Carbamoylphenylpropanol compounds and their uses

Abstract

This invention relates to carbamoylphenylpropanol compounds and methods of using them to treat diseases.

Description

[0001] Priority Statement Pursuant to 35 USC § 119(e), this application claims the benefit of U.S. Provisional Application No. 62 / 404,917, filed October 6, 2016, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to carbamoylphenylpropanol compounds and methods of using them to treat diseases. Background Technology

[0003] (R)-2-amino-3-phenylpropylcarbamate (APC) is a phenylalanine analogue that has been shown to be used to treat a variety of conditions, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue syndrome, depression, bipolar disorder, fibromyalgia, etc. See, for example, U.S. Patent Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741,950; 8,895,609; 8,927,602; 9,226,910; 9,359,290; and U.S. Patent Publications 2012 / 0004300 and 2015 / 0018414. Methods for preparing APC (also known by other names) and related compounds can be found in U.S. Patent Nos. 5,955,499; 5,705,640; 6,140,532 and 5,756,817. All the foregoing patents and applications are incorporated herein by reference in their entirety for all purposes.

[0004] This invention overcomes the shortcomings of the prior art by providing analogs of APC and methods for treating diseases using the drug. Summary of the Invention

[0005] This invention relates to the identification of APC analogs. Therefore, this invention relates to compounds of formula I: I in, R is an optional substituted lower alkyl group containing 1-8 carbon atoms, a halogen, an optional substituted alkoxy group containing 1-3 carbon atoms, a nitro group, a hydroxyl group, a cyano group, a trifluoromethyl group, or an optional substituted thioalkoxy group containing 1-3 carbon atoms. x is an integer from 0 to 3, provided that R can be the same or different when x is 2 or 3; R1, R2, and R3 are independently hydrogen, optionally substituted lower alkyl groups containing 1-8 carbon atoms, optionally substituted aryl groups, optionally substituted aralkyl groups, or optionally substituted cycloalkyl groups containing 3-7 carbon atoms; or R2 and R3 can be linked to form a 5- to 7-membered heterocycle, which is optionally substituted by a member selected from the group consisting of alkyl and aryl groups, wherein the heterocycle may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly connected to each other or to the oxygen atoms. Or its pharmaceutically acceptable salt.

[0006] The present invention further relates to compositions and pharmaceutical compositions comprising the compounds of the present invention.

[0007] The present invention also relates to methods for treating diseases suitable for treatment with APCs in subjects in need, such as narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue syndrome, fibromyalgia, attention deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or obesity, or methods for promoting smoking cessation in subjects in need, including administering the compounds of the present invention to the subjects.

[0008] The present invention will be described in more detail in the following specification. Detailed Implementation

[0009] This invention can be embodied in many different forms and should not be construed as limiting the various embodiments set forth herein. Rather, these embodiments are provided to make this disclosure thorough and complete, and to fully convey the scope of the invention to those skilled in the art. For example, a feature shown with respect to one embodiment may be incorporated into other embodiments, and a feature shown with respect to a particular embodiment may be removed from that embodiment. Furthermore, many variations and additions to the embodiments set forth herein will be apparent to those skilled in the art upon the guidance of this disclosure, without departing from the scope of the invention.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in the description of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention.

[0011] Unless the context otherwise requires, it is specifically intended that the various features of the invention described herein may be used in any combination.

[0012] Furthermore, the present invention also contemplates that in some embodiments of the invention, any feature or combination of features described herein may be excluded or omitted.

[0013] For illustrative purposes, if the specification indicates that the complex comprises components A, B, and C, it is specifically intended that any one or a combination of A, B, or C may be omitted or discarded, either individually or in combination.

[0014] For all purposes, the entire contents of all publications, patent applications, patents and other references mentioned herein are incorporated herein by reference.

[0015] As used in this article, “a,” “one,” or “the” can mean one or more. For example, “one” cell can refer to a single cell or multiple cells.

[0016] As used herein, “and / or” means and includes any and all possible combinations of one or more of the related listed items, as well as combinations that are missing when interpreted in the alternative manner (“or”).

[0017] Furthermore, when referring to measurable values ​​(such as the amount, dosage, time, temperature, etc. of the compounds or agents of the present invention), the term "about" means including 10% 5% 1% 1%, 0.5% or even The prescribed value is 0.1%.

[0018] When used in the compositions of the present invention, the term "substantially composed of" (and grammatical variations) means that the composition may contain other components, provided that the other components do not substantially alter the composition. When used in the compositions, the term "substantially alter" means that the therapeutic effect of the composition is increased or decreased by at least about 20% or more compared to the effect of a composition composed of said components.

[0019] As used herein, the term "therapeutic effective amount" or "effective amount" refers to an amount of the composition, compound, or agent of the present invention that can modulate the condition of a subject suffering from a symptom, disease, or illness. This moderating effect can be beneficial, including, as is well known in the art, improving the condition of the subject (e.g., one or more symptoms), delaying or alleviating the progression of the condition, preventing or delaying the onset of the disease, and / or altering clinical parameters, the disease, or illness. For example, a therapeutic effective amount or effective amount can mean an amount of the composition, compound, or agent that can improve the condition of the subject by at least 5%, such as at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0020] "Treatment" or "treatment" refers to any type of action that can modulate a subject suffering from a symptom, disease, or illness. For example, the moderating effect can be beneficial, including, as is well known in the art, improving the condition of the subject (e.g., one or more symptoms), delaying or alleviating the progression of the symptom, and / or altering clinical parameters, disease, or illness.

[0021] "A condition suitable for treatment with APC" refers to any condition in which administering APC to the subject can treat one or more symptoms of the subject's condition.

[0022] As used herein, "pharmaceutically acceptable" means a material that is not biologically or otherwise undesirable, i.e., that the material can be administered to an individual in conjunction with the compositions of the present invention without causing materially impaired biological effects or interacting in an adverse manner with any other component of the composition comprising it. As is known to those skilled in the art, the material selected should be naturally occurring, with minimal degradation of the active ingredient and minimal adverse side effects on the subject (see, for example, Remington's Pharmaceutical Science, 21st edition, 2005).

[0023] "Concurrently" refers to a time interval small enough to produce a synergistic effect (i.e., concurrently can be the same time, or it can be two or more events occurring before or after each other within a short period of time). In some embodiments, "concurrently" administering two or more compounds means administering two compounds at a sufficiently short interval such that the presence of one compound alters the biological effect of the other. The two compounds can be administered in the same formulation, different formulations, or sequentially. Concurrent administration can be achieved by mixing the compounds before administration, or by administering the compounds in two different formulations, such as at the same time point but at different tissue sites or using different routes of administration.

[0024] The term "alkyl" refers to a straight-chain or branched hydrocarbon chain containing 1 to 12 carbon atoms (e.g., 1 to 8, 1 to 6, or 1 to 4 carbon atoms). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0025] "Substituted alkyl" refers to an alkyl group in which one atom is replaced by, for example, a carbon atom, nitrogen atom, sulfur atom, oxygen atom, silicon atom, or halogen atom, or as an alkyl group replacing a nitrogen atom, sulfur atom, oxygen atom, or halogen atom. The term includes substituents on alkyl, alkenyl, ynyl, and cycloalkyl groups.

[0026] Examples of substituents that can be attached to any atom of the alkyl group in "substituted alkyl" include cycloyl, heterocyclic; aryl, heteroaryl, amino, amide, nitro, cyano, azide, hydroxyl, alkoxy, acyloxy, thioalkoxy, acylthioalkoxy, halogen group, sulfonate group, sulfonamide group, ester group, carboxylic acid, oxygen (e.g., carbonyl), and sulfur (e.g., thiocarbonyl). Substituents also include any chemical functional group that imparts improved water solubility to the molecule (e.g., carboxylic acid, carboxylic acid ester, formamido, morpholino, piperazine, imidazole, thiomorpholino, or tetrazolium; unsubstituted and substituted).

[0027] The terms “halogenated” and “halogen” refer to any group consisting of fluorine, chlorine, bromine, or iodine.

[0028] The term "alkoxy" refers to an oxygen atom attached to an alkyl or substituted alkyl group as defined above.

[0029] The term "thioalkoxy" refers to sulfur attached to an alkyl or substituted alkyl group as defined above.

[0030] The term "cycloalkyl" refers to a monocyclic saturated carbocyclic group containing 3 to 8 carbon atoms (e.g., 3 to 6 carbon atoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0031] The term "aryl" refers to an aromatic 5-8 membered monocyclic or 8-12 membered bicyclic ring system in which 0, 1, 2, or 3 atoms in each ring can be substituted by substituents. The term also includes aromatic bicyclic systems in which hydrogen atoms have been added to one, two, or three carbon atoms of a ring (e.g., partially saturated rings). Examples of aryl groups include phenyl, naphthyl, etc.

[0032] The term "aralkyl" refers to an aryl group attached to an alkyl or substituted alkyl group as defined above.

[0033] The term "heterocycle" refers to an aromatic or non-aromatic 5-8 membered monocyclic or 8-12 membered bicyclic ring system containing 1-3 heteroatoms (if monocyclic) or 1-6 heteroatoms (if bicyclic), wherein the heteroatoms are selected from O, N, or S, and wherein 0, 1, 2, or 3 atoms in each ring may be substituted by substituents. The term also includes aromatic and non-aromatic bicyclic systems in which hydrogen atoms have been added to one, two, or three carbon atoms in one ring (e.g., partially saturated rings). Examples of heterocyclic groups include pyridyl, furyl, benzofuranyl, imidazolyl, benzimidazolyl, pyrimidinyl, phenylthio or thiophene, benzothiophene, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, naphridyl, dihydronaphridyl, quinazolinyl, indole, indazole, thiazolyl, benzothiazolyl, oxazinyl, benzooxazinyl, oxazolyl, benzooxazolyl, dihydrobenzodioxoxenyl, etc.

[0034] Suitable aryl and heteroaryl substituents are the same as those suitable for alkyl substituents.

[0035] This invention relates to the identification and characterization of APC analogs intended to have equivalent or similar biological and therapeutic activities. The structure of the free APC base is as follows.

[0036]

[0037] Therefore, one aspect of the present invention relates to compounds of formula I: I in, R is an optional substituted lower alkyl group containing 1-8 carbon atoms, a halogen, an optional substituted alkoxy group containing 1-3 carbon atoms, a nitro group, a hydroxyl group, a cyano group, a trifluoromethyl group, or an optional substituted thioalkoxy group containing 1-3 carbon atoms. x is an integer from 0 to 3, provided that R can be the same or different when x is 2 or 3; R1, R2, and R3 are independently hydrogen, optionally substituted lower alkyl groups containing 1-8 carbon atoms, optionally substituted aryl groups, optionally substituted aralkyl groups, or optionally substituted cycloalkyl groups containing 3-7 carbon atoms; or R2 and R3 can be linked to form a 5- to 7-membered heterocycle, which is optionally substituted by a member selected from the group consisting of alkyl and aryl groups, wherein the heterocycle may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly connected to each other or to the oxygen atoms. Or its pharmaceutically acceptable salt.

[0038] In some embodiments, the compound is a compound of formula II: II, Or its pharmaceutically acceptable salt.

[0039] In some embodiments, the compound is compound 1 (phenylpropanol ureacarbate): 1, Or its pharmaceutically acceptable salt.

[0040] In some embodiments, the compound is compound 2 (D-phenylalanine ureacarboxylate): 2, Or its pharmaceutically acceptable salt.

[0041] In some embodiments, the compound of Formula I is not compound 1 or 2.

[0042] The compounds, formulations, and unit dosage forms described herein can be used to achieve rapid release of the compounds of the present invention, as well as pharmaceutically acceptable salts, hydrates, isomers, including tautomers, solvates, and complexes of the compounds.

[0043] Suitable salts of the compounds of the present invention include, but are not limited to, acetates, adipates, alginates, aspartates, benzoates, butyrates, citrates, fumarates, glycolates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobroms, hydroiodates, 2-hydroxyethanesulfonates, lactates, maleates, malonates, methanesulfonates, nicotinates, nitrates, oxalates, palmitates, pectates, persulfates, hydroxynaphthalates, neopentanoates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates, and undecanoates. Other acids, such as oxalic acid, although not pharmaceutically acceptable on their own, can be used to prepare salts that can be used as intermediates to obtain the compounds of the present invention and their pharmaceutically acceptable acid addition salts. In some embodiments, said salt is a hydrochloride salt.

[0044] The compounds described in this article include those compounds having any of the basic nitrogen-containing groups that are quaternized.

[0045] For simplicity, the discussion herein does not involve stereoisomers. Those skilled in the art will understand that the compounds of the present invention may contain one or more asymmetric centers, and thus exist as racemic mixtures and single optical isomers. All such isomers of these compounds are explicitly included in this invention.

[0046] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically rich atoms. For example, compounds having the structures of the invention, except that hydrogen is replaced by deuterium or tritium, are rich in isotopes. 13 C- or 14 Carbon substitutions for carbon in C- are all within the scope of this invention. These compounds can be used as analytical tools or probes, for example, in biological experiments.

[0047] The discussion herein does not cover polymorphs, hydrates, complexes, solvates, inclusion compounds, isomers, or other forms of compounds. All such compounds in all these forms are explicitly included in this invention.

[0048] Furthermore, the compounds of the present invention include prodrugs of compounds that are converted into active compounds in vivo. For example, compounds may be modified to enhance cell permeability (e.g., by esterification of polar groups) and then converted by cellular enzymes to produce the active agent. Methods of masking charged or reactive moieties as prodrugs are known to those skilled in the art (see, for example, P. Korgsgaard-Larsen and H. Bundgaard, A Textbook of Drug Design and Development, Reading UK, Harwood Academic Publishers, 1991).

[0049] The term "prodrug" refers to a compound that is rapidly converted in the body to produce the parent compound of the above formula, for example, through hydrolysis in the blood. See, for example, T. Higuchi and V. Stella, Prodrugs as Noveldelivery Systems, ACS Symposium Series, Vol. 14 and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. See also U.S. Patent No. 6,680,299. Exemplary prodrugs include prodrugs metabolized in a subject's body into active pharmaceutical ingredients having the compound activity described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group (such a group is present in the compound); an amide of an amino or carboxylic acid group (if such a group is present in the compound); an amino carbamate (if such a group is present in the compound); an alcohol acetal or ketal (such a group is present in the compound); an amino N-Mannich base or imine (if such a group is present in the compound); a carbonyl Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidinidine (if such a group is present in the compound), as described, for example, in U.S. Patent Nos. 6,680,324 and 6,680,322.

[0050] As used herein, the term "pharmaceutically acceptable prodrug" refers to those prodrugs of the compounds of the present invention that, within reasonable medical judgment, are suitable for contact with human and / or other animal tissues without causing undue toxicity, irritation, allergic reactions, etc., in proportion to their reasonable risk / benefit ratio, and are effective for their intended use, and, where possible, also include zwitterionic forms of the compounds of the present invention.

[0051] The compounds of the present invention can be synthesized by methods known in the art. In some embodiments, compounds such as compound 1 and compound 2 can be synthesized from phenylpropanol or APC using an excess of cyanate ester (e.g., sodium cyanate) in an acidic reaction medium.

[0052] Another aspect of the invention relates to compositions comprising the compounds of the invention, for example, dosage forms. In some embodiments, the composition is a pharmaceutical composition comprising the compounds of the invention and a pharmaceutically acceptable carrier. In some embodiments, the dosage form is an oral dosage form, for example, tablets or capsules, such as immediate-release dosage forms.

[0053] In some embodiments, the dosage form is an immediate-release tablet that releases at least 85% (e.g., at least 85%, 90%, 95%, 96%, 97%, 98%, or 99%) of the compound of the invention contained therein within less than 15 minutes after administration of the tablet to a subject.

[0054] Formulations of the compounds of the present invention (including immediate-release formulations) can be processed into unit dosage forms suitable for oral administration, such as filled capsules, compressed tablets, or capsules, or other dosage forms suitable for oral administration using conventional techniques. Immediate-release dosage forms prepared as described above are suitable for oral administration to achieve and maintain therapeutic levels of the compound over predetermined time intervals. In some embodiments, the immediate-release dosage forms described herein may comprise solid oral dosage forms of any desired shape and size, including circular, elliptical, elongated cylindrical, or polygonal shapes. In one such embodiment, the surface of the immediate-release dosage form may be flat, circular, concave, or convex.

[0055] Specifically, when the immediate-release formulation is formulated as a tablet, the immediate-release tablet contains a relatively large percentage and absolute amount of the compound, and therefore is expected to improve patient compliance and convenience by ingesting a larger amount of liquid or liquid / solid suspension. One or more immediate-release tablets as described herein can be administered orally (e.g., at coherent and compact time intervals) to provide a therapeutically effective dose of the compound to the subject within a relatively short period of time.

[0056] When needed or necessary, the outer surface of immediate-release formulations may be coated, for example, with a color coating or a moisture-proof layer using materials and methods known in the art.

[0057] In some embodiments, one aspect of the invention relates to an immediate-release compressed tablet of a compound of formula I suitable for oral delivery, said tablet comprising: The compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount of about 90-98% of the weight of the tablet; At least one binder, in an amount of about 1-5% of the tablet weight; and At least one lubricant, in an amount of about 0.1-2% of the tablet weight; Within 15 minutes after the tablet is administered to a subject, the tablet releases at least 85% of the compound of formula I contained therein or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the tablet comprises: The compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount of about 91-95% of the weight of the tablet; At least one binder, in an amount of about 2-3% of the tablet weight; At least one lubricant, in an amount of about 0.1-1% of the tablet weight; and Optionally, a cosmetic film coating is used, in an amount of about 3-4% of the tablet weight; Within 15 minutes after the tablet is administered to a subject, the tablet releases at least 85% of the compound of formula I contained therein or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the tablet comprises: The compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount of about 93.22% of the weight of the tablet; At least one binder (e.g., hydroxypropyl cellulose) is present in an amount of about 2.87% of the tablet weight; At least one lubricant (e.g., magnesium stearate), in an amount of about 0.52% of the tablet weight; and Optionally, cosmetic film coating (e.g., Opalry) ® II (yellow), in an amount of approximately 3-4% of the tablet weight; Within 15 minutes after the tablet is administered to a subject, the tablet releases at least 85% of the compound of formula I contained therein or a pharmaceutically acceptable salt thereof.

[0060] The present invention further relates to an immediate-release oral dosage form of a compound of formula I, the oral dosage form comprising: The compound of Formula I or a pharmaceutically acceptable salt thereof, in an amount of about 90-98% of the weight of the oral dosage form; At least one binder, in an amount of about 1-5% by weight of the oral dosage form; and At least one lubricant, in an amount of about 0.1-2% of the weight of the oral dosage form; Within 15 minutes after administration of the oral dosage form to a subject, the oral dosage form releases at least 85% of the compound of formula I contained therein or a pharmaceutically acceptable salt thereof.

[0061] The formulations and unit dosage forms described herein can be used to achieve rapid release of compounds of Formula I, as well as pharmaceutically acceptable salts, hydrates, isomers, including tautomers, solvates, and complexes of compounds of Formula I.

[0062] In some embodiments, within a time frame of less than 15 minutes after administration of the tablet to a subject (e.g., less than 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 minutes), the tablet releases at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the compound of Formula I contained therein or a pharmaceutically acceptable salt thereof. In some embodiments, within a time frame of less than 30 minutes after administration of the tablet to a subject, the tablet releases at least 95%, 96%, 97%, 98%, or 99% of the compound of Formula I contained therein or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the tablets do not contain disintegrants. As used herein, the term "disintegrant" refers to an agent added to a tablet to promote its disintegration in an aqueous environment. The advantage of the tablets of the present invention is that they dissolve rather than disintegrate. In the present invention, the presence of a disintegrant in the formulation effectively slows the release of the compound of formula I.

[0064] In some embodiments, the content of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, or 98% of the tablet weight, or any value or range thereof. In some embodiments, the content of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 90% to about 98%, about 92% to about 98%, about 94% to about 98%, about 96% to about 98%, about 90% to about 92%, about 90% to about 94%, about 90% to about 96%, about 92% to about 94%, about 92% to about 96%, or about 94% to about 96%.

[0065] In some embodiments, the content of the at least one binder is about 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% of the tablet weight, or any value or range thereof. In some embodiments, the content of the at least one binder is about 1% to about 5%, about 2% to about 5%, about 3% to about 5%, about 4% to about 5%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 2% to about 3%, about 2% to about 4%, or about 3% to about 4%. The tablet may contain at least one binder, for example, one, two, three, four, five, or more binders.

[0066] In some embodiments, the at least one adhesive is selected from at least one or any combination of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, povidone, copovidone, pregelatinized starch, dextrin, gelatin, maltodextrin, starch, zein, gum arabic, alginate, carbomer (cross-linked polyacrylate), polymethyl methacrylate, sodium carboxymethyl cellulose, guar gum, hydrogenated vegetable oil (type I), methyl cellulose, magnesium aluminum silicate, and sodium alginate. In some embodiments, the at least one adhesive is hydroxypropyl cellulose.

[0067] In some embodiments, the content of the at least one lubricant is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% of the tablet weight, or any value or range thereof. In some embodiments, the content of the at least one lubricant is about 0.1% to about 2.0%, about 0.5% to about 2.0%, about 1.0% to about 2.0%, about 1.5% to about 2.0%, about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 1.5%, about 0.5% to about 1.0%, about 0.5% to about 1.5%, or about 1.0% to about 1.5% of the tablet weight. The tablet may contain at least one lubricant, for example, one, two, three, four, five or more lubricants. When the immediate-release formulation is provided in tablet form, even lower lubricant levels can still be achieved using a "puffer" system during tableting. Such systems are known in the art and are commercially available, and they apply the lubricant directly to the punch and die surfaces rather than throughout the entire formulation.

[0068] In some embodiments, the at least one lubricant is selected from at least one or any combination of magnesium stearate, stearic acid, calcium stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium stearoyl fumarate, and zinc stearate. In some embodiments, the at least one lubricant is magnesium stearate. In other embodiments, magnesium stearate may be used in combination with one or more other lubricants or surfactants (e.g., sodium lauryl sulfate). Specifically, if it is necessary to overcome the potential hydrophobicity of magnesium stearate, sodium lauryl sulfate may also be included when using magnesium stearate (Remington: the Science and Practice of Pharmacy, 20...). thedition, Gennaro, Ed., Lippincott Williams&Wilkins (2000)).

[0069] In some embodiments, the at least one adhesive is hydroxypropyl cellulose. In some embodiments, the at least one lubricant is magnesium stearate. In some embodiments, the at least one adhesive is hydroxypropyl cellulose and the at least one lubricant is magnesium stearate.

[0070] In some embodiments, the tablet is coated. The coating may be, but is not limited to, a colored coating.

[0071] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is a hydrochloride salt of the compound.

[0072] The tablet may be of any shape suitable for immediate release and, within 15 minutes of administration to a subject, achieves the release of at least 85% of the compound of formula I contained therein or a pharmaceutically acceptable salt thereof. In some embodiments, the surface area to volume ratio of the tablet is maximized to promote rapid dissolution. In some embodiments, the tablet is oval-shaped.

[0073] The tablet may contain any amount of a compound of formula I suitable for administration in unit dosage form or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet contains about 1 mg to about 1000 mg of the drug or any range or value thereof, such as about 10 mg to about 500 mg, for example about 37.5 mg, about 75 mg, about 150 mg or about 300 mg.

[0074] This document discloses methods for treating conditions suitable for treatment with APC by administering an effective amount of one or more dosage forms described herein. For example, the dosage forms of the invention can be administered to a subject in need of treatment to treat narcolepsy, cataplexy, excessive daytime sleepiness, drug addiction, sexual dysfunction, fatigue syndrome, fibromyalgia, attention deficit / hyperactivity disorder, restless legs syndrome, depression, bipolar disorder, or obesity, or to encourage a subject in need to quit smoking. See, for example, U.S. Patent Nos. 8,232,315; 8,895,609; 8,927,602; 9,226,910 and 9,359,290; and U.S. Publications 2012 / 0004300 and 2015 / 0018414; the entire contents of the above documents are incorporated herein by reference regarding the conditions to be treated.

[0075] Compounds of the present invention with similar affinity for dopamine transporter (DAT) and α2-adrenergic receptors (see binding profiles in Example 2) can be used as cognitive enhancers and for the treatment of post-traumatic stress disorder (PTSD). Specifically, compounds such as methylphenidate (Ritalin, Concerta) that inhibit dopamine (DA) reuptake in DAT have been shown to be effective for attentional and cognitive impairments such as attention deficit hyperactivity disorder (ADHD). Increased DA signaling can enhance creative thinking and attentional focus. Furthermore, inhibition of DAT reuptake can also inhibit norepinephrine (NE) reuptake and increase NE signaling. NE has a high affinity for α2-adrenergic receptors, and its activity on α2 receptors has been shown to enhance prefrontal cortex (PFC) delayed-related seizures and improve PFC function. Therefore, the compounds of the present invention can be used to treat conditions involving: impaired attention, impaired attentional processing, and impaired cognitive or executive function, including mental illnesses such as ADHD, bipolar disorder, major depressive disorder, schizoaffective disorder, and PTSD; and neurological disorders such as Alzheimer's disease, Parkinson's disease, various forms of dementia, and multiple sclerosis. Therefore, one aspect of the present invention relates to a method of inducing cognitive pro-cognitive effects in a subject in need, comprising administering the compounds of the present invention to the subject.

[0076] In addition to the pro-cognitive effects described above, the compounds of the present invention, having similar affinity for dopamine transporter (DAT) and α2-adrenergic receptors, can be used to treat nightmares and sleep-related disorders associated with PTSD. Prazocin, an α1-receptor antagonist, has been used to treat symptoms of PTSD. Based on their similar activity against α-adrenergic autoreceptors, the compounds of the present invention can be used to treat PTSD symptoms. Activity against α2 receptors may impair the emotional response of the amygdala, and when combined with enhanced excitation in the PFC, may lead to decreased emotional responsiveness and enhanced executive function in PTSD. Therefore, another aspect of the present invention relates to a method of treating nightmares and / or sleep-related disorders associated with PTSD in a subject of need, comprising administering the compounds of the present invention to the subject.

[0077] The dosage forms disclosed herein may also be provided as kits, including, for example, individually packaged containers containing multiple immediate-release tablets or capsules, wherein the tablets or capsules may be individually packaged, such as in foil sleeves or in blister packs. The tablets or capsules may be packaged in various configurations with or without desiccants or other materials to prevent moisture penetration. Instructional materials or information (such as printed labels) may also be included to instruct their administration, for example, sequential administration at predetermined time periods and / or at predetermined intervals, to produce desired levels of the compound in the body within a predetermined time period for the treatment of a predetermined condition.

[0078] The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered at daily doses of about 1 to about 2000 mg to achieve the therapeutic results disclosed herein. For example, daily doses of about 10-1000 mg may be administered as a single dose or in fractions, such as about 20-500 mg daily. In some embodiments, the daily dose may be about 0.01 to about 150 mg / kg body weight, such as about 0.2 to about 18 mg / kg body weight.

[0079] In one embodiment of the invention, the compound of the invention is administered to a subject in need to treat a disease. The compound may be administered continuously or intermittently. In one embodiment, the compound is administered to the subject more than once daily, for example, twice, three, or four times daily, or once every 1, 2, 3, 4, 5, 6, or 7 days. In another embodiment, the compound is administered to the subject no more than once per week, for example, no more than once every two weeks, once per month, once every two months, once every three months, once every four months, once every five months, once every six months, or for longer periods. In a further embodiment, the compound is administered using two or more different regimens, for example, initially administered more frequently (e.g., to accumulate to a certain level, e.g., once daily or more), and then administered less frequently (e.g., once per week or less). In other embodiments, the compound may be administered via any discontinuous dosing regimen. In one embodiment, the compound may be administered no more than once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, or once every ten days, or for longer periods. The administration may be continued for one, two, three, or four weeks, or for one, two, three months, or longer. Optionally, after a stop-loss period, the compound may be administered under the same or different regimens. Depending on the pharmacodynamic effects of the compound on the subject, the stop-loss period may be one, two, three, or four weeks, or longer. In another embodiment, the compound may be administered to accumulate to a certain level, then maintained at a constant level, followed by a tailing dosage.

[0080] In one aspect of the invention, the compound of the invention is delivered to a subject simultaneously with other therapeutic agents. These other therapeutic agents may be delivered in the same composition as the compound or in a separate composition. The other therapeutic agents may be delivered to the subject in a different manner or via a different route compared to the compound. The other therapeutic agents may be any agent that provides benefit to the subject. Other agents include, but are not limited to, stimulants, antipsychotics, antidepressants, neurological disorders, and chemotherapeutic agents. One therapeutic agent that can be administered concurrently is Xyrem®, commercially available from Jazz Pharmaceuticals, for the treatment of narcolepsy and cataplexy. See U.S. Patent Nos. 8,952,062 and 9,050,302.

[0081] This invention can be used in research as well as in veterinary and medical applications. Suitable subjects are generally mammal subjects. The term “mammal” as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, etc.). Human subjects include newborns, infants, adolescents, and adults.

[0082] In one specific embodiment, the subject is a human subject suffering from a condition suitable for treatment with APC. In other embodiments, the subject used in the method of the present invention is an animal model of a condition suitable for treatment with APC.

[0083] The subject may be a subject who "needs" the method of the present invention, for example, who needs the therapeutic effect of the method of the present invention. For example, the subject may be a subject with a condition suitable for treatment with APC, a subject suspected of having a condition suitable for treatment with APC, and / or a subject expected to have a condition suitable for treatment with APC, and the composition of the method of the present invention may be used for therapeutic and / or preventive treatment.

[0084] The invention will be explained in more detail in the following non-limiting embodiments.

[0085] Example 1 Synthesis of Compound 2 APC (15.0 g) and sodium cyanate (6.4 g) were suspended in dichloromethane (150 mL) and cooled in an ice bath. Methanesulfonic acid (10.6 mL) was added dropwise to the reaction mixture over 45 minutes. The ice bath was removed, and the reaction mixture was stirred overnight at room temperature. Before the reaction was complete and the reaction mixture was cooled in an ice bath, additional amounts of sodium cyanate (4.2 g) and methanesulfonic acid (4.2 mL) were added. After stirring for another 6 hours at room temperature, the reaction mixture was cooled in an ice bath, and the pH of the reaction mixture was adjusted to approximately 9 by adding a 10% aqueous sodium hydroxide solution. The organic phase was separated and washed with brine, then dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product as a white solid (5.7 g). 1H NMR (DMSO-d6, δ ppm): 2.49-2.51 (1H, m), 2.62 (1H, dd, J=3.9, 5.9 Hz) 3.10 (1H, m), 3.32 (3H, s, br), 3.82 (1H, dd, J=6.5, 5.4 Hz), 3.90 (1H, dd, J=10.5, 5.1 Hz), 7.06-7.32 (7H,m).

[0086] The free base obtained in the above process was dissolved in methanol (20 mL), and a 4.5 N hydrogen chloride solution in isopropanol (5.8 mL) was added to the mixture. The mixture was then placed in a refrigerator. The white precipitate was collected by filtration, washed with acetone, and then washed with ether. After drying, the product weighed 5.9 g (90.2%). mp (uncorrected): 199.1–199.2°C. ¹H NMR (DMSO-d6, δ ppm): 2.89 (¹H, dd, J=12.9, 9.5 Hz), 3.10 (¹H, dd, J=13.5, 5.2 Hz), 3.38 (¹H, s, br), 3.98 (¹H, dd, J=11.5, 6.0 Hz), 4.20 (¹H, dd, J=11.7, 2.1 Hz), 7.14–7.37 (7H, m), 8.46 (3H, s, br), 9.76 (¹H, s). Elemental analysis: Calculated C 48.27%, H 5.89%, N 15.35%; Measured C 48.36%, H 5.82%, N 15.18%; C48.50%, H 5.86%, N 15.39%.

[0087] Example 2 Characterization of the combined spectrum The pharmacological activity of compound 2 was compared with that of APC. Eight binding assays were performed to provide the binding profile of each compound, including binding to dopamine transporter (DAT), norepinephrine transporter (NET), serotonin (5-HT) transporter (SERT), α2A adrenergic receptor (Alpha2A), α2C adrenergic receptor (Alpha2C), D2S dopamine receptor (D2S), D2L dopamine receptor (D2L), and vesicular monoamine transporter (VMAT2). Each compound was subjected to a competitive binding assay using radiolabeled ligands at 10 μM. The radioligands for each target are as follows: DAT–BTCP, NET-protriptyline, SERT-imipramine, Alpha2A-yohimbine, Alpha2C-yohimbine, D2S-7-OH-DPAT, D2L-butanediol, VMAT2-bubenazine. The receptor and transporter sources are prepared using the cell membrane fraction.

[0088] The results are shown in Table 1. The similarity of the binding spectra of APC and compound 2 indicates similar biological activities.

[0089] Table 1: Combination spectrum

[0090] The above description is illustrative of the invention and should not be construed as limiting it. The invention is defined by the appended claims and their equivalents. All publications, patent applications, patents, patent publications, and other references cited herein are incorporated herein by reference in their entirety for the purpose of teaching the relevant sentences and / or paragraphs.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing cognitive-promoting effects in subjects in need. I in, R is an optional substituted lower alkyl group containing 1-8 carbon atoms, a halogen, an optional substituted alkoxy group containing 1-3 carbon atoms, a nitro group, a hydroxyl group, a cyano group, a trifluoromethyl group, or an optional substituted thioalkoxy group containing 1-3 carbon atoms. x is an integer from 0 to 3, provided that R can be the same or different when x is 2 or 3; R1, R2, and R3 are independently hydrogen, optionally substituted lower alkyl groups containing 1-8 carbon atoms, optionally substituted aryl groups, optionally substituted aralkyl groups, or optionally substituted cycloalkyl groups containing 3-7 carbon atoms; or R2 and R3 can be linked to form a 5- to 7-membered heterocycle, which may optionally be substituted by a member selected from the group consisting of alkyl and aryl groups, wherein the heterocycle may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly connected to each other or to the oxygen atoms.

2. The use as described in claim 1, wherein the subject suffers from bipolar disorder, major depressive disorder, schizoaffective disorder, PTSD, Alzheimer's disease, Parkinson's disease, dementia, or multiple sclerosis.

3. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of PTSD-related nightmares and / or sleep-related disorders in subjects of need. I in, R is an optional substituted lower alkyl group containing 1-8 carbon atoms, a halogen, an optional substituted alkoxy group containing 1-3 carbon atoms, a nitro group, a hydroxyl group, a cyano group, a trifluoromethyl group, or an optional substituted thioalkoxy group containing 1-3 carbon atoms. x is an integer from 0 to 3, provided that R can be the same or different when x is 2 or 3; R1, R2, and R3 are independently hydrogen, optionally substituted lower alkyl groups containing 1-8 carbon atoms, optionally substituted aryl groups, optionally substituted aralkyl groups, or optionally substituted cycloalkyl groups containing 3-7 carbon atoms; or R2 and R3 can be linked to form a 5- to 7-membered heterocycle, which may optionally be substituted by a member selected from the group consisting of alkyl and aryl groups, wherein the heterocycle may contain 1-2 nitrogen atoms and 0-1 oxygen atoms, wherein the nitrogen atoms are not directly connected to each other or to the oxygen atoms.

4. The use according to any one of claims 1-3, wherein the compound is a compound of formula II: II, Or its pharmaceutically acceptable salt.

5. The use as described in any one of claims 1-3, wherein the compound is compound 1: 1， Or its pharmaceutically acceptable salt.

6. The use according to any one of claims 1-3, wherein the compound is compound 2: 2， Or its pharmaceutically acceptable salt.

7. The use according to any one of claims 1-6, wherein the compound is in the form of a composition comprising the compound.

8. The use according to any one of claims 1-6, wherein the compound is in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier.

9. The use as described in claim 7 or 8, wherein the composition is a dosage form.

10. The use as described in claim 9, wherein the composition is an immediate-release oral dosage form.

11. The use as described in claim 10, wherein the composition is a tablet or capsule.

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