JP2019163298A - Promotion of smoking cessation - Google Patents

Abstract

To provide methods for promoting smoking cessation.SOLUTION: The invention relates to the use of an effective amount of a certain carbamate compound for production of a pharmaceutical to promote cessation or reduction in the smoking and/or chewing of tobacco or nicotine-containing products in a subject who is neither addicted to nor dependent on nicotine. Further, the invention relates to the use of an effective amount of a certain carbamate compound for production of a pharmaceutical for preventing relapse smoking and/or chewing of tobacco or nicotine-containing products in a subject who is neither addicted to nor dependent on nicotine.SELECTED DRAWING: None

Description

  The present invention claims the benefit of priority over US Provisional Application No. 61 / 845,438, filed July 12, 2013, the entire contents of which are hereby incorporated by reference.

  The present invention provides for cessation or reduction in smoking and / or chewing of a tobacco or nicotine-containing product in a subject in need thereof, comprising administering to the subject an effective amount of a specific carbamate compound. It relates to a method for promoting. The present invention also provides recurrence in a subject in need of smoking and / or chewing tobacco or a nicotine-containing product comprising administering to the subject a therapeutically effective amount of a particular carbamate compound. It relates to a method for preventing.

  Smoking and chewing of tobacco products are recognized as major health problems. On average, 435,000 people die each year from smoking-related illnesses in the United States. A variety of treatments are available to help people reduce or stop tobacco use. One common treatment is to administer nicotine transdermally or incorporated into a chewing gum base. Other approved treatments include Zyban (R) (buproprion) and Chantix (R) (Varenicline).

  The present invention provides an effective and convenient way to help people reduce and / or interrupt tobacco use and to prevent recurrence in people who have stopped using tobacco.

（上記式において、Ｒは炭素原子数１〜８のアルキル、ハロゲン、炭素原子数１〜３のアルコキシ、ニトロ、ヒドロキシ、トリフルオロメチル及び炭素原子数１〜３のチオアルコキシからなる群から選択され；
ｘは０〜３の整数であり、ｘが２又は３の場合、Ｒは同じか又は異なり；
Ｒ_１及びＲ_２は水素、炭素原子数１〜８のアルキル、アリール、アリールアルキル、炭素原子数３〜７のシクロアルキルからなる群から独立して選択されるか；又は
Ｒ_１及びＲ_２は共に結合して、一つ以上のアルキル基又はアリール基で置換されているか又は置換されていない５〜７員のヘテロ環を形成することができ、上記ヘテロ環は１〜
２個の窒素原子及び０〜１個の酸素原子を含むことができ、このとき、上記窒素原子は互いに直接連結されていないか又は酸素原子と直接連結されていない）。 Accordingly, one embodiment of the present invention is a method for promoting cessation or reduction of smoking and / or chewing of tobacco or nicotine-containing products in a subject in need thereof, comprising:
Administering to a subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof,
With respect to a method wherein smoking and / or chewing cessation or reduction of the tobacco or nicotine-containing product is promoted:

(In the above formula, R is selected from the group consisting of alkyl having 1 to 8 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy having 1 to 3 carbon atoms. ;
x is an integer from 0 to 3, and when x is 2 or 3, R is the same or different;
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl having 3 to 7 carbon atoms; or R ₁ and R ₂ are They can be joined together to form a 5- to 7-membered heterocycle, which is substituted or unsubstituted with one or more alkyl or aryl groups, wherein the heterocycle is 1-
2 nitrogen atoms and 0-1 oxygen atoms can be included, wherein the nitrogen atoms are not directly connected to each other or to oxygen atoms).

（上記式において、Ｒは炭素原子数１〜８のアルキル、ハロゲン、炭素原子数１〜３のアルコキシ、ニトロ、ヒドロキシ、トリフルオロメチル及び炭素原子数１〜３のチオアルコキシからなる群から選択され；
ｘは０〜３の整数であり、ｘが２又は３の場合、Ｒは同じか又は異なり；
Ｒ_１及びＲ_２は水素、炭素原子数１〜８のアルキル、アリール、アリールアルキル、炭素原子数３〜７のシクロアルキルからなる群から独立して選択されるか；又は
Ｒ_１及びＲ_２は共に結合して、一つ以上のアルキル基又はアリール基で置換されているか又は置換されていない５〜７員のヘテロ環を形成することができ、上記ヘテロ環は１〜２個の窒素原子及び０〜１個の酸素原子を含むことができ、このとき、上記窒素原子は互いに直接連結されていないか又は酸素原子と直接連結されていない）。 Another embodiment of the present invention is a method of preventing recurrence in a subject in need of smoking and / or chewing tobacco or a nicotine-containing product comprising:
Administering to a subject an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof,
A method wherein smoking and / or chewing recurrence of the tobacco or nicotine-containing product is prevented:

(In the above formula, R is selected from the group consisting of alkyl having 1 to 8 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy having 1 to 3 carbon atoms. ;
x is an integer from 0 to 3, and when x is 2 or 3, R is the same or different;
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl having 3 to 7 carbon atoms; or R ₁ and R ₂ are They can be joined together to form a 5-7 membered heterocycle, which is substituted or unsubstituted with one or more alkyl or aryl groups, wherein the heterocycle contains 1 to 2 nitrogen atoms and 0 to 1 oxygen atom can be included, in which case the nitrogen atoms are not directly connected to each other or to oxygen atoms).

  In another embodiment of the present invention, the method comprises administering to a subject an effective amount of an enantiomer of Formula I or a mixture of enantiomers predominantly of Formula I that is substantially free of other enantiomers. Including the steps of:

In another embodiment, the compound of formula I is a compound of formula Ia, a pharmaceutically acceptable salt or ester thereof.

In another embodiment, the compound of formula I is a compound of formula Ib, a pharmaceutically acceptable salt or ester thereof.

  The above compound is named (R)-(beta-amino-benzenepropyl) carbamate or O-carbamoyl- (D) -phenylalaninol and is selectively ADX-N05, SKL-N05, SK-N05, YKP10A and It can be called R228060.

  Embodiments of the present invention include the use of a compound of formula I to promote cessation or reduction of smoking and / or chewing of tobacco or nicotine-containing products in a subject in need thereof. Other embodiments of the present invention include the use of compounds of formula I to prevent recurrence in subjects in need of smoking and / or chewing tobacco or nicotine-containing products.

  Embodiments of the invention include the use of a compound of formula I for the manufacture of a medicament for promoting smoking and / or chewing cessation or reduction of tobacco or nicotine-containing products. Another embodiment of the present invention involves the use of a compound of formula I for the manufacture of a medicament for preventing recurrence in a subject in need of smoking and / or chewing tobacco or a nicotine-containing product. Including.

  The present invention provides an effective and convenient way to help people reduce and / or interrupt tobacco use and to prevent recurrence in people who have stopped using tobacco.

  The present invention will be described more specifically with reference to the accompanying drawings and examples showing embodiments of the present invention. However, the present invention may be embodied in various other forms and should not be construed as limited to the embodiments disclosed herein. Rather, such embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

  Unless defined otherwise, 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 belongs. . The terminology used in the detailed description of the invention is used for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

  The various features of the invention disclosed herein can be used in any combination, unless otherwise indicated by context. The invention may also exclude or omit any feature or combination of features described herein in some embodiments of the invention. For the sake of illustration, when a composition containing components A, B and C is described in the specification, any one or combination of A, B or C is omitted alone or in any combination or Can be eliminated.

Definitions As used herein, the article (a, an or the) means one or more. For example, “a cell” can mean a single cell or multiple cells.

  Also, “and / or” as used in the present invention is meant to include any possible combination of one or more of the relevant description items, and is selectively interpreted as (“or”). Can also be understood that combinations can be excluded.

  The term “about” refers to ± 20%, ± 10%, ± 5% of a specified amount when specifying a measurable numerical value, such as a dosage (eg, an amount of a compound) described herein. , ± 1%, ± 0.5%, or ± 0.1% variation.

  As used herein, the term “comprise”, “comprises”, “comprising” identifies the presence of an explicit feature, ingredient, step, operation, element, and / or component. However, this does not impede the presence or addition of one or more features, ingredients, steps, actions, elements, configurations and / or groups thereof.

  As used herein, the transitional phrase “consisting essentially of” means that the scope of the claim is substantially the same as the specific material or step “and the basic and new features as specified in the claim. Meaning something that has no effect on it. In re Herz, 537 F.R. 2d 549, 551-52, 190 U.S. S. P. Q. 461, 463 (CCPA 1976) (emphasis in the original); and MPEP § 2111.03. Thus, when the term “consisting essentially of” is used in the claims and detailed description of the present invention, it is not intended to be construed as equivalent to “including”.

  As used herein, “effective amount” refers to an amount of a compound, composition and / or formulation of the present invention sufficient to produce a desired effect that is a therapeutic and / or beneficial effect. Is. The effective amount depends on the age, gender, subject's symptoms, severity of the disease being treated, the particular formulation administered, the duration of the treatment, the characteristics of any treatment being performed simultaneously, the pharmaceutically acceptable used Depending on factors such as the carrier to be used, it can vary within the knowledge and experience of those skilled in the art. If desired, an “effective amount” in any individual case can be determined by one skilled in the art with reference to the relevant text and literature and / or general experimentation.

  As used herein, a “subject” is generally a mammalian subject, preferably a human. The subject includes females and / or males of any age and includes children, adolescents, adults and elderly subjects. In one embodiment, the subject is a subject who is not nicotine addicted, ie, shows only minimal withdrawal symptoms or does not feel withdrawal symptoms when nicotine consumption stops. In one embodiment, the subject is a subject that is dependent on nicotine but is not nicotine addicted. In one embodiment, the subject is a subject who does not take nicotine at a rate sufficient to maintain a steady state nicotine level. In one embodiment, the subject is a “light and intermittent smoker”, ie, a subject who smokes no more than five cigarettes per day. In another embodiment, the subject is a subject who consumes nicotine less than the daily rate.

The term “nicotine addiction” is a subject who feels withdrawal symptoms when steady-state nicotine levels are not maintained, for example, when nicotine intake stops. Withdrawal symptoms include, for example, irritability, depression, restlessness, anxiety, lack of concentration, light dizziness, insomnia, tremor and increased hunger and weight gain However, it is not limited to this.

  As used herein, the term `` nicotine dependence '' includes all physical and behavioral dependence and is minimal when steady-state nicotine levels are not maintained, e.g., when nicotine intake stops. Subjects who show only limited withdrawal symptoms or do not feel withdrawal symptoms, but have difficulty in stopping nicotine intake.

  In the method of the present invention, a “subject in need” currently smokes and / or chews tobacco or nicotine-containing products, or relapses of smoking and / or chewing tobacco or nicotine-containing products. A potential subject.

  The term “smoking and / or chewing a tobacco or nicotine-containing product” is intended to mean the use of any product that provides nicotine when used by a subject. The terms are smoking (eg, cigarette, cigar, pipe) or chewing (eg, chewing tobacco, dipping tobacco, snuff, as used herein) Tobacco products to be snus and non-tobacco nicotine delivery products (eg gums, transdermal patches, nasal sprays, inhalers, vaporizers, pills, tablets, lozenges, Including the use of strips, sticks).

  The term “cessation” is intended to mean complete cessation of activity, for example smoking and / or chewing of tobacco or nicotine-containing products.

  The terms “reduce, reduceds, reduced, reduction” and similar terms used herein are at least about 5%, 10%, 15%, 20%, 25%, 35%, 50% 75%, 80%, 85%, 90%, 95%, 97% or more reduction, for example, reduced smoking and / or chewing frequency of tobacco or nicotine-containing products or reduced nicotine intake . In certain embodiments, the reduction results in an undetectable or substantially undetectable activity or amount (ie, a small amount, eg, less than about 10% or 5%).

  The term “promoting” as used herein in connection with smoking and / or chewing interruption or reduction of tobacco or nicotine-containing products is an increase in the subject's ability to reduce or stop nicotine intake. Means. In one embodiment, the promotion includes reduced craving for nicotine and / or reduced physical and / or behavioral dependence on nicotine.

  The term “preventing relax” as used herein in connection with cessation or reduction of smoking and / or chewing of a tobacco or nicotine-containing product refers to the subject following an interruption in the subject's nicotine intake. It means prevention of nicotine intake. In one embodiment, the term includes a permanent interruption of nicotine intake. In other embodiments, the term includes a delay in resuming nicotine intake compared to a resumption time by a subject not receiving a compound of the invention. The delay in the restart is, for example, time (for example, 1, 6, 12, 24 hours), day (for example, 1, 2, 3, 4, 5, 6, 7 days), week, month or longer It can be. In other embodiments, the term includes reducing the risk of resuming nicotine absorption, for example, reducing the risk by at least about 10%, 20%, 30%, 40%, 50% or more. including.

  The term “pharmaceutically acceptable salt or ester” refers to a non-toxic salt or ester of the compound used in the present invention, generally a free salt reacted with a suitable organic or inorganic base. Is reacted with a suitable organic or inorganic acid. Examples of such salts are acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, calcium edetate, cansylate (Camsylate), carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicylate, estrate, esylate, fumarate, gluceptate, gluconic acid Salt, glutamate, glycolylarsanylate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, iodide Isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsyl acid Salt, nitrate, oleate, oxalate, pamoate, palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium , Stearates, basic acetates, succinates, tannates, tartrate, theocrate, tosylate, triethiodide, and valerate.

  As used herein, the term “combinant administration” or “combination administration” of a compound, therapeutic agent or known drug and a compound of the present invention is a known pharmaceutical or drug. And in addition, means that at least one compound of the invention is administered at a time when the known drug and the compound of the invention all have a therapeutic or beneficial effect. In some cases, this therapeutic or beneficial effect can be synergistic. Such co-administration can be simultaneous (ie, simultaneous), prior or subsequent administration of known drugs in connection with the administration of the compounds of the present invention. One skilled in the art can readily determine the appropriate timing, sequence and dosage for administration of a particular drug and a compound of the present invention.

  Furthermore, in some embodiments, the compounds of the invention are used alone or in combination with each other or in combination with one or more other therapeutic or beneficial agents described above, or in the form of their salts or esters. Thus, it can be used in the manufacture of a medicament for the purpose of promoting the interruption or reduction of tobacco / nicotine use or preventing the recurrence of tobacco / nicotine use for patients or subjects in need of treatment.

  The present invention is based in part on the discovery that Formula I phenylalkylaminocarbamates have novel and unique pharmaceutical properties. Although the exact mechanism of action is not fully understood, it is said that such compounds do not act by the same mechanism as other known stimulants that exhibit these effects. Nicotine withdrawal symptoms are partially affected by a decrease in dopamine levels (De Biasi et al., Annu. Rev. Neurosci. 34: 105 (2011)). Buproprion can help quit smoking by normalizing dopamine levels (De Biasi et al., Annu. Rev. Neurosci. 34: 105 (2011); Roddy, BMJ 328: 509 (2004)). Compounds of formula I increase dopamine and norepinephrine levels like buproprion. In addition, the compounds of formula I share other properties with buproprion such as psychoexcitatory and antidepressant effects without sexual side effects and propose similarities of effects on activities such as smoking cessation. For this reason, the compounds of formula I are particularly suitable for use as a deterrent for tobacco and nicotine use.

（上記式において、Ｒは炭素原子数１〜８のアルキル、ハロゲン、炭素原子数１〜３のアルコキシ、ニトロ、ヒドロキシ、トリフルオロメチル及び炭素原子数１〜３のチオアルコキシからなる群から選択され；
ｘは０〜３の整数であり、ｘが２又は３の場合、Ｒは同じか又は異なり；
Ｒ_１及びＲ_２は水素、炭素原子数１〜８のアルキル、アリール、アリールアルキル、炭素原子数３〜７のシクロアルキルからなる群から独立して選択されるか；又は
Ｒ_１及びＲ_２は共に結合して、一つ以上のアルキル基又はアリール基で置換されているか又は置換されていない５〜７員のヘテロ環を形成することができ、上記ヘテロ環は１〜２個の窒素原子及び０〜１個の酸素原子を含むことができ、このとき、上記窒素原子は互いに直接連結されていないか又は酸素原子と直接連結されていない） In one embodiment of the present invention, the present invention is a method for promoting cessation or reduction of tobacco or nicotine-containing product smoking and / or chewing in a subject in need thereof, comprising:
Administering to the subject a therapeutically effective amount of a compound of formula (I) below, a pharmaceutically acceptable salt or ester thereof,
It relates to a method in which smoking and / or chewing cessation or reduction of the tobacco or nicotine-containing product is promoted.

(In the above formula, R is selected from the group consisting of alkyl having 1 to 8 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy having 1 to 3 carbon atoms. ;
x is an integer from 0 to 3, and when x is 2 or 3, R is the same or different;
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl having 3 to 7 carbon atoms; or R ₁ and R ₂ are They can be joined together to form a 5-7 membered heterocycle, which is substituted or unsubstituted with one or more alkyl or aryl groups, wherein the heterocycle contains 1 to 2 nitrogen atoms and 0 to 1 oxygen atom can be included, in which case the nitrogen atoms are not directly connected to each other or to oxygen atoms)

（上記式において、Ｒは炭素原子数１〜８のアルキル、ハロゲン、炭素原子数１〜３のアルコキシ、ニトロ、ヒドロキシ、トリフルオロメチル及び炭素原子数１〜３のチオアルコキシからなる群から選択され；
ｘは０〜３の整数であり、ｘが２又は３の場合、Ｒは同じか又は異なり；
Ｒ_１及びＲ_２は水素、炭素原子数１〜８のアルキル、アリール、アリールアルキル、炭素原子数３〜７のシクロアルキルからなる群から独立して選択されるか；又は
Ｒ_１及びＲ_２は共に結合して、一つ以上のアルキル基又はアリール基で置換されているか又は置換されていない５〜７員のヘテロ環を形成することができ、上記ヘテロ環は１〜２個の窒素原子及び０〜１個の酸素原子を含むことができ、このとき、上記窒素原子は互いに直接連結されていないか又は酸素原子と直接連結されていない） In another embodiment of the present invention, a method of preventing recurrence in a subject in need of smoking and / or chewing tobacco or a nicotine-containing product comprising:
Administering to the subject a therapeutically effective amount of a compound of formula (I) below, a pharmaceutically acceptable salt or ester thereof,
It relates to a method in which the smoking and / or chewing recurrence of the tobacco or nicotine-containing product is prevented.

(In the above formula, R is selected from the group consisting of alkyl having 1 to 8 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy having 1 to 3 carbon atoms. ;
x is an integer from 0 to 3, and when x is 2 or 3, R is the same or different;
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl having 3 to 7 carbon atoms; or R ₁ and R ₂ are They can be joined together to form a 5-7 membered heterocycle, which is substituted or unsubstituted with one or more alkyl or aryl groups, wherein the heterocycle contains 1 to 2 nitrogen atoms and 0 to 1 oxygen atom can be included, in which case the nitrogen atoms are not directly connected to each other or to oxygen atoms)

  In one embodiment of the above method, R is selected from the group consisting of alkyl having 1 to 3 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy and trifluoromethyl. In one embodiment of the above method, R is selected from the group consisting of alkyl having 1 to 3 carbon atoms, halogen, and alkoxy having 1 to 3 carbon atoms.

In one embodiment of the above method, R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, and cycloalkyl having 3 to 7 carbon atoms. In one embodiment of the above method, R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkyl having 1 to 8 carbon atoms. In one embodiment of the above method, R ₁ and R ₂ are independently selected from the group consisting of hydrogen and alkyl having 1 to 3 carbon atoms.

  Substituents and substitution patterns of the compounds of the present invention are chemically stable by those skilled in the art and can be readily synthesized not only by the methods specified herein but also by techniques known in the art. Can be selected to provide compounds that can be made.

In one embodiment, the compound of formula I is a compound of formula Ia, a pharmaceutically acceptable salt or ester thereof.

In other embodiments, the compound of formula I above has an enantiomer (compound of formula Ib), wherein R ₁ and R ₂ are hydrogen and x is 0, a pharmaceutically acceptable salt thereof Salt or ester.

  The above compounds are (R) enantiomers and (R)-(beta-amino-benzenepropyl) carbamate when named by structure. This compound is a dextrorotary enantiomer and can therefore be named O-carbamoyl- (D) -phenylalaninol. These names can be used interchangeably herein.

  The present invention includes the use of an isolated enantiomer of a compound of formula I (eg, a compound of formula Ia or Ib). In one embodiment, a pharmaceutical composition comprising an isolated S-enantiomer of Formula I can be used to treat a subject. In other embodiments, a pharmaceutical composition comprising an isolated R-enantiomer of formula I can be used to treat a subject.

  The invention also includes the use of a mixture of enantiomers of formula I. In one embodiment of the invention, one enantiomer may be predominate. The predominant enantiomer in the mixture is one that is present in an amount greater than any other enantiomer present in the mixture, eg, greater than 50%. In one embodiment, one enantiomer may dominate as much as 90% or as much as 91%, 92%, 93%, 94%, 95%, 96%, 97% or 98% or more. In one embodiment, the predominant enantiomer in a composition comprising a compound of formula I is the S-enantiomer of a compound of formula I.

  The present invention provides a method of using an enantiomer or mixture of enantiomers of a compound represented by Formula I. The carbamate enantiomer of Formula I contains an asymmetric chiral carbon in the benzylic position, which is the second aliphatic carbon adjacent to the phenyl ring.

  One isolated enantiomer is substantially free of the corresponding enantiomer. Thus, an isolated enantiomer refers to a compound that is separated by separation techniques or that is prepared such that there is no corresponding enantiomer.

  The term “substantially free” as used herein means that the compound is configured such that a single enantiomer makes up a very large proportion. In a preferred embodiment, the compound comprises at least about 90% by weight of one enantiomer. In another embodiment of the invention the compound comprises at least about 99% by weight of one enantiomer.

  Compounds of formula I can be synthesized by methods well known to those skilled in the art. Salts and esters of compounds of formula I are prepared by treating the above compounds with the appropriate mineral or organic acid (HX) in a suitable solvent or by other means well known in the art. be able to.

  US Pat. No. 5,705,640, US Pat. No. 5,756,817 are detailed descriptions of reaction schemes for the synthesis of compounds of formula I and representative examples for the preparation of specific compounds. U.S. Pat. No. 5,955,499, and U.S. Pat. No. 6,140,532, all of which are incorporated herein by reference.

  From formula 1, it is clear that some of the compounds of the invention have at least one and more asymmetric carbon atoms. The present invention includes within its scope not only the stereochemically pure isomeric forms of the compounds, but also their racemates. Stereochemically pure isomeric forms are obtained by applying principles known in the art. Diastereoisomers can be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers can be obtained by selective crystallization of diastereomeric salts using optically active acids or bases or chirally. They can be separated from one another by chromatography. Pure stereoisomers can also be synthesized from the appropriate stereochemically pure starting materials or prepared using stereoselective reactions.

It is essential and / or desirable to protect sensitive or reactive groups on any of the molecules involved during any process for making the compounds of the present invention. This is described in Protective Groups in Organic Chemistry, ed. J. et al. F. W. McOmie, Plenum Press, 1973; W. Green & P. G. M.M. It can be achieved by conventional protecting groups as described in Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1999. The protecting group can be removed at an appropriate subsequent stage using methods well known in the art.

  The compounds may be administered orally, buccal, topical, systemic (eg, transdermal, nasal, or suppository) or parenteral (eg, intramuscular, subcutaneous, or intravenous). It can be administered to a subject by any conventional route of administration, including but not limited to. Direct administration of the above compounds to the nervous system can be achieved, for example, by intracranial, intraventricular, intraventricular, intracerebral, intracerebral, or intracerebral or intracerebral by delivery using a needle or catheter with or without a pump device. Administration may be by the ventral, intrathecal, intracisternal, intraspinal, or peri-spinal route. Depending on the route of administration, the compound of Formula I can be configured in any form. For example, forms suitable for oral administration include solid forms such as pills, gelcaps, tablets, caplets, capsules, granules and powders (including immediate release, timed release and sustained release dosage forms, respectively). Forms suitable for oral administration also include liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. In addition, forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

  In certain embodiments, the pharmaceutical composition of the present invention comprises one or more compounds of Formula I, or salts or esters thereof, without any pharmaceutical carrier or excipient. In other embodiments, the pharmaceutical composition of the present invention is one in which one or more compounds of Formula I, or salts or esters thereof, are intimately mixed with a pharmaceutical carrier by conventional pharmaceutical synthesis techniques. Carriers are inert pharmaceutical excipients and include, but are not limited to, binders, suspending agents, lubricants, flavors, sweeteners, preservatives, dyes and coating agents. Any common pharmaceutical carrier can be used in the manufacture of compositions for oral administration. For example, suitable carriers and additives for liquid oral formulations include water, glycols, oils, alcohols, fragrances, preservatives, colorants, etc .; suitable carriers and additives for solid oral formulations include starch , Sugars, diluents, granulating agents, lubricants, binders, disintegrants and the like.

The composition can be a tablet, pill, capsule, semi-solid, powder, sustained release formulation.
release formulation), solutions, suspensions, emulsions, syrups, elixirs, aerosols, or other suitable composition forms; and at least one compound of the present invention is at least pharmaceutically acceptable It can be included in any combination with one excipient. Suitable excipients are well known to those of ordinary skill in the art and the formulation of the composition is described in Alfonso AR: Remington's.
Pharmaceutical Science, 17th edition ed. Mack Publishing Company, Easton Pa. , 1985, the entire contents and purpose of which are incorporated herein by reference. Suitable liquid carriers, particularly for injectable solutions, include water, aqueous brine, aqueous dextrose solution, and glycol.

The carbamate compound can be provided as an aqueous suspension. The aqueous suspension of the present invention can contain the carbamate compound mixed with excipients suitable for the preparation of the aqueous suspension. This excipient includes, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and naturally occurring phospholipids (eg lecithin), fatty acids and Condensates of alkylene oxides (eg, polyoxyethylene stearate), condensates of ethylene oxide and long chain aliphatic alcohols (eg, heptadecaethyleneoxycetanol), condensates of ethylene oxide and fatty acid and partial esters derived from hexitol (eg, Polyoxyethylene sorbitol mono-oleate) or condensates of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (eg, polyoxyethylene sorbitan - it can include dispersing or wetting agents such as oleate).

  The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoic acid, one or more colorants, one or more fragrances, and sucrose, aspartame or saccharin. One or more sweeteners can be included. The osmotic concentration of the formulation can be adjusted.

  Oil suspensions for use in the method of the present invention are suspensions of carbamate compounds in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin, or in mixtures thereof. Can be blended. The oil suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as glycerol, sorbitol or sucrose can be added to provide a palatable oral preparation. Such formulations can be stored with the addition of an anti-oxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. et al. Pharmacol. Exp. Ther. 281: 93 (1997). The pharmaceutical formulation of the present invention may also be in the form of an oil-in-water emulsion. The oil phase can be the vegetable oil or mineral oil described above, or a mixture thereof.

  Suitable emulsifying agents include naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phospholipids such as soy lecithin, fatty acids and esters or partial esters derived from hexitol anhydrides such as sorbitan mono-oleate, and Includes condensation products of partial esters and ethylene oxide such as polyoxyethylene sorbitan mono-oleate. The emulsion may also contain sweetening and flavoring agents as syrup and elixir formulations. Such formulations may also contain a demulcent, preservative, or coloring agent.

  In one embodiment, the compound is a vaporizer, such as an electronic cigarette, which vaporizes a liquid solution containing the compound in an aerosol mist for inhalation or insufflation. Can be provided in the form of

  The selected compounds can be prepared alone or with other suitable ingredients as an aerosol formulation (ie, they can be “nebulized”) and administered by inhalation. Aerosol formulation can be placed in a pressurized acceptable propellant such as dichlorodifluoromethane, propane, nitrogen and the like.

For example, formulations of the present invention suitable for parenteral administration, such as in the joint, intravenous, intramuscular, intraepidermal, intraperitoneal, and subcutaneous routes, include antioxidants, buffers, bacterial growth. Water-soluble and water-insoluble isotonic sterile injection solutions that can contain inhibitors, and solutes that render the formulation isotonic with the blood of the intended recipient; and suspending agents, Water-soluble and water-insoluble sterile suspensions that can contain solubilizers, thickeners, stabilizers, and preservatives can be included. Among the acceptable vehicles and solvents that may be employed are water and Ringer's solution, isotonic sodium chloride. In addition, sterile fixed oils can usually be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used for the preparation of injectables. Such solutions are sterilized and generally free of undesirable materials.

  If the compounds are sufficiently soluble, they can be dissolved directly in saline with or without the use of a suitable organic solvent such as propylene glycol or polyethylene glycol. The finely divided compound dispersant may comprise an aqueous starch or sodium carboxymethylcellulose solution, or a suitable oil such as peanut oil. Such formulations can be sterilized by conventional, well-known sterilization techniques. Since the above-mentioned preparation is close to physiological conditions, a pH regulator and a buffer such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc., and a toxicity regulator are used as necessary. Pharmaceutically acceptable auxiliary substances.

  In such formulations, the concentration of the carbamate compound is very diverse and can be selected based primarily on the fluid volume, viscosity, weight, etc., depending on the particular mode of administration selected and the needs of the patient. . For IV administration, the formulation can be a sterile injectable formulation, such as a sterile injectable aqueous or oleaginous suspension. The suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Recommended formulations can be presented in unit-dose or multi-dose sealed containers such as ampoules and vials. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

  Carbamate compounds suitable for use in the practice of the present invention can preferably be administered orally. The amount of the compound of the invention in the composition can vary depending on the type of composition, the size of the unit dosage, the type of excipient, and other factors well known to those skilled in the art. Generally, the final composition comprises, for example, 0.000001% by weight (% w) to 100% w, for example 0.00001% w to 50% w carbamate compound with the balance excipients. it can.

  Pharmaceutical formulations for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art at dosages suitable for oral administration. Such carriers are formulated in unit dosage forms suitable for patient intake such as tablets, pills, powders, dragees, capsules, liquids, troches, gels, syrups, slurries, suspensions, etc. Allows to be done. In other embodiments, pharmaceutical formulations for oral administration can be formulated without any pharmaceutically acceptable carrier.

  Formulations suitable for oral administration include: (a) a liquid solution such as an effective amount of a pharmaceutical formulation suspended in a diluent such as water, saline or PEG 400; (b) a predetermined amount of the active ingredient in a liquid, solid form Capsules, sachets or tablets, each containing as granules or gelatin; (c) a suspension in a suitable liquid; and (d) a suitable emulsion.

Oral pharmaceutical preparations are prepared by mixing the compound of the invention with a solid excipient, optionally crushing the resulting mixture and, if necessary, obtaining a suitable tablet or dragee core. It is obtained by processing the mixture of granules after adding the compound. Suitable solid excipients are carbohydrates or protein fillers and sugars including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; methylcellulose, hydroxymethylcellulose, hydroxypropyl Cellulose such as methyl-cellulose or sodium carboxymethylcellulose; and gums including arabic and tragacanth; and proteins such as gelatin and collagen, but are not limited thereto.

  If desired, disintegrating or solubilizing agents can be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof such as sodium alginate. Tablet forms include one or more lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other shaping Agents, colorants, fillers, binders, diluents, buffers, wetting agents, preservatives, fragrances, dyes, disintegrants, and pharmaceutically compatible carriers can be included. Lozenge forms can contain the active ingredient in flavors such as, for example, sucrose, and in addition to the active ingredient, known carriers known in the art, gelatin and glycerin or sucrose And pastilles containing the active ingredient in an inert base such as an acacia emulsion, gel, and the like.

  The compounds of the present invention can also be administered in the form of suppositories for rectal administration of the drug. Such formulations are solid at normal temperatures but liquid at rectal temperatures and are therefore mixed with suitable non-irritating excipients that melt in the rectum to release the drug Can be done. Such materials include cocoa butter and polyethylene glycol.

  The compounds of the present invention can also be administered by nasal, intraocular, intravaginal, and rectal routes, including suppositories, inhalants, powders and aerosol formulations (as examples of steroid inhalers, Rohatagi, J Clin. Pharmacol.35: 1187 (1995); Tjwa, Ann. Allergy Asthma Immunol.75: 107 (1995)).

  The compounds of the present invention are formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, patches and aerosols and delivered transdermally via the topical route Can be done.

  Encapsulating materials can also be used with the compounds of the present invention, and the term “composition” refers to the active ingredient with the encapsulating material as a formulation, with or without other carriers. Can be included. For example, the compounds of the present invention can also be delivered as microspheres for slow release in the body. In one embodiment, the microspheres are as biodegradable and injectable gel formulations (see, eg, Gao, Pharm. Res. 12: 857 (1995)); or as microspheres for oral administration (eg, Eyeles, J. Pharm). Pharmacol. 49: 669 (1997)); gradually released subcutaneously (Rao, J. Biometer Sci. Polym. Ed. 7: 623 (1995) microsphere-containing drugs (eg, mifepristone) Both transdermal and intradermal routes can provide sustained delivery for weeks or months, and cachets for delivery of the compounds of the present invention. Can also be used.

In other embodiments, the compounds of the present invention are fused to cell membranes or by endocytosed liposomes, ie, bound to cell surface membrane protein receptors and endocytosis. ) Result in the use of a ligand attached to the liposome. The active ingredient can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

  The use of liposomes focuses on the delivery of carbamate compounds to target cells in vivo, especially when the liposome surface has a specific ligand for the target cell or vice versa and preferentially goes to a specific organ. (Al-Muhammed, J. Microencapsul. 13: 293 (1996); Chonn, Curr. Opin. Biotechnol. 6: 698 (1995); Ostro, Am. J. Hosp. Pharm. 46: 1576 (1989). )reference).

  The active drug can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are bound. Active agents can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinyl-pyrrolidone, pyran copolymers, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. it can. Furthermore, the active agent can be combined with a group of biodegradable polymers useful for achieving controlled release of the drug, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid. A cross-linked or amphiphilic block copolymer of a copolymer, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate and hydrogel.

  In certain embodiments, the composition is a tablet, pill, capsule, powder, granule, sterile parenteral solution or for oral, parenteral, intranasal, sublingual or rectal administration, or administration by inhalation or insufflation. A unit dosage form such as a suspension, metered aerosol or liquid spray, drop, ampoule, patch, auto-injector or suppository.

  Such compositions can optionally be prepared in a form suitable for weekly or monthly administration; for example, an insoluble salt of an active compound such as a decanoate is a depot for intramuscular injection. Suitable for providing.

  In the present specification, the pharmaceutical composition is effective dose as described above per dosage unit such as tablet, capsule, powder, injection, teaspoonful, suppository and the like. ) Can contain a substantial amount of the active ingredient necessary for transport. For example, the pharmaceutical compositions herein can contain from about 10 to about 1000 mg of active ingredient per unit dosage form, such as from about 25 to about 600 mg of active ingredient, such as from about 75 to about 400 mg. Active ingredients, e.g. about 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550 The active ingredient can be contained in 575 or 600 mg or more or in its range.

In some embodiments of the present invention, carbamate compounds suitable for use in the practice of the present invention are alone or at least one other compound or therapeutic agent, such as smoking cessation or smoke reduction or other that promotes recurrence prevention. Can be administered with the formulation. Such therapeutic agents include, for example, Zyban® (buproprion) and Chantix® (Varenicline) as well as other antidepressants (docepin, imipramine, desipramine, clomipramine, nortriptyline, amitriptyline, protriptyline. , Trimipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, phenelzine, tranylcypromine, amoxapine, maprotiline, trazodone, venlafaxine, mirtazapine), anxiolytics (isovaleramide, buspirone, hydroxyzine, meprobamate), opioid antagonists ( Naltrexone, naloxone, nalmefene, 17- (cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxymorphinan-6-one, 4, -Epoxy-3,14-dihydroxy-17- (2-propenyl) morphinan-6-one) and nicotinic cholinergic receptor binding compounds (mecamylamine, hexamethonium, dihydro-beta) -Erythroidine, d-tubocurarine, penpidine, chlorisondamine, erysodine, trimethaphan cansylate, amantadine) can also be included without limitation.

  The above methods can be used in conjunction with an effective amount of one or more other compounds or therapeutic agents that have the ability to provide a beneficial binding effect, such as the ability to increase the effect of a compound of the invention, to a patient in need of treatment. Administering an effective amount of one of the carbamate compounds disclosed in the specification.

  Pharmaceutically acceptable salts and esters are salts and esters that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that can be formed when acidic protons present in the compound can react with inorganic or organic bases. Suitable inorganic salts include, for example, those formed with alkali metals such as sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include, for example, those formed with organic bases such as amine bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. Pharmaceutically acceptable salts also have amine moieties in the parent compound such as inorganic acids (eg, hydrochloric acid and hydrobromic acid) and organic acids (eg, acetic acid, citric acid, maleic acid, and methanesulfonic acid and benzenesulfone). Acid addition salts formed by reaction with acid-like alkane- and arene-sulfonic acids) can be included. Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonooxy groups present in the compound. Where two acidic groups are present, the pharmaceutically acceptable salt or ester is a mono-acid-mono-salt or ester or di-salt or ester; similarly, there are two or more acidic groups In some cases, some or all of such groups can be salified or esterified.

  The compounds named in the present invention can exist in a non-chlorinated or esterified form, or in a chlorinated and / or esterified form, and the name of such compound is the original compound (salt and ester). And all of its pharmaceutically acceptable salts and esters. The present invention includes pharmaceutically acceptable salt or ester forms of Formula I. There can be one or more crystalline forms of the enantiomer of formula I, which are also included in the present invention.

  The pharmaceutical composition of the present invention can optionally contain at least one other therapeutic or beneficial formulation in addition to the carbamate compound to promote smoking cessation or smoke reduction, or prevention of recurrence. For example, the carbamate compound of Formula I can be physically combined with other compounds in a fixed dose combination to simplify administration.

  Methods for formulating pharmaceutical compositions are described in Pharmaceutical Dosage Forms: Tablets. Published by Marcel Dekker, inc. Second edition. Revised and Expanded. Volumes 1-3 (edited by Lieberman et al.); Pharmaceutical Dosage Forms: Parental Medicines. Volumes 1-2 (edited by Avis et al.); And Pharmaceutical Dosage Forms: Disperse Systems. Volumes 1-2 (edited by Lieberman et al.); And these are incorporated herein by reference for all and all purposes.

  Such pharmaceutical compositions are generally sterile, substantially isotonic and are formulated in full compliance with the rules of the Good Manufacturing Practice (GMP) of the US Food and Drug Administration.

  The present invention provides a method of using a carbamate compound to provide a treatment to promote or prevent the relapse or prevention of tobacco / nicotine use in mammals. The amount of carbamate compound required to produce an effect is defined as an effective dose. The dosage schedule and the amount effective for its use, i.e., dosing or dosage regimen, depends on various factors including stage of disease, physical condition of patient, age, etc. . In calculating the dosage regimen for a patient, the mode of administration is also considered.

  Those skilled in the art can determine the pharmaceutically effective amount of a particular substituted carbamate compound for practicing the present invention without undue experimentation and with reference to that technique and this specification (eg, See Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, 1999, The Art, Science and Technology of Pharmaceutical Compounding; and Pickar, 1999, Dul. An effective amount is also one in which the therapeutically beneficial effect is greater than any toxic or adverse side effects of the active ingredient from a clinical point of view. In addition, each particular subject, particular dosage regimen, must be evaluated and adjusted over time according to individual requirements and the professional diagnosis of the person administering or supervising the compound.

  For therapeutic purposes, the compositions or compounds disclosed herein can be delivered in a single bolus delivery, continuous delivery over a long period, or a repeated administration protocol (eg, every hour , Daily or weekly repeated administration protocol). The pharmaceutical formulations of the invention can be administered, for example, once or more daily, three times a week, or once a week. In one embodiment of the invention, the pharmaceutical formulation of the invention is administered orally once or twice daily.

  In such a context, an effective amount of the biologically active agent can include repeated doses within a long-term treatment regime that yields clinically noticeable results. In such a context, the determination of an effective amount is generally based on animal model studies involving human clinical trials, and effective doses that significantly reduce the onset or severity of targeted signs or symptoms in the subject and Guided by determining the administration protocol. In this regard, suitable models include, for example, murines, rats, pigs, cats, non-human primates and other acceptable animal model subjects known in the art. Optionally, an effective amount can be determined using in vitro models (eg, immunological and histopathological assays).

  Using such a model, the appropriate concentration and dosage for administration of an effective amount of the biologically active agent (eg, an effective amount for oral administration, effective for intranasal administration to elicit the desired response) Routine calculations and adjustments are generally required to determine the effective amount for transdermal administration, the effective amount for intravenous administration, or the effective amount for intramuscular administration. However, the effective amount can vary depending on the particular compound used, the mode of administration, the strength of the preparation, the mode of administration and the level of nicotine dependence. In addition, dosage may need to be adjusted according to factors associated with the particular patient being treated, including patient age, weight, dietary habits and administration time.

  In an exemplary embodiment of the invention, the unit dosage form of the compound is manufactured according to a standard administration regimen. In this manner, the composition can be appropriately subdivided with a smaller dosage according to the physician's instructions. For example, a unit dose can consist of a packaged powder, vial or ampoule, preferably a capsule or tablet form.

  An effective amount of a carbamate compound of the invention can be, for example, from about 0.01 mg / kg / dose to about 150 mg / kg / dose at an oral or parenteral dose. For example, from about 0.1 mg / kg / dose to about 25 mg / kg / dose, for example from about 0.2 mg / kg / dose to about 18 mg / kg / dose, for example from about 0.5 mg / kg / dose to about 10 mg / dose It can be administered in kg / dose. Thus, a therapeutically effective amount of the active ingredient is, for example, from about 1 mg / day to about 7000 mg / day, such as from about 10 mg / day to about 2000 mg / day, such as about 50 mg / day, for a subject with an average body weight of 70 kg. To about 600 mg / day, for example, about 10, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 525, 550, 575 or 600 mg / day or more or within that range. In one embodiment, the compound of formula (I) is administered at a dosage of about 10 mg to about 1000 mg without any excipients in capsule form.

  The methods of the invention also provide kits that can be used to promote interruption or reduction of tobacco / nicotine use or prevention of recurrence. A pharmaceutical composition comprising one or more other compounds that are beneficial and can be added and one or more carbamates of the present invention is formulated in a suitable carrier and then placed in a suitable container to stop tobacco / nicotine use. Or it can be labeled to promote reduction or prevention of recurrence. In addition, other medications, including at least one other therapeutic agent or beneficial formulation, can be placed in the container and labeled with the indicated disease treatment label. Such labeling can include, for example, instructions relating to the amount, frequency and method of administration of each drug.

  All publications, patent applications, patents and other references cited herein are for teaching purposes related to the sentence and / or paragraph in which the reference is described, and other Incorporated as a whole for reference purposes.

Claims (20)

An effective amount for the manufacture of a medicament for promoting cessation or reduction in a subject who is not nicotine addicted to smoking and / or chewing tobacco or nicotine-containing products and is not dependent on nicotine Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

(In the above formula, R is selected from the group consisting of alkyl having 1 to 8 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy having 1 to 3 carbon atoms. ;
x is an integer from 0 to 3, and when x is 2 or 3, R is the same or different;
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl having 3 to 7 carbon atoms; or R ₁ and R ₂ are They can be joined together to form a 5-7 membered heterocyclic ring which is substituted or unsubstituted with one or more alkyl or aryl groups, said heterocyclic ring having 1 to 2 nitrogen atoms and 0 to 1 oxygen atom can be included, in which case the nitrogen atoms are not directly linked to each other or to oxygen atoms) An effective amount of a chemical formula for the manufacture of a medicament for preventing recurrence in a subject who is not nicotine addicted to smoking and / or chewing tobacco or nicotine-containing products and is not dependent on nicotine ( Use of a compound of I) or a pharmaceutically acceptable salt thereof.

(In the above formula, R is selected from the group consisting of alkyl having 1 to 8 carbon atoms, halogen, alkoxy having 1 to 3 carbon atoms, nitro, hydroxy, trifluoromethyl, and thioalkoxy having 1 to 3 carbon atoms. ;
x is an integer from 0 to 3, and when x is 2 or 3, R is the same or different;
R ₁ and R ₂ are independently selected from the group consisting of hydrogen, alkyl having 1 to 8 carbon atoms, aryl, arylalkyl, cycloalkyl having 3 to 7 carbon atoms; or R ₁ and R ₂ are They can be joined together to form a 5-7 membered heterocyclic ring which is substituted or unsubstituted with one or more alkyl or aryl groups, said heterocyclic ring having 1 to 2 nitrogen atoms and 0 to 1 oxygen atom can be included, in which case the nitrogen atoms are not directly linked to each other or to oxygen atoms)   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein x = 0. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ₁ and R ₂ are hydrogen and x = 0.   The compound of formula (I) is an enantiomer substantially free of other enantiomers or a mixture of enantiomers in which one of the compounds of formula (I) is predominant. Use of a compound of formula (I) according to one or a pharmaceutically acceptable salt thereof.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein the enantiomer of formula (I) predominates to a degree of about 90% or more.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein the enantiomer of formula (I) predominates to a degree of about 98% or more. 6. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 5, wherein the enantiomer of formula (I) is an enantiomer of formula (1a).

  Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein the enantiomer of formula (Ia) is an (R) or (D) enantiomer.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 8, wherein the enantiomer of formula (Ia) is an (S) or (L) enantiomer.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 10, wherein the enantiomer of formula (Ia) predominates to a degree of about 90% or more. .   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 10, wherein the enantiomer of formula (Ia) predominates to a degree of about 98% or more. . The enantiomer of formula (I), which is substantially free of other enantiomers, is a compound of formula (Ib) or an enantiomeric mixture predominately of the compound of formula (Ib) or a pharmaceutically acceptable salt thereof. Use of a compound of formula (I) according to claim 5 or a pharmaceutically acceptable salt thereof.

  14. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein the compound of formula (Ib) predominates to a degree of about 90% or more.   14. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein the compound of formula (Ib) predominates to a degree of about 98% or more.   16. An effective amount of the compound of formula (I) is about 0.01 mg / kg / dose to about 150 mg / kg / dose, or the compound of formula (I) or pharmacy according to any one of claims 1 to 15 Use of its salts that are acceptable.   16. An effective amount of the compound of formula (I) is about 1 mg / kg / dose to about 7000 mg / kg / dose, or a compound of formula (I) according to any one of claims 1 to 15, or pharmaceutically Acceptable use of its salts.   Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein the medicament comprising a compound of formula (I) is prepared for oral administration.   19. The medicament comprising the compound of formula (I) is manufactured in the form of a capsule or tablet, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-18. use.   20. The medicament comprising a compound of formula (I) is manufactured in the form of a capsule without any excipient and comprising from about 10 mg to about 1000 mg of a compound of formula (I). Or a pharmaceutically acceptable salt thereof.