JP2002535273A - How to support smoking cessation - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method for assisting smoking cessation by administering to a patient who wants to quit smoking, an effective amount of a compound, particularly phenylcyclobutylbutylamine, to assist the patient in overcoming the craving for tobacco after smoking cessation. The method also relates to preventing weight gain in a smoking cessation patient, optionally using a nicotine patch or another smoking cessation aid or smoking cessation assistance program.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a smoking cessation support method. More specifically, methods are available to help patients who want to quit, to help them overcome their craving after smoking.
It relates to treatment in which an effective amount of the compound is administered, in particular phenylcyclobutylbutylamine. The method also relates to preventing weight gain in a smoking cessation patient.

BACKGROUND OF THE INVENTION Getting out of the habit of using nicotine is extremely difficult for many smokers, and many smokers who use strict smoking cessation programs are more likely to return to smoking within a year. Extremely intense nicotine withdrawal symptoms, such as increased anxiety and hostility and depression, occur between 48 and 72 hours after quitting smoking, but in the long run the former smoker gains weight Fears or desires to resume smoking.

[0003] While smoking is a health hazard, it would be beneficial to provide an effective smoking cessation method because it is difficult for a very large number of smokers to completely abandon their smoking habits.

SUMMARY OF THE INVENTION [0004] The present invention relates to compositions containing substances that selectively enhance noradrenaline action. It also relates to methods of administering such compositions to take advantage of the effects of noradrenergic agents on various types of appetite.

[0005] Substances such as those described above are effective against nicotine craving after smoking cessation, and also have a positive effect on other withdrawal symptoms of smoking cessation, such as increased appetite and other nervous system activities associated with nicotine withdrawal. It has the advantage of having an effect. The invention more particularly relates to the use of sibutramine to achieve these objectives.

[0006] In one embodiment of the present invention, individuals who are trying to quit smoking are ameliorated or prevent emotional disorders and / or suppress weight gain that is frequently seen in individuals who are trying to quit smoking. And sufficient amounts of sibutramine to reduce smoking habits.

[0007] In another embodiment, sibutramine is administered in combination with the patient's participation in a behavior modification program.

In yet another embodiment, sibutramine is administered in combination with the use of a nicotine patch and the patient's participation in a behavior modification program.

[0009] Administration of noradrenergic compounds according to the methods of the present invention strongly assists humans who have developed withdrawal symptoms and increased appetite with smoking cessation. This is because the compounds act to reduce or prevent such undesirable symptoms.

Although the biochemistry of nicotine addiction and tobacco withdrawal is not fully understood,
The basic theory of treatment has been established. Withdrawal symptoms caused by withdrawal or addiction are accompanied by a sharp increase in sympathetic outflow from the brainstem. In particular, noradrenergic neurons in the locus, which contains half of the noradrenergic neurons in the mammalian brain, show a marked increase in the rate of inflammation during withdrawal (Amaral
and Sinnamon, 1978).

DETAILED DESCRIPTION The treatment of tobacco withdrawal symptoms is provided by the methods described below and in a modified manner with the addition of any possible steps.

More particularly, the present invention provides a therapeutically effective amount of a formula I comprising an enantiomer:

[0013]

Embedded image Wherein R ₁ and R ₂ independently represent H or methyl, and a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier, for administration to a human in need of treatment And how to support smoking cessation.

Preferred compounds of formula I are N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine or a pharmaceutically acceptable salt thereof, such as hydrochloride or hydrobromic acid Salts and other salts known in the art.

A particularly preferred form of this compound is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methyl-butylamine hydrochloride monohydrate (Sibutramine hydrochloride), The substance is described in EP 230742.

When a compound of formula I has a single chiral center, it may exist in two enantiomeric forms. It includes the use of the individual enantiomers and enantiomeric mixtures of the present invention. Enantiomers can be resolved by methods known to those skilled in the art. For example, a diastereoisomer salt or complex may be formed and resolved by, for example, crystallization, or a diastereoisomer derivative may be formed and separated by, for example, crystallization, gas-liquid chromatography. Or a selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or enzymatic reduction,
The modified and unmodified enantiomers may then be separated, or they may be separated in chiral environments, for example on chiral supports such as silica with attached chiral ligands or in the presence of chiral solvents. -Liquid chromatography or liquid chromatography may be performed. It will be appreciated that when converting the desired enantiomer to another chemical entity by any of the above resolution procedures, an additional step is required to liberate the desired enantiomeric form. Alternatively, a particular enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation. Good.

Preferred compounds of the formula I are N , N -dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine, N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine, and
1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, including racemates, individual enantiomers and mixtures thereof, and pharmaceutically acceptable salts thereof.

The compound of formula I can be administered in any of the known pharmaceutical dosage forms. The amount of compound to be administered will depend on several factors, such as the age of the patient, the severity of the disease, and the patient's past medical history, and may be considered to be always at the discretion of the attending physician. Typically, the dose of compound to be administered is 0.1-50 mg, preferably 1 to 50 mg per day.
It is believed to be in the range of -30 mg, and this dose is administered in single or divided doses.

The oral dosage form is a composition form preferably used in the present invention. These are known pharmaceutical forms, for example, dosage forms such as tablets, capsules, granules, syrups and aqueous or oily suspensions. The excipients used in preparing these compositions are those known in the pharmaceutical art. Tablets contain the active compound together with fillers such as calcium phosphate, disintegrants such as corn starch, lubricants such as magnesium stearate, binders such as microcrystalline cellulose or polyvinylpyrrolidone, and mixtures thereof. Can be prepared from a mixture with another optional ingredient known in the art that can be tableted by the method described above. If desired, tablets may be coated using known methods and excipients, which may include an enteric coating such as hydroxypropylmethylcellulose phthalate.

Tablets may be formulated in a manner known to those skilled in the art to form a depot preparation of the compound of the present invention. If desired, such tablets may be provided with an enteric coating, according to known methods, for example using cellulose acetate phthalate. Similarly, capsules such as hard or soft gelatin capsules containing the active compound, with or without excipients, can be prepared in a known manner and, if desired, enteric-coated by known methods. May be provided. The contents of the capsule can be formulated in a known manner to provide a sustained release formulation of the active compound. Tablets and capsules are conveniently formed so that one tablet or capsule contains 1-50 mg of the active compound.

Other dosage forms suitable for oral administration include, for example, aqueous suspensions of the active compounds in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl cellulose, and peanut oil. Oily suspensions containing a compound of the present invention in a suitable vegetable oil such as The active compounds can be formulated in granular form with or without additional excipients. The patient may take the granules directly orally, or after adding a suitable liquid carrier (eg, water). The granules may contain a disintegrant such as a combined boiling agent formed from an acid and a carbonate or bicarbonate to facilitate dispersion in the liquid medium.

The therapeutically active compound of Formula I may be formulated as a composition in which the patient maintains the active compound in the oral cavity through the oral mucosa.

Suitable dosage forms for rectal administration are those known in the art for such administration, for example,
It is a suppository based on cocoa butter or polyethylene glycol.

Suitable dosage forms for parenteral administration are pharmaceutical forms known for such administration, such as a sterile suspension or solution in a suitable solvent.

Suitable dosage forms for topical administration include a matrix in which the pharmacologically active compound of the present invention is dispersed, the compound being in contact with the skin in such a manner as to be administered transdermally. Will be retained. Suitable transdermal compositions include a pharmaceutically active compound, a topical vehicle such as mineral oil petrolatum and / or a wax such as paraffin wax or beeswax, and
It may be prepared by mixing with a potential transdermal enhancer, such as dimethyl sulfoxide or propylene glycol. Alternatively, a pharmaceutically acceptable cream,
The active compound may be dispersed in a gel or ointment base. The amount of active compound contained in the topical formulation must be such that a therapeutically effective amount of the compound is delivered during the time the topical formulation is to be maintained on the skin.

The therapeutically active compound of formula I may be formulated in a composition to be dispersed in the oral or nasal cavity of a patient in the form of an aerosol. Such aerosols may be applied from a pump pack or a pressurized pack containing a volatile propellant.

The therapeutically active compounds of formula I used in the method of the invention may also be administered by continuous infusion from an external source, for example intravenous infusion, or are administered from a compound source implanted in the body. You may. Internal sources include implantable reservoirs or implants which contain the compound to be injected and which release the compound continuously, for example by osmotic pressure. The implant may be a liquid, such as (a) an oily suspension of the compound to be injected, wherein the compound to be injected is in the form of a poorly water soluble derivative such as a dodecanoate salt or a lipophilic ester; Alternatively, the implant may be (b) a solid body in the form of a support of the compound to be embedded, for example a support made of synthetic resin or wax material, or a group of bodies each containing a partial amount of the compound to be delivered. Solids in the form of The amount of active compound present in the internal source must be such that a therapeutically effective amount of the compound is delivered over an extended period of time.

In some formulations, it may be advantageous to use the compounds of the invention in the form of very small particles, such as those obtained by fluid energy grinding.

When practicing the method of the present invention, it is advisable to give the patient who is trying to quit smoking an additional behavior modification program. There are many behavior modification programs known to those skilled in the art.
Programs include self-help programs, programs educated by others, and programs that combine both.

It should be understood that the following examples are merely representative of the present invention and do not limit the scope of the invention in any way.

Example 1 The present invention will be used by patients who have decided to quit smoking in the hope of quitting.
Oral administration of 15 mg of sibutramine once a day (or 10 mg per day) is started in the morning one week before the scheduled day of smoking cessation. This dose of sibutramine is continued daily until 6 months after the scheduled date of smoking cessation. Give behavior modification program in combination with sibutramine. The program may consist of an individual counseling plan and a group counseling plan. Patients will meet with the attending physician two weeks prior to the scheduled abstinence, one month after the scheduled abstinence, three months after the scheduled abstinence, six months after the scheduled abstinence, and nine months after the scheduled abstinence.

Example 2 The present invention will be used by patients who have decided to quit smoking in the hope of quitting.
Oral administration of 15 mg of sibutramine once daily (or 10 mg per day) is started in the morning two weeks before the scheduled day of smoking cessation. This dose of sibutramine is continued daily until 6 months after the scheduled date of smoking cessation. Give behavior modification program in combination with sibutramine. The program may consist of an individual counseling plan and a group counseling plan. Apply a nicotine patch on the day of the scheduled smoking cessation and maintain for 2 months. Two weeks before the scheduled date of smoking cessation, one month after the scheduled date of smoking cessation,
Interview with the attending physician three months after the scheduled date of smoking cessation, six months after the scheduled date of smoking cessation, and nine months after the scheduled date of smoking cessation.

Example 3 The present invention was used for a patient who decided to stop smoking in hope of stopping smoking. From the morning two weeks before the scheduled date of smoking cessation, 15 mg of sibutramine once a day (or 10m / day)
Oral administration of g) was started. Administration of this dose of sibutramine was continued daily for up to 4 weeks on the scheduled day of smoking cessation. A behavior modification program was given in combination with sibutramine. The program will include a self-help pamphlet on the program's first cessation plan and a five- to ten-minute lifestyle modification plan designed to support efforts to refrain from smoking whenever meeting or talking to others. Each patient consisted of giving. This clinical intervention based on the ACHPR guidelines provides advice on success / continuation of smoking cessation (eg, alcohol abatement, other smokers in the home), adverse effects of smoking (eg, family, social, health effects, And explanations on previous smoking cessation experiences), points out the dangers of smoking (acute, long-term, spouse and child dangers), explains that low tar tobacco does not eliminate these risks, and explains the rewards arising from smoking cessation Included.

The following data was obtained:

[0035]

[Table 1]

Example 4 The present invention was used for patients who decided to stop smoking in hope of stopping smoking. From the morning two weeks before the scheduled date of smoking cessation, 15 mg of sibutramine once daily (or 10 mg per day)
mg) was started. Administration of this dose of sibutramine was continued daily for up to 4 weeks on the scheduled day of smoking cessation. A behavior modification program was given in combination with sibutramine.
The program will include a self-help pamphlet on the program's first cessation plan and a five- to ten-minute lifestyle modification plan designed to support efforts to refrain from smoking whenever meeting or talking to others. Each patient consisted of giving. This clinical intervention based on the ACHPR guidelines provides advice on success / continuation of smoking cessation (eg, alcohol abatement, other smokers in the home),
Explanation of adverse effects of smoking (eg, effects on family, society, health, and previous experience of quitting smoking), indications about smoking risks (acute, long-term, risks to spouses and children), and low tar tobacco And a description of the rewards for smoking cessation.

A nicotine patch was applied on the day of the scheduled smoking cessation and maintained for one month. The patient interviewed the attending physician two weeks before the scheduled date of smoking cessation and one month after the scheduled date of smoking cessation. The following data was obtained:

[0038]

[Table 2]

The invention has been described with reference to various specific embodiments. Nevertheless, it will be understood that many variations and modifications may be made without departing from the scope and spirit of the invention.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN , CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LR, LS, LT, LU, LV, MD, MK, MX, NO, NZ, PL, PT, RO, RU, SE, SG, SI, SK, TJ, TM, TR, UA, UZ, Y (72) inventor Rotherham, Neil UK, Notsuteingamu F-term (reference) 4C206 AA01 AA02 FA08 KA17 MA01 MA04 MA33 MA37 MA43 MA51 MA57 MA61 MA72 MA77 MA79 MA80 MA86 MA87 NA14 ZA02 ZC54

Claims (28)

[Claims] 1. A therapeutically effective amount of Formula I: Wherein R ₁ and R ₂ independently represent H or methyl; or a pharmaceutically acceptable salt and hydrate thereof. 2. The method according to claim 1, wherein the compound of formula I comprises N, N -dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. . 3. The method of claim 1, wherein the compound of formula I is N, N -dimethyl-1-form in the form of a monohydrate.
The method according to claim 1, which is [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. 4. The method of claim 1, wherein the administration of the compound of Formula I is performed in combination with the patient's participation in a behavior modification program for smoking cessation. 5. The method of claim 1, wherein the administration of the compound of formula I is performed in combination with the patient's participation in a behavior modification program for smoking cessation and in combination with the application of nicotine replacement therapy. 6. The compound according to claim 1, wherein the compound of formula I is (+)- N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine. 5. The method according to 3 or 4. 7. The compound according to claim 1, wherein the compound of formula I is (-)- N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine. 5. The method according to 3 or 4. 8. The compound of claim 1, wherein the compound of formula I is (+)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.
The method according to 3 or 4. 9. The compound according to claim 1, wherein the compound of formula I is (-)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.
The method according to 3 or 4. Compounds according to claim 10 of formula I is, (+) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - claims, characterized in that the dimethylamine Item 5. The method according to item 1, 3 or 4. Compound of claim 11 of formula I is, (-) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - claims, characterized in that the dimethylamine Item 5. The method according to item 1, 3 or 4. Compounds according to claim 12 of formula I is, (±) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - claim 1, characterized in that the methyl amine 5. The method according to 3 or 4. 13. The compound according to claim 1, wherein the compound of formula I is (±) -1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.
5. The method according to 3 or 4. Compound of claim 14 of formula I is, (±) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - claims, characterized in that the dimethylamine Item 5. The method according to item 1, 3 or 4. 15. A therapeutically effective amount of Formula I: A method of inhibiting weight gain in a patient running a smoking cessation program, comprising administering a compound of formula: wherein R ₁ and R ₂ independently represent H or methyl, or a pharmaceutically acceptable salt thereof. 16. The method according to claim 15, wherein the compound of formula I comprises N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride. . 17. A compound of formula I wherein N, N -dimethyl-1 in the monohydrate form
16. The method according to claim 15, wherein it is-[1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine. 18. The method according to claim 15, wherein the administration of the compound of the formula I is carried out in combination with the patient's participation in a behavior modification program for smoking cessation. 19. The method of claim 15, wherein the administration of the compound of Formula I is performed in combination with the patient's participation in a behavior modification program for smoking cessation and in combination with the application of nicotine replacement therapy. 20. The compound according to claim 15, wherein the compound of formula I is (+)- N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine. , 18 or 19. 21. The compound according to claim 15, wherein the compound of formula I is (-)- N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N -methylamine. , 18 or 19. 22. The method according to claim 1, wherein the compound of formula I is (+)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.
The method according to 5, 18 or 19. 23. The method according to claim 1, wherein the compound of formula I is (-)-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.
The method according to 5, 18 or 19. Compound of claim 24 of formula I is, (+) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - claims, characterized in that the dimethylamine Item 19. The method according to Item 15, 18, or 19. Compound of claim 25 of formula I is, (-) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - claims, characterized in that the dimethylamine Item 19. The method according to Item 15, 18, or 19. Compound of claim 26 of formula I is, (±) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - claim 15, characterized in that methylamine , 18 or 19. 27. The compound according to claim 1, wherein the compound of formula I is (±) -1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.
The method according to 5, 18 or 19. Compound of claim 28 of formula I is, (±) - N - { 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} - N - N - claims, characterized in that the dimethylamine Item 19. The method according to Item 15, 18, or 19.