Varenicline-related compounds and methods for treating diseases and disorders, including tobacco use disorders

Abstract

Provided herein are compounds, pharmaceutically acceptable salts, pharmaceutical compositions comprising these compounds or their pharmaceutically acceptable salts, kits comprising these compounds or their pharmaceutically acceptable salts, methods for producing these compounds or their pharmaceutically acceptable salts, and methods for treating and preventing diseases and conditions using these compounds or their pharmaceutically acceptable salts. In some embodiments, provided are pharmaceutical compositions comprising pharmaceutically acceptable salts or compounds of Formulas I-VIII and pharmaceutically acceptable excipients, diluents, carriers, or any combination thereof. In some embodiments, the pharmaceutical composition can be in unit dose form.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 403,529, filed September 2, 2022, the entire contents of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0002] (overview) In some embodiments, Formula I: [ka] Provided herein are pharmaceutically acceptable salts of the formula: - can be a pharmaceutically acceptable anion, A can be a C1-C10 alkyl or branched alkyl group bearing a hydroxyl group, or any amino acid side chain, and Z is hydrogen or a pharmaceutically acceptable cation, or the following fragment of a pharmaceutically acceptable salt of a compound of formula I: [ka] and may be in the D-, L-, or racemic or achiral form; for example, the fragment may be a fragment of any of the following amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, or selenocysteine; or a salt of any of these.

[0003] In some embodiments, Formula 1A: [ka] wherein A is a C1-C10 alkyl or branched alkyl group bearing a hydroxyl group, or a C1-C10 straight or branched alkyl group bearing a carboxylic acid group, or a pharmaceutically acceptable salt thereof.

[0004] With the above in mind, pharmaceutically acceptable salts of compounds of formula IB include those of formula IB: [ka] The compound may be a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, in the pharmaceutically acceptable salt of Formula I or Formula IB, X - can be an anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate. In some embodiments, in the pharmaceutically acceptable salts of the compound of Formula I, Z can be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salts of the compound of Formula I, Z can be a pharmaceutically acceptable organic or inorganic cation.

[0006] In some embodiments, the pharmaceutically acceptable salt of Formula I is Formula II: [ka] It may have the structure:

[0007] In some embodiments, the pharmaceutically acceptable salt of Formula I is Formula III: [ka] It may have the structure:

[0008] In some embodiments, the compound of formula IV: [ka] wherein, independently, X can be a pharmaceutically acceptable anion, Y can be a C1-C10 straight or branched chain alkyl group bearing a carboxylic acid group, or a pharmaceutically acceptable salt thereof, and Z can be hydrogen or a pharmaceutically acceptable cation.

[0009] In some embodiments, in the pharmaceutically acceptable salt of formula IV, X - can be an anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate. In some embodiments, in the pharmaceutically acceptable salt of the compound of Formula IV, Z can be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salt of the compound of Formula IV, Z can be a pharmaceutically acceptable organic or inorganic cation.

[0010] In some embodiments, the pharmaceutically acceptable salt of Formula IV is Formula V: [ka] It may have the structure:

[0011] In some embodiments, the pharmaceutically acceptable salt of Formula VI has the formula VI: [ka] It may have the structure:

[0012] In some embodiments, the compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein each A can independently be a C1-C5 straight or branched chain methyl group.

[0013] In some embodiments, in the compound of formula VII or a pharmaceutically acceptable salt thereof, each A can independently be methyl.

[0014] In some embodiments, the compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 can independently be hydrogen (H) or C1-C5 branched or linear alkyl, or R 1 and R 2 and Z can be taken together with the nitrogen atom to which they are attached to form a 5-, 6-, or 7-membered ring, and Z can be hydrogen (H) or a pharmaceutically acceptable cation.

[0015] In some embodiments, in the compound of formula VIII or a pharmaceutically acceptable salt thereof, R 1 and R 2 and Z can be hydrogen.

[0016] In some embodiments, a pharmaceutical composition is provided that includes a pharmaceutically acceptable salt or compound of Formula I-VIII and a pharmaceutically acceptable excipient, diluent, carrier, or any combination thereof. In some embodiments, the pharmaceutical composition may be in unit dose form.

[0017] In some embodiments, methods of treating or preventing a disease or condition in a subject or a subject in need thereof (which may be a human subject or a human subject in need thereof, which may be a human subject in need thereof) are provided, comprising administering to the subject, human subject, subject in need thereof, or human subject in need thereof a pharmaceutical composition (which may be in unit dose form) comprising a pharmaceutically acceptable salt or compound of Formulas I-VIII, or one or more thereof, and a pharmaceutically acceptable carrier, excipient, diluent, or any combination thereof, in an effective amount or therapeutically effective amount sufficient to treat the disease or condition. In some embodiments, the disease or condition may be tobacco use disorder, nicotine use disorder, smoking, Parkinson's disease, or any combination thereof. In some embodiments, the disease or condition comprises tobacco use disorder. In some embodiments, the administration may be once per day, twice per day, or three times per day; or once every two days; or once every three days. In some embodiments, the administration may be daily, weekly, monthly, six months, one year, two years, three years, four years, five years, lifetime, or as long as needed. In some embodiments, the human or human in need thereof may be male or female. In some embodiments, the human or human in need thereof may be 18 years of age or older. In some embodiments, the administration may be oral, inhaled, intranasal, subcutaneous, intramuscular, or intravenous. In some embodiments, any pharmaceutically acceptable salt or compound herein (including a pharmaceutically acceptable salt or compound of Formulas I-VIII) may be administered at a dosage ranging from about 1 mg to about 20 mg, or from about 1 mg to about 15 mg, or from about 1 mg to about 10 mg, or from about 1 mg to about 5 mg, or from about 1 mg to about 3 mg.In some embodiments, any pharmaceutically acceptable salt or compound herein (including pharmaceutically acceptable salts or compounds of Formulas I-VIII) may be administered at a dosage ranging from about 0.00001 mg per kg to about 10,000 mg per kg, where mg is mg of the pharmaceutically acceptable salt or compound and kg is the subject's body weight. For example, they may be administered at about 0.001 mg per kg, about 0.01 mg per kg, about 0.1 mg per kg, about 1 mg per kg, about 10 mg per kg, or about 100 mg per kg.

[0018] In some embodiments, a kit is provided that includes a pharmaceutically acceptable salt or compound of Formulas I-VIII, or a pharmaceutical composition comprising one or more of these, and a container.

[0019] In some embodiments, a method of manufacturing the kit is provided, the method comprising placing a pharmaceutically acceptable salt or compound of Formula I-VIII, or any pharmaceutical composition comprising same, into the container.

[0020] In some embodiments, methods for preparing compounds of Formulas I-VIII or pharmaceutically acceptable salts thereof are provided, as are intermediate compounds and salts thereof useful for preparing them, and methods for preparing them.

[0021] This summary is intended to present exemplary embodiments herein and is not intended to be limiting in any way.

[0022] (Incorporated by reference) All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief explanation of the drawings]

[0023] BRIEF DESCRIPTION OF THE DRAWINGS The features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0024] [Figure 1] Figure 1A-1B are schematic diagrams and response curves showing the monitoring of striatal dopamine in awake, behaving animals in response to varenicline. Figure 1A shows the fiber photometry system and fiber placement used to monitor DA-induced fluorescence changes in awake, behaving mice, with representative images showing GPCR activation-based DA (GRAB-DA) and fiber placement in the striatum. Scale bar, 200 µm. Figure 1B shows the striatal dopamine response before and after intraperitoneal (IP) administration of nicotine.

[0025] [Figure 2] Figures 2A-2C are bar graphs and response curves showing striatal dopamine responses to nicotine. Figure 2A shows dopamine responses (averaged over 30 min after nicotine administration) in animals pretreated with either vehicle, varenicline (1.5 mg / kg (mpk) and 4.5 mg / kg (mpk)), servarenicline chloride, varenicline-enacarbil, varenicline-CBT, or varenicline glycinamide. Figures 2B-2C show exemplary traces and quantification of striatal dopamine responses before and after IP administration of nicotine. Mice were pretreated with either varenicline (light gray) or varenicline-enacarbil (dark gray).

[0026] [Figure 3]Figures 3A-3B are bar graphs and response curves showing striatal dopamine responses to oral compound administration. Figure 3A shows the dopamine response (averaged over 30 minutes after compound administration) in animals given either vehicle, varenicline (1.5 mpk and 4.5 mpk), servarenicline chloride, varenicline-enacarbil, varenicline-CBT, or varenicline glycosamide. Figure 3B shows the temporal kinetics of the dopamine response in animals given either vehicle, varenicline (1.5 mpk and 4.5 mpk), servarenicline chloride, varenicline-enacarbil, varenicline-CBT, or varenicline glycosamide.

[0027] [Figure 4] Figure 4 is a schematic diagram showing an approach to stabilizing the dopamine response. Figure 4 shows the dopamine response to treatment with a smoking cessation product or vehicle, followed by a dose of nicotine. Note how an ideal "prodrug" would stabilize the dopamine response throughout the day.

[0028] [Figure 5] Figure 5 is a bar graph showing the open field response to oral administration of compounds. Figure 5 shows the time spent in the center of the open field test in animals given either vehicle, varenicline (1.5 mpk and 4.5 mpk), cervarenicline chloride, varenicline-enacarbil, varenicline-CBT, or varenicline glycinamide. DETAILED DESCRIPTION OF THE INVENTION

[0029] (Detailed Description of the Invention) (definition) Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this application pertains. In some cases, terms having a commonly understood meaning are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as indicating a substantial departure from what is commonly understood in the art.

[0030] In this specification, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and that the description in range format should not be construed as an indefinite limitation on the scope of the present disclosure. Thus, the description of a range should be interpreted as including all specifically disclosed possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be interpreted as including specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range (e.g., 1, 2, 3, 4, 5, and 6). This is true regardless of the width of the range.

[0031] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a sample" includes multiple samples (including mixtures thereof).

[0032] The terms "determining," "measuring," "evaluating," "assaying," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement, and these terms include determining whether an element may be present or not (e.g., detecting). These terms can include quantitative determinations, qualitative or quantitative determinations, and qualitative determinations. Assessing can alternatively be relative or absolute. "Detecting the presence of" includes determining the amount of something present, as well as determining whether it may or may not be present.

[0033] The terms "subject," "individual," or "patient" are often used interchangeably herein. A "subject" can be a biological entity containing expressed genetic material. The biological entity can be a plant, an animal, or a microorganism (including, for example, bacteria, viruses, fungi, and protozoa). The subject can be tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject can be diagnosed with a disease or suspected of being at high risk for the disease. The disease can be endometriosis, tobacco use disorder, nicotine use disorder, or smoking. In some cases, the subject may not necessarily be diagnosed with the disease or suspected of being at high risk for the disease.

[0034] The term "in vivo" can be used to describe events that take place within the body of a subject.

[0035] The term "ex vivo" can be used to describe an event that occurs outside of a subject's body. An "ex vivo" assay may not be performed on a subject. Rather, it may be performed on a sample that is separate from the subject. An example of an "ex vivo" assay performed on a sample would be an "in vitro" assay.

[0036] The term "in vitro" can be used to describe events that occur in a container for holding a laboratory reagent so that it can be separated from the living biological source organism from which the substance is obtained. In vitro assays can include cell-based assays in which living or dead cells are used. In vitro assays can also include cell-free assays in which intact cells are not used.

[0037] As used herein, the term "about" a number can refer to that number plus 10% of that number or to that number minus 10% of that number. The term "about" a range can refer to that range minus 10% of its minimum value and to that range plus 10% of its maximum value.

[0038] As used herein, the term "treatment" or "treating" may refer to a pharmaceutical or other intervention regimen to obtain beneficial or desired results in a recipient. Beneficial or desired results may include, but are not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit may refer to the eradication or amelioration of the underlying disorder being treated, or the eradication or amelioration of one or more symptoms of the disorder. Therapeutic benefit may also be achieved by the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement may be observed in the subject, even though the subject may still be afflicted with the underlying disorder. A prophylactic effect may include delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, subjects at risk of developing a particular disease or who report one or more of the physiological symptoms of the disease may receive treatment even though a diagnosis of the disease may not have been made.

[0039] As used herein, the terms "unit dose" and "dosage form" may be used interchangeably and may refer to a form of pharmaceutical product sold for use in which a specific mixture of active ingredients and inactive ingredients or additives in a specific configuration is apportioned to a specific dose to be delivered. Although the U.S. Food and Drug Administration (FDA) distinguishes between unit dose "packaging" or "dispensing," the term "unit dose" can sometimes also include non-reusable packaging. More than one unit dose may refer to separate pharmaceutical products packaged together, or a single pharmaceutical product containing multiple drugs and / or multiple doses. The term "unit dose" may also sometimes refer to particles containing pharmaceutical compositions and any related mixtures. The type of unit dose may vary depending on the route of administration for drug delivery and the substance being delivered. A solid unit dose may be a solid form of a single dose of a compound used as a pharmaceutically acceptable drug or medicine for administration or consumption.

[0040] As used herein, a "dose" may refer to a measured amount of a therapeutic agent to be taken at one time.

[0041] As used herein, "pharmaceutically acceptable salts" may refer to pharmaceutical molecules that may be formed as weak acids or weak bases chemically prepared into their salt forms (e.g., as hydrochlorides, sodium salts, or sulfates). Pharmaceuticals synthesized as salts may enhance drug dissolution, increase absorption into the bloodstream, promote therapeutic effects, and increase their efficacy. Pharmaceutically acceptable salts may also facilitate the development of controlled-release dosage forms, improve drug stability, extend shelf life, enhance targeted drug delivery, and improve drug efficacy.

[0042] As used herein, the term "effective amount" or "therapeutically effective amount" of a drug used to treat a disease can be an amount that can reduce the severity of the disease, reduce the severity of one or more symptoms associated with the disease or its treatment, or delay the onset of more severe symptoms or more severe diseases that may occur with a certain frequency after the treated condition. An "effective amount" can be determined empirically and in a conventional manner in relation to the stated purpose.

[0043] The terms "substantially" or "essentially" may refer to a quantitative condition indicating the whole or nearly the whole extent or degree of a desired characteristic or property. In some cases, substantially may refer to a level of pain or dopamine response that varies by plus or minus the following percentages from the mean or median level of pain or dopamine response: about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73% 2%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. For example, substantially can refer to a 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% reduction in pain or dopamine response. In some cases, substantially can refer to at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100% of the total range or extent of a desired feature or characteristic.

[0044] (overview) Diseases or conditions such as tobacco use disorder, nicotine use disorder, smoking, and Parkinson's disease are harmful to individuals who have these diseases. They (e.g., tobacco use disorder and nicotine use disorder) are associated with drug-seeking or drug-addictive behavior, and the molecule or a pharmaceutically acceptable salt thereof may be useful in helping individuals reduce or quit using tobacco or nicotine in any and all forms, including, but not limited to, smoking and snuff.

[0045] In some embodiments, Formula I: [ka] Provided herein are pharmaceutically acceptable salts of the formula: - can be a pharmaceutically acceptable anion, A can be a C1-C10 alkyl or branched alkyl group bearing a hydroxyl group, and Z can be hydrogen or a pharmaceutically acceptable cation.

[0046] In any compound or pharmaceutically acceptable salt herein that includes one or more alkyl or branched alkyl groups, each alkyl or branched alkyl group can be, for example, independently, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, or a decyl group.

[0047] In some embodiments, in any salt herein (including pharmaceutically acceptable salts of Formula I), the anion and / or X -can be an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate. In some embodiments, in a pharmaceutically acceptable salt of a compound of Formula I, Z can be hydrogen (H). In some embodiments, in a pharmaceutically acceptable salt of Formula I, Z can be a pharmaceutically acceptable organic or inorganic cation. In some embodiments, the inorganic cation can be a sodium cation, a lithium cation, or a potassium cation. A magnesium cation (in some cases, the inorganic cation is associated with two molecules or pharmaceutically acceptable salts herein when the cation is a magnesium cation or a calcium cation and has a +2 charge), a lithium cation, a calcium cation (in some cases, the inorganic cation is associated with two molecules or pharmaceutically acceptable salts herein when the calcium cation has a +2 charge), or a potassium cation.

[0048] In some embodiments, Formula 1A: [ka] wherein A is a C1-C10 alkyl or branched alkyl group bearing a hydroxyl group, or a C1-C10 straight or branched alkyl group bearing a carboxylic acid group, or a pharmaceutically acceptable salt thereof.

[0049] With the above in mind, pharmaceutically acceptable salts of compounds of formula IB include those of formula IB: [ka] The compound may be a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, in the pharmaceutically acceptable salt of Formula I or Formula IB, X -can be an anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate. In some embodiments, in the pharmaceutically acceptable salt of Formula I, Z can be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salt of Formula I, Z can be a pharmaceutically acceptable organic or inorganic cation.

[0051] In some embodiments, the pharmaceutically acceptable salt of Formula I is Formula II: [ka] It may have the structure:

[0052] In some embodiments, the pharmaceutically acceptable salt of Formula I is Formula III: [ka] It may have the structure:

[0053] In some embodiments, the compound of formula IV: [ka] wherein, independently, X can be a pharmaceutically acceptable anion, Y can be a C1-C10 straight or branched chain alkyl group bearing a carboxylic acid group, or a pharmaceutically acceptable salt thereof, and Z can be hydrogen or a pharmaceutically acceptable cation.

[0054] Any pharmaceutically acceptable salt or compound herein may be in the form of an enantiomer, diastereomer, racemic mixture of enantiomers, or mixture of diastereomers, if applicable. When any compound or pharmaceutically acceptable salt herein contains one or more stereocenters, each stereocenter may independently be R or S. In some embodiments, any compound or pharmaceutically acceptable salt herein may have an enantiomeric excess or optical purity, as determined, for example, by optical rotation of linearly polarized light at the sodium D line, ranging from about 0% to about 100%, or about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 79%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%. In some embodiments, any compound or pharmaceutically acceptable salt herein can have a diastereomeric excess or diastereomeric purity in the range of about 0% to 100%, or about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 79%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, as determined, for example, by optical rotation of linearly polarized light at the sodium D line.

[0055] In some embodiments, in the pharmaceutically acceptable salt of formula IV, X - can be an anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate. In some embodiments, in the pharmaceutically acceptable salt of Formula IV, Z can be hydrogen (H). In some embodiments, in the pharmaceutically acceptable salt of Formula IV, Z can be a pharmaceutically acceptable organic or inorganic cation.

[0056] In some embodiments, the pharmaceutically acceptable salt of Formula IV is Formula V: [ka] It may have the structure:

[0057] In some embodiments, the pharmaceutically acceptable salt of Formula VI has the formula VI: [ka] It may have the structure:

[0058] In some embodiments, the compound of formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein each A can independently be a C1 to C5 straight or branched chain alkyl group.

[0059] In some embodiments, in the compound of formula VII or a pharmaceutically acceptable salt thereof, each A can independently be methyl.

[0060] In some embodiments, the compound of formula VIII: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 can independently be hydrogen (H), or C1-C5 branched or linear alkyl, or R 1 and R 2 and Z can be taken together with the nitrogen atom to which they are attached to form a 5-, 6-, or 7-membered ring, and Z can be hydrogen (H) or a pharmaceutically acceptable cation.

[0061] In some embodiments, in the compound of formula VIII or a pharmaceutically acceptable salt thereof, R 1 and R 2 and Z can be hydrogen.

[0062] In some embodiments, the compound of formula: [ka] or a pharmaceutically acceptable salt thereof, wherein X is OR1, halogen, fluorine, chlorine, bromine, iodine, or NR2R3, where R1 is hydrogen, an organic or inorganic cation, or a C1-C10 straight or branched chain alkyl, and R2 and R3 are each independently a C1-C10 straight or branched chain alkyl, or R2 and R3 together with the nitrogen atom to which they are attached form a 5- to 7-membered ring.

[0063] In some embodiments, a pharmaceutical composition is provided that includes a compound of Formula I-VIII or a pharmaceutically acceptable salt of Formula I-VIII and a pharmaceutically acceptable excipient, diluent, carrier, or any combination thereof.

[0064] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient may include a pharmaceutically acceptable additive. As used herein, "additive" may refer to a substance formulated with an active pharmaceutical ingredient for long-term stabilization, to bulk up solid formulations containing small amounts of potent active ingredients, and / or to impart therapeutic enhancements to the active ingredient in the final dosage form. Additives may promote drug absorption, reduce viscosity, or enhance solubility. Additives may also facilitate handling of the active ingredient, improve in vitro stability, and / or extend the shelf life of the pharmaceutical product. The choice of additive may vary depending on the route of administration for drug delivery, the unit dose, and the composition containing the active ingredient.

[0065] In some embodiments, the pharmaceutically acceptable excipients include calcium phosphate anhydrous, calcium phosphate dihydrate, hydroxypropyl methylcellulose, croscarmellose sodium, GMO-free croscarmellose sodium, carbomer, magnesium aluminum metasilicate, mannitol, povidone (PVP), crospovidone, sorbitol, dimethicone, sodium stearyl fumarate, sodium starch glycolate, hydroxypropyl cellulose, native corn starch, modified corn starch, carrageenan, alginate, silicon dioxide, microcrystalline cellulose, sodium carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na CMC), carbomer, natural gums, sorbitol, maltitol, glucose syrup, silicone, carbomer, fatty alcohols, alcohols, carbohydrates, petrolatum derivatives, butter, wax, DMSO. Procipient, ester, fatty acid, oil-in-water (O / W) emulsifier, water-in-oil (W / O) emulsifier, silica, fumed silica, polysorbate, isopropyl myristate, cellulose derivatives, xanthan gum, propylene glycol, noveon AA-1 polycarbophil, dimethyl isosorbate, polysilicone elastomer 1100, polysilicone elastomer 1148P, preservatives, flavors, colors, functional coatings, aesthetic coatings, pharmaceutically acceptable salts of any of these, or any combination thereof.

[0066] In some embodiments, the pharmaceutically acceptable excipients include gum arabic, acesulfame potassium, acetic acid (glacial), acetone, tributyl acetyl citrate, triethyl acetyl citrate, agar, albumin, alcohol, alginic acid, aliphatic polyesters, alitame, almond oil, alpha tocopherol, aluminum hydroxide adjuvant, aluminum oxide, aluminum phosphate adjuvant, aluminum stearate, ammonia solution, ammonium alginate, ascorbic acid, ascorbyl palmitate, aspartame, attapulgite, bentonite, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, boric acid, bronopol, butylhydroxyanisole, butylhydroxytoluene, butylparaben, calcium alginate, calcium carbonate, calcium hydrogen phosphate anhydrous, calcium hydrogen phosphate dihydrate, tricalcium phosphate, calcium stearate, calcium sulfate, canola oil, carbomer, carbon dioxide, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, castor oil. , hydrogenated castor oil, cellulose (e.g., microcrystalline cellulose, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate, cellulose acetate phthalate), ceratonia, cetostearyl alcohol, cetrimide, cetyl alcohol, cetylpyridinium chloride, chitosan, chlorhexidine, chlorobutanol, chlorocresol, chlorodifluoroethane, chlorofluorocarbons, chloroxylenol, cholesterol, citric acid monohydrate, colloidal silicon dioxide, colorant, copovidone, corn oil, cottonseed oil, cresol, croscarmellose Sodium, crospovidone, cyclodextrin, cyclomethicone, denatonium benzoate, dextrate, dextrin, dextrose, dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate, difluoroethane, dimethicone, dimethyl ether, dimethyl phthalate, dimethyl sulfoxide, dimethylacetamide, sodium edetate, sodium docusate, edetic acid, erythorbic acid, erythritol, ethyl acetate, ethyl lactate, ethyl maltol, ethyl oleate, ethyl vanillin,Ethyl cellulose, ethylene glycol palmitostearate, ethylene vinyl acetate, ethylparaben, fructose, fumaric acid, gelatin, glucose, glycerin, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate palmitostearate), glycofurol, guar gum, hectorite, heptafluoropropane, hexetidine, hydrocarbons, hydrochloric acid, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, hypromellose acetate succinate, hypromellose phthalate, honey, imidourea, inulin, iron oxides, isomalt, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, kaolin, lactic acid, lactitol, lactose anhydrous, lactose monohydrate, spray-dried lactose, lanolin, lanolin alcohol, hydrolyzed lanolin, lauric acid, lecithin, leucine, linoleic acid, macrogol hydroxystearate, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate Ingredients include: sodium, malic acid, maltitol, maltitol solution, maltodextrin, maltol, maltose, mannitol, medium chain triglycerides, meglumine, menthol, methylcellulose, methylparaben, mineral oil, mineral oil (light mineral oil), mineral oil and lanolin alcohols, monoethanolamine, monosodium glutamate, monothioglycerol, myristic acid, neohesperidin dihydrochalcone, nitrogen, nitrous oxide, octyldodecanol, oleic acid, oleyl alcohol, olive oil, palmitic acid, paraffin, peanut oil, pectin, petrolatum, petrolatum and lanolin alcohols, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, phosphoric acid, polacrilin potassium, poloxamer, polycarbophil, polydextrose, polyethylene glycol, polyethylene oxide, polymethacrylatePoly(methyl vinyl ether / maleic anhydride), polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyvinyl acetate phthalate, polyvinyl alcohol, potassium alginate, potassium benzoate, potassium bicarbonate, potassium chloride, potassium citrate, potassium hydroxide, potassium metabisulfite, potassium sorbate, povidone, propionic acid, propyl gallate, propylene carbonate, propylene glycol, propylene glycol alginate, propylparaben, 2-pyrrolidone, raffinose, saccharin, saccharin sodium, saponite, sesame oil, shellac, simethicone, sodium acetate, sodium alginate, sodium ascorbate, benzoate Sodium carbonate, sodium bicarbonate, sodium borate, sodium chloride, sodium citrate dihydrate, sodium cyclamate, sodium hyaluronate, sodium hydroxide, sodium lactate, sodium lauryl sulfate, sodium metabisulfite, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium propionate, sodium starch glycolate, sodium stearyl fumarate, sodium sulfite, sorbic acid, sorbitan esters (sorbitan fatty acid esters), sorbitol, soybean oil, starch, starch (e.g., pregelatinized starch, sterilizable corn starch), stearic acid, stearyl alcohol, sucralose, sucrose, compressible sugar, powdered sugar, sugar spheres sphere), sulfobutyl ether beta-cyclodextrin, sulfuric acid, sunflower oil, suppository base, hard fat, talc, tartaric acid, tetrafluoroethane, thaumatin, thimerosal, thymol, titanium dioxide, tragacanth, trehalose, triacetin, tributyl citrate, triethanolamine, triethyl citrate, vanillin, vegetable oil (hydrogenated), water, wax (anionic emulsifying), wax (e.g., carnauba wax, cetyl esters, microcrystalline wax, nonionic emulsifying wax, wax (white), wax (yellow)), xanthan gum, xylitol, zein, zinc acetate, zinc stearate,or any combination thereof.

[0067] In some embodiments, the pharmaceutically acceptable additive may include carbohydrates, alginates, povidone, carbomers, flavorings, natural gums, silicones, alcohols, butters, waxes, fatty acids, preservatives, pharmaceutically acceptable salts of any of these, or any combination thereof. In some embodiments, the pharmaceutically acceptable additive may include carbohydrates. In some embodiments, the carbohydrates may include lactose, microcrystalline cellulose, cellulose, mannitol, sorbitol, starch, starch glycolate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, cyclodextrin, maltodextrin, croscarmellose sodium, corn starch, carrageenan, sorbitol, maltitol, glucose, pharmaceutically acceptable salts of any of these, or any combination thereof.

[0068] (Water as a carrier) In some cases, the pharmaceutically acceptable carrier or diluent may include water. In some embodiments, the water may be sterile. In some embodiments, the water may contain a buffer, a carbohydrate, a salt, a pH adjuster, or any combination thereof. Simple sugars such as mannitol, sucrose, glucose, and trehalose may be added in amounts of 1 mg / ml to 50 mg / ml to inhibit aggregation of the peptide or polypeptide. Citrate may be used as a buffer. In some cases, sodium chloride and phosphate may or may not be used. Larger polysaccharides may also be used to enhance stability.

[0069] A carrier may refer to a reagent, cell, compound, substance, composition, dosage form, or any combination thereof that may be compatible with a therapeutically administered agent. In some cases, the carrier may be suitable for use in contact with the tissue of a subject. In some cases, the carrier may not be toxic, irritating, allergic, or any combination thereof. Carriers that may be suitable for use may include liquids, solid substances (e.g., pills or suppositories), or any combination thereof. In some cases, the carrier may be designed to resist degradation within the body (non-biodegradable), or the carrier may be designed to degrade within the body (biodegradable). Biodegradable substances may also be bioresorbable or bioabsorbable. In some cases, biodegradable substances may be degraded and removed from the body by conversion to other substances or degradation and removal through natural pathways.

[0070] (Typical dosage form) In some embodiments, the composition or pharmaceutical composition may be in the form of a capsule, tablet, gummy, oil, liquid, inhalable dosage form (which may be a powder or liquid that can be delivered as an aerosol), tincture, lotion, cream, balm, candy, chocolate, food, beverage, oil, suppository, injectable liquid (which may be, for example, an intravenous, intramuscular, or subcutaneous liquid); syrup, or any combination thereof.

[0071] In some embodiments, the pharmaceutical composition may be in unit dosage form.

[0072] In some embodiments, methods are provided for treating or preventing a disease or condition in a subject, which may be a subject in need thereof, which may be a mammal, which may be a human subject, which may be a human subject in need thereof, comprising administering to the human subject a pharmaceutical composition of a compound of Formulas I-VIII or a pharmaceutically acceptable salt thereof in an amount sufficient to treat the disease or condition. In some embodiments, the disease or condition may be tobacco use disorder, nicotine use disorder, smoking, Parkinson's disease, or any combination thereof. In some embodiments, the disease or condition comprises tobacco use disorder.

[0073] (Administration schedule and dosage) In some embodiments, the administration may be once per day, twice per day, or three times per day; or once every two days; or once every three days. In some embodiments, the administration may be carried out daily, weekly, monthly, six months, one year, two years, three years, four years, five years, lifetime, or as long as needed. In some embodiments, the human, subject, or mammal may be male or female. In some embodiments, the human, subject, or mammal may be 18 years of age or older. In some embodiments, the administration may be oral, inhaled, intranasal, subcutaneous, intramuscular, or intravenous. In some embodiments, the compound or pharmaceutically acceptable salt or compound of Formulas I-VIII may be administered at a dosage ranging from about 1 mg to about 20 mg, or from about 1 mg to about 15 mg, or from about 1 mg to about 10 mg, or from about 1 mg to about 5 mg, or from about 1 mg to about 3 mg.

[0074] In some cases, the amount of the compound or a pharmaceutically acceptable salt thereof can be administered in an amount ranging from about 0.0001 mg / kg of the subject's body weight to about 1000 mg / kg of the subject's or subject in need thereof body weight or about 1000 mg / kg of the subject's or subject in need thereof body weight; the dosage can be, for example, about 100 mg / kg of the pharmaceutically acceptable salt or compound or a pharmaceutically acceptable salt thereof per kg of the subject's body weight. The amount of the derivatives may be based on mg of these derivatives, which may be about 0.0001 g, about 0.001 g, about 0.01 g, about 0.1 g, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 15 g, about 20 g, about 25 g, about 30 g, about 35 g, about 40 g, about 45 g, about 50 g, about 55 g, about 60 g, about 65 g, about 70 g, about 75 g, about 80 g, about 85 g, about 90 g, about 100 g, about 15 ...160 g, about 165 g, about 170 g, about 175 g, about 180 g, about 185 g, about 190 g, about 200 g, about 210 g, about 215 g, about 220 g, about 225 g, about 230 g, about 235 g, about 240 g, about 245 g, about 250 g, about 250 g, about 260 g, about 265 g, about 270 g, about 275 g, about 280 g, about 285 g, about 290 g, about 30 g, about 95 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500 g, about 600 g, about 700 g, about 800 g, about 900 g, or about 1000 g per kg of the subject's body weight, or about 0.0001 mg, about 0.001 mg, about 0.01 mg, about 0.1 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 1000 g per kg of the subject's body weight. It can be 5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0075] In some cases, the amount of the compound or pharmaceutically acceptable salt administered to a subject or a subject in need thereof can range from 0.00001 mg to 1000 g; the dosage can be, for example, about 0.0001 g, about 0.001 g, about 0.01 g, about 0.1 g, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, Approximately 7g, approximately 8g, approximately 9g, approximately 10g, approximately 15g, approximately 20g, approximately 25g, approximately 30g, approximately 35g, approximately 40g, approximately 45g, approximately 50g, approximately 55g, approximately 60g, approximately 65g, Approximately 70g, approximately 75g, approximately 80g, approximately 85g, approximately 90g, approximately 95g, approximately 100g, approximately 200g, approximately 300g, approximately 400g, approximately 500g, approximately 600g, approximately 700g, approximately It can be 800 g, about 900 g, or about 1000 g or about 0.0001 mg, about 0.001 mg, about 0.01 mg, about 0.1 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg.

[0076] (Route of Administration) In some embodiments, the pharmaceutical composition or compound or a pharmaceutically acceptable salt thereof may be administered to the subject by oral, injection, sublingual, buccal, rectal, vaginal, ocular, aural, nasal, internal, inhalation, cutaneous, subcutaneous, intramuscular, intravenous, transdermal, or any combination thereof.

[0077] In some embodiments, the pharmaceutical composition or compound or its pharmaceutically acceptable salt can be formulated for oral administration.In some embodiments, the pharmaceutical composition can be in the form of a pill or liquid.In some embodiments, a second treatment can be administered simultaneously with or consecutively to the pharmaceutical composition.In some embodiments, the second treatment is administered as part of the pharmaceutical composition.In some embodiments, the second treatment is administered separately from the pharmaceutical composition.

[0078] In some embodiments, a kit is provided that includes a compound of Formula I-VIII or a pharmaceutically acceptable salt, or a pharmaceutical composition comprising one or more of these, and a container.

[0079] In some embodiments, a method of manufacturing the kit is provided, the method comprising placing a compound of Formula I-VIII or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, into the container.

[0080] In some embodiments, methods for preparing compounds of Formulas I-VIII or pharmaceutically acceptable salts thereof, as well as intermediate compounds and salts thereof useful for preparing the same, are also provided.

[0081] In some embodiments, the compound of Formulas I-VIII or a pharmaceutically acceptable salt thereof may have one or more unexpectedly superior characteristics when compared to a substantially similar amount of varenicline or a pharmaceutically acceptable salt thereof administered by the same route of administration, including an unexpectedly superior release profile, an unexpectedly superior peak plasma concentration (Cmax), an unexpectedly superior 8-hour area under the curve (AUC), an unexpectedly superior 16-hour area under the curve (AUC), or an unexpectedly superior 24-hour area under the curve (AUC), or an unexpectedly superior area under the curve to infinity (AUC), or an unexpectedly superior half-life. [Example]

[0082] (Example) The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure. Example 1 [ka]

[0083] (Synthesis of Nicotinoyl-Asp(OtBu)-OtBu [2]): To H-Asp(OtBu)-OtBu.HCl (1.0 equivalent) in dichloromethane (DCM) was added EtN (2.0 equivalents). Nicotinoyl chloride hydrochloride (2.0 equivalents) was added portionwise (four times over 20 minutes) in an ice bath. After the addition, the mixture was stirred below 5°C for 1 hour. Water (30 mL) was added to quench the reaction, followed by the addition of DCM. The DCM layer was further washed with 5% NaHCO and brine and dried over NaSO. The solvent was evaporated, and the residue was purified by silica gel column chromatography (MeOH / DCM).

[0084] (Synthesis of Varenicline-N-CO2CH2-Cl [3]); Varenicline (1.0 equiv.) was purified and the initial synthesis was carried out in DCM and cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.0 equiv.) was added, and the resulting mixture was stirred for 10 minutes. Chloromethyl chloroformate (2.5 equiv.) in DCM was added slowly. The ice bath was removed, and the reaction was stirred at room temperature for 5 hours. Ethyl acetate was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated, washed with 1N HCl and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography.

[0085] (Synthesis of varenicline-N—CO2CH2-nicotinoyl-Asp(OtBu)-OtBu [5]): Chloromethyl carbamate of varenicline (1.5 equivalents) and nicotinoyl-Asp(OtBu)-OtBu [2] (1.0 equivalents) in acetonitrile were heated at 70° C. for 24 hours. The solvent was evaporated. The residue was purified by silica gel column chromatography.

[0086] (Synthesis of [6]chloride): Varenicline-N-CO2CH2-nicotinoyl-Asp(OtBu)-OtBu chloride in 4N HCl / dioxane was stirred for 3 hours. The solvent was evaporated. The residue was co-evaporated with DCM, then dissolved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 x 2 mL), and dried in vacuo to yield solid [6]chloride.

[0087] Example 2 [ka] [ka] (Synthesis of Cervarenicline Chloride) (Synthesis of Nicotinoyl-Ser(tBu)-OtBu): To H-Ser(tBu)-OtBu (1.0 equiv.) in DCM was added EtN (2.0 equiv.). Nicotinoyl chloride hydrochloride (2.0 equiv.) was added portionwise (four times over 20 min) in an ice bath. After the addition, the mixture was stirred below 5° C. for 1 h. Water (30 mL) was added to quench the reaction, followed by the addition of DCM. The DCM layer was further washed with 5% NaHCO and brine and dried over NaSO. The solvent was evaporated, and the residue was purified by silica gel column chromatography (MeOH / DCM).

[0088] (Synthesis of Varenicline-N-CO2CH2-Cl [7]): Varenicline (1.0 equiv.) in DCM was cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.0 equiv.) was added, and the resulting mixture was stirred for 10 minutes. Chloromethyl chloroformate (2.5 equiv.) in DCM was added slowly. The ice bath was removed, and the reaction was stirred at room temperature for 5 hours. Ethyl acetate was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated, washed with 1N HCl and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography.

[0089] (Synthesis of varenicline-N—CO2CH2-nicotinoyl-Ser(tBu)-OtBu [8]): Chloromethyl carbamate of varenicline (1.5 equivalents) and nicotinoyl-Ser(tBu)-OtBu (1.0 equivalents) in acetonitrile were heated at 70° C. for 24 hours. The solvent was evaporated. The residue was purified by silica gel column chromatography.

[0090] (Synthesis of cervarenicline chloride): Varenicline-N-CO2CH2-nicotinoyl-Ser(tBu)-OtBu chloride in 4N HCl / dioxane was stirred for 3 hours. The solvent was evaporated. The residue was co-evaporated with DCM, then dissolved in DCM (4 mL) and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 x 2 mL), and dried in vacuo to yield a solid.

[0091] Example 3. Synthesis of varenicline-enacarbil [ka] [ka] Synthesis of 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate: Zinc oxide (1 g, 12 mmol) was added to a solution of toluene (40 ml) and isobutyric acid (10 ml) and refluxed for 1 hour. The water generated in the process was removed using a Dean-Stark apparatus. After the temperature was lowered to 60 °C, 1-1-chloroethyl 4-nitrophenyl carbonate (1 g, 4 mmol) and NaI (1 g, 6.4 mmol) were added to the reaction mixture. The mixture was stirred at 60 °C for 24 hours. The next day, the reaction mixture was evaporated to a residue, which was then dissolved in EtOAc. The organic solution was washed with saturated NaHCO3 solution and then with brine. The organic layer was separated and dried over MgSO4. The dried organic layer was evaporated to give 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate.

[0092] (Varenicline enacarbyl [9]): To varenicline (1.0 eq., 5.75 g, 0.03 mol) in toluene (50 ml), chlorotrimethylsilane (2.0 eq.) and tributylamine (2.0 eq.) were added, which was then stirred at room temperature to obtain a clear solution. 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate (1.0 eq.) in toluene (20 ml) was then added to the reaction mixture, which was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was washed with 1N HCl (150 ml) and water (2 x 100 ml). The organic layer was dried over MgSO4, evaporated, and purified by silica gel column chromatography to obtain the desired product.

[0093] Example 4. Synthesis of varenicline-CBT [ka] [ka] (Synthesis of 4-nitrophenyl Boc-Tyr-OMe): The mixture of Boc-Tyr-OMe, 4-nitrophenyl chloroformate and DIEA in DCM was stirred at room temperature for 18 hours. After completion of the reaction, the organic layer was washed with water, dried with MgSO4 and evaporated. The crude product was used directly for the following step.

[0094] (Synthesis of Varenicline-CBT

[10] ): A DMF solution of varenicline was added to a mixture of 4-nitrophenylBoc-Tyr-OMe and diisopropylethylamine (DIEA) in N,N-dimethylformamide (DMF), followed by stirring at room temperature for 3 hours. After completion of the reaction, EtOAc was added to the reaction mixture, which was then washed with 1N HCl (150 ml) and water (2 × 100 ml). The organic layer was dried over MgSO4, evaporated, and purified by silica gel column chromatography to obtain the desired product. The purified product was stirred in 6N HCl / dioxane at 40 °C for 24 hours. The solvent was evaporated. The residue was co-evaporated with DCM, then dissolved in DCM (4 mL), and TBME (25 mL) was added. The resulting solid was collected, washed with TBME (4 × 2 mL), and dried in vacuo to give a solid.

[0095] Example 5 The compounds of Formulas I-VIII or pharmaceutically acceptable salts are individually formulated into therapeutically effective dosage forms and administered individually to individual subjects, where the compounds or pharmaceutically acceptable salts optionally exhibit extended release profiles and plasma concentrations sufficient to be therapeutically effective.

[0096] Example 6 [ka] (Synthesis of Varenicline-Glycinamide) (Chloromethyl carbamate of varenicline); A solution of chloromethyl chloroformate in DCM (dichloromethane) was added to an ice bath temperature mixture of varenicline, 4-DMAP and DCM, warmed and stirred at room temperature for 5 hours. (varenicline-glycinamide); A mixture of ammonium hydroxide and chloromethyl carbamate of varenicline was stirred at room temperature for 3 hours.

[0097] Example 7 Varenicline's ability to reduce nicotine use stems from its ability to block nicotine-induced dopamine signaling in the striatum. Real-time detection of dopamine levels in awake, behaving mice was measured using a fluorescent dopamine sensor (GRAB-DA) and its fluorometric measurement (fiber photometry). Figure 1A shows the experimental placement of the fiber in the striatum and an exemplary fluorescence image generated during the experiment. Figure 1B shows exemplary fluorescence response curves before and after intraperitoneal administration of nicotine.

[0098] The varenicline derivatives designed herein were found to be as effective as or more effective than varenicline in reducing nicotine-induced dopamine release (Figure 2A). These data showed that the response to nicotine after 2 hours was the same regardless of the dose of varenicline. Although cervarenicline chloride and varenicline enacarbil (Figures 2B-C) showed better efficacy when compared directly with varenicline, all of the derivatives performed at least as well as varenicline.

[0099] Varenicline increased striatal dopamine levels after administration. This increase may potentially reduce nicotine craving, but it may also be associated with unwanted side effects of varenicline. The varenicline-based molecules described herein were found to have varying abilities to induce dopamine after oral administration (Figures 3A-3B). Some molecules (e.g., cervarenicline chloride, varenicline-CBT, or varenicline glycinamide) do not result in dopamine release, while others (varenicline-enacarbil) mimic the effects of varenicline.

[0100] This series of compounds offered two novel advantages: first, a set of molecules engineered to mimic varenicline's response but for a longer duration; and second, molecules that smoothed out the dopamine response, preventing the dopamine surge typically seen with varenicline's partial agonist function.

[0101] Varenicline also affected mobility and anxiety-like behavior in mice. In the open-field assay (FIG. 5), animals avoided the open area and exhibited anxiety-like behavior (dramatically reduced time in the center). This effect was not observed with cervarenicline chloride, varenicline-CBT, or varenicline glycinamide, suggesting that these varenicline derivatives may have different side-effect profiles.

[0102] While preferred embodiments have been shown and described herein, such embodiments are provided for illustrative purposes only. Numerous changes, modifications, and substitutions will now occur to those skilled in the art without departing from the disclosure herein. It should be understood that various alternative forms of the embodiments described herein may be used.

Claims

1. Formula I: 【Chemical 31】 A pharmaceutically acceptable salt of － A pharmaceutically acceptable salt wherein: A is a pharmaceutically acceptable anion; A is a C1-C10 alkyl or branched alkyl group bearing a hydroxyl group; and Z is hydrogen or a pharmaceutically acceptable cation.

2. X － 2. The pharmaceutically acceptable salt of Formula I of claim 1, wherein is a pharmaceutically acceptable anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate.

3. 3. A pharmaceutically acceptable salt of formula I of claim 1 or claim 2, wherein Z is H.

4. A pharmaceutically acceptable salt of formula I according to any one of claims 1 to 3, wherein Z is a pharmaceutically acceptable organic or inorganic cation.

5. Formula II: 【Chemical 32】 2. A pharmaceutically acceptable salt of formula I according to claim 1 having the structure:

6. Formula III: 【Chemical 33】 2. A pharmaceutically acceptable salt of formula I according to claim 1 having the structure:

7. Formula IV: 【Chemical 34】 A pharmaceutically acceptable salt of a compound of the formula: － is a pharmaceutically acceptable anion, Y is a C1-C10 straight or branched chain alkyl group bearing a carboxylic acid group or a pharmaceutically acceptable salt thereof, and Z is hydrogen or a pharmaceutically acceptable cation.

8. X － 8. The pharmaceutically acceptable salt of formula IV of claim 7, wherein is a pharmaceutically acceptable anion selected from the group consisting of chloride, bromide, sulfate, phosphate, acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and besylate.

9. 9. A pharmaceutically acceptable salt of formula IV according to claim 7 or claim 8, wherein Z is H.

10. A pharmaceutically acceptable salt of formula IV according to any one of claims 7 to 9, wherein Z is a pharmaceutically acceptable organic or inorganic cation.

11. Formula V: 【Chemistry 35】 8. A pharmaceutically acceptable salt of formula IV according to claim 7, having the structure:

12. Formula VI: 【Chemical 36】 8. A pharmaceutically acceptable salt of formula IV according to claim 7, having the structure:

13. Formula IA: 【Chemical 37】 wherein A is a C1-C10 alkyl or branched alkyl group bearing a hydroxyl group, or a C1-C10 straight or branched alkyl group bearing a carboxylic acid group, or a pharmaceutically acceptable salt thereof.

14. Formula VII: 【Chemical 38】 or a pharmaceutically acceptable salt thereof, wherein each A is independently a C1-C5 straight or branched chain group.

15. 15. The compound of formula VII of claim 14, or a pharmaceutically acceptable salt thereof, wherein each A is independently a methyl group.

16. Formula VIII: 【Chemical Formula 39】 or a pharmaceutically acceptable salt thereof, １ and R ２ are independently hydrogen or C1-C5 branched or linear alkyl, or R １ and R ２ are taken together with the nitrogen atom to which they are attached to form a 5-, 6-, or 7-membered ring, and Z is hydrogen or a pharmaceutically acceptable cation, or a pharmaceutically acceptable salt thereof.

17. R １ and R ２ 17. The compound of formula VIII according to claim 16, or a pharmaceutically acceptable salt thereof, wherein is hydrogen and Z is hydrogen.

18. 18. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any one of claims 1 to 17 and a pharmaceutically acceptable excipient, diluent, or carrier.

19. 20. The pharmaceutical composition of claim 18 in unit dosage form.

20. 1. A method of treating or preventing a disease or condition in a human subject in need thereof, comprising: administering to said human subject a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 or claim 19, in an amount sufficient to treat said disease or condition. A method comprising:

21. 21. The method of claim 20, wherein the disease or condition comprises smoking, a tobacco use disorder, or both.

22. 22. The method of claim 21, wherein the disease or condition comprises a tobacco use disorder.

23. 23. The method of any one of claims 20 to 22, wherein the administration is once per day, twice per day, or three times per day; or once every two days; or once every three days.

24. The method according to any one of claims 20 to 23, wherein the administration is oral administration or inhalation administration or nasal administration.

25. 25. The method of any one of claims 20-24, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dosage ranging from about 1 mg to about 20 mg, or from about 1 mg to about 15 mg, or from about 1 mg to about 10 mg, or from about 1 mg to about 5 mg, or from about 1 mg to about 3 mg.

26. A kit comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 18 to 19, and a container.

27. 27. A method for producing the kit of claim 26, comprising: placing the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 18 to 19, in said container; A method comprising:

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