METHOD TO AID SMOKING CESSATION

PROCEDE PERMETTANT D'AIDER A LA DESACCOUTUMANCE AU TABAC

English Abstract

This invention relates to a method to aid smoking cessation by treating a
patient who wishes to stop smoking with an effective amount of a compound, in
particular a phenylcyclobutylbutylamine, in order to aid the patient in
overcoming the craving following smoking cessation. The method relates to
preventing weight gain in a patient who ceases to smoke and optionally is
using a nicotine patch or other agent or program to aid in ceasing to smoke.

French Abstract

L'invention concerne un procédé permettant d'aider à la désaccoutumance au tabac consistant à traiter un patient souhaitant arrêter de fumer avec une quantité efficace d'un composé, notamment une phénylcyclobutylbutylamine, de manière à assister le patient à surmonter son état de manque lié à la désaccoutumance au tabac. Ce procédé consiste à éviter que le patient arrêtant de fumer ne prenne du poids et à utiliser éventuellement un timbre à la nicotine, un autre agent ou un programme d'assistance à la désaccoutumance au tabac.

Claims

CLAIMS
1. A method of causing smoking cessation which comprises administering a
therapeutically effective amount of a compound of formula I
<IMG>
or pharmaceutically acceptable salts and hydrates thereof, in which R, and
R2 are independently H or methyl.
2. The method as claimed in claim 1 wherein the compound of formula I
comprises N,N-dimethyl-1[1-(4-chlorophenyl)cyclobutyl]-3-
methybutylamine hydrochloride.
3. The method as claimed in claim 1 wherein the compound of formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methybutylamine in
the form of its monohydrate.
15

4. The method as recited in claim 1 wherein the compound of formula I is
administered in conjunction with the patient participating in a behavior
modification program related to smoking cessation.
5. The method of claim 4 wherein the compound of formula I is administered
in conjunction with the patient participating in a behavior modification
program related to smoking cessation and in conjunction with the
administration of nicotine replacement therapy.
6. A method as claimed in claim 1, 3 or 4 wherein the compound of formula
1 is (+)N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-
methylamine.
7. A method as claimed in claim 1, 3 or 4 wherein the compound of formula
1 is (-)-N-{1-[1-(4-chlorophenyl)cyclobutyl-3-methylbutyl}-N-
methylamine.
8. A method as claimed in claim 1, 3 or 4 wherein the compound of formula
1 is (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
9. A method as claimed in claim 1, 3 or 4 wherein the compound of formula
1 is (-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
16

10 A method as claimed in claim 1, 3 or 4 wherein the compound of formula
1 is (+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-
dimethylamine.
11. The method as claimed in claim 1, 3 or 4 wherein the compound of
formula I is (-)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-
dimethylamine.
12. The method as claimed in claim 1, 3 or 4 wherein the compound of
formula I is (~)-N-{1-[1-(4-chlorophenyl)cyclobutyl-3-methylbutyl}-N-
methylamine.
13. The method as claimed in claim l, 3 or 4 wherein the compound of
formula I is (~)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
14. The method as claimed in claim 1, 3 or 4 wherein the compound of
formula I is (~)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-
N-dimethylamine.
15. A method of controlling weight gain in a patient who is undergoing a
program for smoking cessation which comprises administering a
therapeutically effective amount of a compound of formula I
<IMG>
17

or pharmaceutically acceptable salts thereof, in which R1 and R2 are
independently H or methyl.
16. The method as claimed in claim 15 wherein the compound of formula I
comprises N,N-dimethyl-1 [1 -(4-chlorophenyl)cyclobutyl]-3-
methybutylamine hydrochloride.
17. The method as claimed in claim 15 wherein the compound of formula I is
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methybutylamine in
the form of its monohydrate.
18. The method as recited in claim 15 wherein the compound of formula I is
administered in conjunction with the patient participating in a behavior
modification program related to smoking cessation.
19. The method of claim 15 wherein the compound of formula I is
administered in conjunction with the patient participating in a behavior
modification program related to smoking cessation and in conjunction
with the administration of nicotine replacement therapy.
18

20. A method as claimed in claim 15, 18 or 19 wherein the compound of
formula 1 is (+)N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-
methylamine.
21. A method as claimed in claim 15, 18 or 19 wherein the compound of
formula 1 is (-)-N-{1-[1-(4-chlorophenyl)cyclobutyl-3-methylbutyl}-N-
methylamine.
22. A method as claimed in claim 15, 18 or 19 wherein the compound of
formula 1 is (+)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
23. A method as claimed in claim 15, 18 or 19 wherein the compound of
formula 1 is (-)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine.
24. A method as claimed in claim 15, 18 or 19 wherein the compound of
formula 1 is (+)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-
N-dimethylamine.
25. The method as claimed in claim 15, 18 or 19 wherein the compound of
formula I is (-)-N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N-N-
dimethylamine.
26. The method as claimed in claim 15, 18 or 19 wherein the compound of
formula I is (~)-N-{1-[1-(4-chlorophenyl)cyclobutyl-3-methylbutyl}-N-
methylamine.
19

27. The method as claimed in claim 15, 18 or 19 wherein the compound of
formula I is (~)-1-[1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamine.
28. The method as claimed in claim 15, 18 or 19 wherein the compound of
formula I is (~)-N-{1-[1-(4-chlorophenyl)cyclobutyl)-3-methylbutyl}-N-
N-dimethylamine.
20

Description

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METHOD TO AID SMOKING CESSATION
This invention relates to a method to aid smoking cessation. More
particularly the method relates to treating a patient who wishes to stop
smoking
with an effective amount of a compound, in particular a
phenylcyclobutylbutylamine, in order to aid the patient in overcoming the
craving
following smoking cessation. In addition, the method relates to preventing
weight
gain in a patient who ceases to smoke.
to
BACKGROUND OF THE INVENTION
Discontinuing the use of nicotine is extremely difficult for many smokers
and many who seek help to cease smoking in formal programs return to smoking
15 within a year. Although nicotine withdrawal causes symptoms that are most
intense 48 - 72 hours after smoking is discontinued, such as increased
anxiety,
hostility and depression, in the long term the ex-smoker is at risk for weight
gain
and a craving to return to smoking.
Because of the adverse effects of smoking on health and the difficulty
2o so many smokers have in giving up the habit of smoking entirely, it would
be
advantageous to have an effective method for smoking cessation.

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SUMMARY OF THE INVENTION
The present invention relates to compositions containing agents which
selectively enhance noradrenergic effects and to a method of administering
such
compositions in order to take advantage of a noradrenergic agent's effect on
appetites of various types.
In addition to an effect on nicotine craving following smoking cessation, it
is advantageous for the agent to have a positive effect on other symptoms of
1 o smoking cessation such as an increased appetite and other nervous system
activities associated with nicotine withdrawal. The present invention more
particularly relates to the use of sibutramine to accomplish these objectives.
In one embodiment of this invention sibutramine is administered to
individuals who are attempting to quit smoking in a quantity sufficient to
1 s ameliorate or prevent the mood disturbances and/or to suppress the weight
gain
frequently evident in individuals trying to give up smoking, as well as to
reduce
recidivism.
In another embodiment sibutramine is administered in conjunction with
the patient's participation in a behavior modification program.
2o In yet another embodiment, administration of sibutramine is carried out in
conjunction with the use of a nicotine patch and the patient's participation
in a
behavior modification program.

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Administration of a noradrenergic compound according to the method of
the present invention can be of great benefit to persons who experience
withdrawal symptoms and increased appetite associated with giving up smoking
because the compounds act to alleviate or prevent such adverse symptoms.
While the biochemistry of nicotine habituation and of cigarette withdrawal
is not completely understood, a theoretical basis for treatment has been
established. The abstinence syndrome produced by withdrawal or addictive
substances is associated with an abrupt increase in sympathetic outflow from
the
brain stem. In particular, noradrenergic neurones in the locus coeruleus
(containing half the noradrenergic neurons in the mammalian brain) show a
marked increase in firing rate during withdrawal (Amaral and Sinnamon, 1978).
DETAILED DESCRIPTION OF THE INVENTION
The treatment of smoking withdrawal symptoms is provided by the
method described below, and variations made possible through the optional
steps.
More particularly, the present invention relates to a method of aiding
smoking cessation by administration of a therapeutically effective amount of a
2o compound of formula I
CH3
H3C~HCHZCHNR~R2
CI

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including enantiomers and pharmaceutically acceptable salts thereof, in which
R,
and RZ are independently H or methyl, is administered in conjunction with a
pharmaceutically acceptable diluent or carrier to a human in need thereof.
A preferred compound of formula I is N,N-dimethyl-1-[1 -(4-
chlorophenyl)cyclobutyl]-3-methylbutylamine or a pharmaceutically acceptable
salt thereof, for example, the hydrochloride or hydrobromide salt and other
salts
as are known in the art.
A particularly preferred form of this compound is N,N-dimethyl-1-[1-(4-
to chlorophenyl)cyclobutyl]-3-methyl-butylamine hydrochloride monohydrate
(sibutramine hydrochloride) which is described in European Patent Number
23 0742.
When a compound of formula I contains a single chiral center it may exist
in two enantiomeric forms. The present invention includes the use of the
15 individual enantiomers and mixtures of the enantiomers. The enantiomers may
be
resolved by methods known to those skilled in the art, for example by
formation
of diastereoisomeric salts or complexes which may be separated, for example,
by
crystallisation; via formation of diastereoisomeric derivatives which may be
separated, for example, by crystallisation, gas-liquid chromatography;
selective
2o reaction of one enantiomer with an enantiomer-specific reagent, for example
enzymatic oxidation or reduction, followed by separation of the modified and

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unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral
environment, for example on a chiral support, for example silica with a bound
chiral ligand or in the presence of a chiral solvent. It will be appreciated
that
where the desired enantiomer is converted into another chemical entity by one
of
the separation procedures described above, a further step is required to
liberate the
desired enantiomeric form. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active reagents,
substrates,
catalysts or solvents, or by converting one enantiomer to the other by
asymmetric
transformation.
l0 Preferred compounds of 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 may be administered in any of the known
pharmaceutical dosage forms. The amount of the compound to be administered
will depend on a number of factors including the age of the patient, the
severity of
the condition and the past medical history of the patient and always lies
within the
sound discretion of the administering physician but it is generally envisaged
that

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the dosage of the compound to be administered will be in the range 0. 1 to 50
mg,
preferably 1 to 30 mg per day given in one or more doses.
Oral dosage forms are the preferred compositions for use in the present
invention
and these are the known pharmaceutical forms or such administration, for
example
tablets, capsules, granules, syrups and aqueous or oil suspensions. The
excipients used in
the preparation of these compositions are the excipients known in the
pharmacist's art.
Tablets may be prepared from a mixture of the active compound with fillers,
for example
calcium phosphate; disintegrating agents, for example maize starch;
lubricating agents,
for example magnesium stearate; binders, for example microcrystalline
cellulose or
polyvinylpyrrolidone and other optional ingredients known in the art to permit
tableting
the mixture by known methods. The tablets may, if desired, be coated using
known
methods and excipients which may include enteric coating using for example
hydroxypropylmethylcellulose phthalate.
The tablets may be formulated in a manner known to those skilled in the
art so as to give a sustained release of the compounds of the present
invention.
Such tablets may, if desired, be provided with enteric coatings by known
methods,
for example by the use of cellulose acetate phthalate. Similarly, capsules,
for
example hard or soft gelatin capsules, containing the active compound with or
without added excipients, may be prepared by known methods and, if desired,
2o provided with enteric coatings in a known manner. The contents of the
capsule
may be formulated using known methods so as to give sustained release of the

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active compound. The tablets and capsules may conveniently each contain 1 to
50
mg of the active compound.
Other dosage forms for oral administration include, for example, aqueous
suspensions containing the active compound in an aqueous medium in the
presence of a non-toxic suspending agent such as sodium carboxy-
methycellulose,
and oily suspensions containing a compound of the present invention in a
suitable
vegetable oil, 5 for example arachis oil. The active compound may be
formulated
into granules with or without additional excipients. The granules may be
ingested
directly by the patient or they may be added to a suitable liquid carrier (for
1 o example, water) before ingestion. The granules may contain disintegrants,
eg an
effervescent couple formed from an acid and a carbonate or bicarbonate salt to
facilitate dispersion in the liquid medium.
The therapeutically active compounds of formula I may be formulated into
a composition which the patient retains in his mouth so that the active
compound
15 is administered through the mucosa of the mouth.
Dosage forms suitable for rectal administration are the known
pharmaceutical forms for such administration, for example, suppositories with
cocoa butter or polyethylene glycol bases.
Dosage forms suitable for parenteral administration are the known
2o pharmaceutical forms for such administration, for example sterile
suspensions or
sterile solutions in a suitable solvent.

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Dosage forms for topical administration may comprise a matrix in which
the pharmacologically active compounds of the present invention are dispersed
so
that the compounds are held in contact with the skin in order to administer
the
compounds transdermally. A suitable transdermal composition may be prepared
by mixing the pharmaceutically active compound with a topical vehicle, such as
a
mineral oil petrolatum and/or a wax, e.g. paraffin wax or beeswax, together
with a
potential transdermal accelerant such as dimethyl sulphoxide or propylene
glycol.
Alternatively the active compounds may be dispersed in a pharmaceutically
acceptable cream, gel or ointment base. The amount of active compound
l0 contained in a topical formulation should be such that a therapeutically
effective
amount of the compound is delivered during the period of time for which the
topical formulation is intended to be on the skin.
The therapeutically active compound of formula I may be formulated into
a composition which is dispersed as an aerosol into the patients oral or nasal
15 cavity. Such aerosols may be administered from a pump pack or from a
pressurized pack containing a volatile propellant.
The therapeutically active compounds of formula I used in the method of
the present invention may also be administered by continuous infusion either
from
an external source, for example by intravenous infusion or from a source of
the
2o compound placed with the body. Internal sources include implanted
reservoirs
containing the compound to be infused which is continuously released for

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example by osmosis and implants which may be (a) liquid such as an oily
suspension of the compound to be infused for example in the form of a very
sparingly water-soluble derivative such a dodecanoate salt or a lipophillic
ester or
(b) solid in the form of an implanted support, for example of a synthetic
resin or
waxy material, for the compound or a series of several bodies each containing
part
of the compound to be delivered. The amount of active compound present in an
internal source should be such that a therapeutically effective amount of the
compound is delivered over a long period of time.
In some formulations it may be beneficial to use the compounds of the
1 o present invention in the form of particles of very small size, for example
as
obtained by fluid energy milling.
In carrying out the method of the invention a behavior modification
program may also be offered to the patient who is attempting to quit smoking.
There are many behavior modification programs known to one skilled in the art.
15 The programs include self help programs and programs that are taught by
others
as well as programs that combine both methods.
The following examples are illustrative only and are not meant to limit the
invention m any manner.
9

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EXAMPLE 1
The invention will be used by patients who desire to quit smoking and
who have decided upon a quit date. Sibutramine 15 mg orally once daily (or 1 0
mg daily) in the morning will be initiated one week before the planned quit
date.
Sibutramine will be continued at this daily dose until six months after the
planned
quit date. A behavior modification program will be offered in conjunction with
sibutramine. This program may consist of individual counseling sessions or
group counseling sessions. Patients will be seen by the treating physician two
1 o weeks before the planned quit date, one month after the planned quit date,
three
months after the planned quit date, six months after the planned quite date,
and
nine months after the planned quit date.
EXAMPLE 2
The invention will be used by patients who desire to quit smoking and
who have decided upon a quit date. Sibutramine 15 mg orally once daily (or 10
mg daily) in the morning will be given for the two weeks before the planned
quite date. Sibutramine will be continued at this daily dose until six months
after
2o the planned quit date. A behavior modification program will be offered in
conjunction with sibutramine. This program may consist of individual
counseling
to

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sessions or group counseling sessions. Beginning on the planned quit date, a
nicotine patch will also be applied for two months. Patients will be seen by
the
treating physician two weeks before the planned quit date, one month after the
planned quit date, three months after the planned quit date, six months after
the
planned quite date, and nine months after the planned quit date.
EXAMPLE 3
l0 The invention was used by patients who desired to quit smoking and who
had decided upon a quit date. Sibutramine 15 mg orally once daily in the
morning
was initiated two weeks before the planned quit date. Sibutramine was
continued
at this daily dose until four weeks after the planned quit date. A behavior
modification program was given in conjunction with sibutramine. This program
consisted of giving each patient a self help pamphlet on smoking cessation at
the
start of the program and 5- to 10-minute structured lifestyle modification
sessions
designed to enhance their efforts to abstain from smoking at all visits and
during
telephone contacts. This clinical intervention, which was based on ACHPR
guidelines, included advice on successful quitting/continued abstinence (e.g.
2o abstinence form alcohol, other smoker in the household), explaining the
relevance
of smoking (e.g., impact on family, social, health, and prior quitting
experience,
11

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identifying the risks of smoking (acute, long-term, risks to spouse and
children),
explaining that low-tar cigarettes do not eliminate these risks, and
explaining the
rewards of quitting.
The following data were obtained.
Sibutramine (15 mg) v. placebo
Placebo Sibutramine p value
(n=212) (n=211 )
4-week quit rate 11.8% 10.9% --
Mean weight change0.8 kg -1.0 kg <0.0001
Mean weight change2.2 kg -0.4 kg < 0.005
in quitters
of quitters who 16% 52% <0.02
did
not gain weight
to
EXAMPLE 4
The invention was used by patients who desire to quit smoking and who
decided upon a quit date. Sibutramine 15 mg orally once daily in the morning
15 was initiated two weeks before the planned quite date. Sibutramine was
continued at this daily dose until four weeks after the planned quit date. A
12

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behavior modification program was given in conjunction with sibutramine. This
program consisted of giving each patient a self help pamphlet on smoking
cessation at the start of the program and 5- to 10-minute structured lifestyle
modification sessions designed to enhance their efforts to abstain from
smoking at
all visits and during telephone contacts. This clinical intervention, which
was
based on ACHPR guidelines, included advice on successful quitting/continued
abstinence (e.g. abstinence form alcohol, other smoker in the household),
explaining the relevance of smoking (e.g., impact on family, social, health,
and
prior quitting experience, identifying the risks of smoking (acute, long-term,
risks
l0 to spouse and children), explaining that low-tar cigarettes do not
eliminate these
risks, and explaining the rewards of quitting.
Beginning on the planned quit date, a nicotine patch was also applied for
one month. Patients were seen by the treating physician two weeks before the
planned quit date and one month after the planned quit date.
15 The following data were obtained.
13

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Sibutramine (15 mg) plus patch v. Placebo plus patch
Placebo plus Sibutramine plus p value
patch patch
(n=190) (n=189)
4-Week quit rate 24.7% 33.3% 0.063
Mean weight change0.7 kg -0.5 kg <0.0001
Mean weight change0.5 kg -0.2 kg <0.02
in quitters
of quitters who 28% 33.3% <0.005
did
not gain weight
The invention has been described with reference to various specific
embodiments. However, many variations and modifications may be made while
remaining within the scope and spirit of the invention.
14