i.e., pharmaceutically acceptable organic or inorganic carrier substances) suitable for parenteral, enteral (e.g., oral or inhalation) or topical application that do not adversely react with the active composition.Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solution, alcohol, gum arabic, vegetable oil, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (e.g., lactose, amylose or starch), magnesium stearate, talc, titanium dioxide, silicic acid, viscous paraffin, perfume oil, fatty acid ester, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations may be sterilized and, if desired, mixed with auxiliary substances (e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants, flavorings and / or aromatic substances, etc.) which do not deleteriously react with the active compositions. They may also be combined, if desired, with other active agents (e.g., vitamins).

[0060] In some embodiments of the invention, the dosage forms include instructions for the use of such compositions.

[0061] For parenteral application, particularly suitable are injectable sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampoules, vials, and syringe cartridges are convenient unit doses.

[0062] "Unit dosage form" is intended to mean a single drug administration entity, for example a single tablet, capsule, dragee, or troche, suppository, or syringe.

[0063] Also, for parenteral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules.Syrups, elixirs, and the like can be used when a sweetened vehicle is used.Sublingual and buccal forms are also particularly mentioned.

[0064] Sustained or directed release compositions can be formulated (e.g., liposomes or those in which the active components are protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.). It is also possible to lyophilize the new composition and use the resulting lyophilizates, e.g., for the preparation of injectable products. The present invention provides, for example, the following items. (Item 1) [ka] Substantially free of [ka] Pharmaceutical dosage forms of. (Item 2) About 0.5 to about 100 mg [ka] 2. The pharmaceutical dosage form according to item 1, comprising: (Item 3) About 1 to about 20 mg [ka] 3. The pharmaceutical dosage form according to item 2, comprising: (Item 4) 1. A method for the therapeutic treatment of a subject in need of enhanced stimulation of a sigma 1 receptor, the method comprising: [ka] Substantially free of [ka] 23. A method comprising administering a therapeutically effective dose of a pharmaceutical preparation comprising: (Item 5) The therapeutically effective amount is about 0.5 to about 100 mg. [ka] The method according to item 4, comprising: (Item 6) The therapeutically effective amount is about 1 to about 20 mg. [ka] The method according to item 5, comprising: (Item 7) 1. A method for treating Alzheimer's disease in a subject in need of such treatment, the method comprising: [ka] A therapeutically effective amount substantially free of [ka] A method according to the method of administering. (Item 8) The therapeutically effective amount is about 0.5 to about 100 mg. [ka] 8. The method according to item 7, comprising: (Item 9) The therapeutically effective amount is about 1 to about 20 mg. [ka] The method according to item 8, comprising: (Item 10) 1. A method for classifying a cell with respect to a sigma receptor type, the method comprising: [ka] Substantially free of detectable amounts of [ka] and determining the level of sigma receptor binding.

Claims

[Claim 1] The method described in the specification.

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