CA2359564A1 - Method to aid smoking cessation - Google Patents
Method to aid smoking cessation Download PDFInfo
- Publication number
- CA2359564A1 CA2359564A1 CA002359564A CA2359564A CA2359564A1 CA 2359564 A1 CA2359564 A1 CA 2359564A1 CA 002359564 A CA002359564 A CA 002359564A CA 2359564 A CA2359564 A CA 2359564A CA 2359564 A1 CA2359564 A1 CA 2359564A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- formula
- cyclobutyl
- chlorophenyl
- methylbutyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 50
- 230000005586 smoking cessation Effects 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 230000004584 weight gain Effects 0.000 claims abstract description 5
- 235000019786 weight gain Nutrition 0.000 claims abstract description 5
- 230000004048 modification Effects 0.000 claims description 15
- 230000006399 behavior Effects 0.000 claims description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 7
- WQSACWZKKZPCHN-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutan-1-amine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N)CC(C)C)CCC1 WQSACWZKKZPCHN-UHFFFAOYSA-N 0.000 claims description 5
- PLXKZKLXYHLWHR-UHFFFAOYSA-N 1-[1-(4-chlorophenyl)cyclobutyl]-n,3-dimethylbutan-1-amine Chemical compound C=1C=C(Cl)C=CC=1C1(C(CC(C)C)NC)CCC1 PLXKZKLXYHLWHR-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000004682 monohydrates Chemical class 0.000 claims 2
- 238000002670 nicotine replacement therapy Methods 0.000 claims 2
- 150000004677 hydrates Chemical class 0.000 claims 1
- 230000000391 smoking effect Effects 0.000 abstract description 23
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 abstract description 8
- 229960002715 nicotine Drugs 0.000 abstract description 8
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 abstract description 8
- 235000019788 craving Nutrition 0.000 abstract description 3
- 239000000779 smoke Substances 0.000 abstract description 3
- ZRAFRSFHPUGXSX-UHFFFAOYSA-N n-(4-cyclobutylbutyl)aniline Chemical compound C=1C=CC=CC=1NCCCCC1CCC1 ZRAFRSFHPUGXSX-UHFFFAOYSA-N 0.000 abstract description 2
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 22
- 229960004425 sibutramine Drugs 0.000 description 20
- 239000000203 mixture Substances 0.000 description 12
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 239000003826 tablet Substances 0.000 description 6
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- 206010021654 increased appetite Diseases 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
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- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 206010020400 Hostility Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010057852 Nicotine dependence Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical class CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000000627 locus coeruleus Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 235000019809 paraffin wax Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- -1 racemates Chemical compound 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960003466 sibutramine hydrochloride Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Addiction (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Psychiatry (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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.
Description
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.
WO 00/43002 PCT/iJS00/01217 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.
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
H3C~HCHZCHNR~R2 CI
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 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 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 active compound. The tablets and capsules may conveniently each contain 1 to 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.
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 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.
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.
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 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.
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, 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 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
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.
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.
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.
WO 00/43002 PCT/iJS00/01217 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.
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
H3C~HCHZCHNR~R2 CI
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 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 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 active compound. The tablets and capsules may conveniently each contain 1 to 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.
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 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.
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.
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 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.
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, 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 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
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.
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.
Claims (28)
1. A method of causing smoking cessation which comprises administering a therapeutically effective amount of a compound of formula I
or pharmaceutically acceptable salts and hydrates thereof, in which R, and R2 are independently H or methyl.
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.
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.
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.
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
or pharmaceutically acceptable salts thereof, in which R1 and R2 are independently H or methyl.
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.
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.
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.
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.
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PCT/US2000/001217 WO2000043002A1 (en) | 1999-01-20 | 2000-01-19 | Method to aid smoking cessation |
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BG105820A (en) | 2002-06-28 |
SK10312001A3 (en) | 2002-03-05 |
IL144390A0 (en) | 2002-05-23 |
NZ513638A (en) | 2001-09-28 |
BR0007633A (en) | 2002-01-02 |
JP2002535273A (en) | 2002-10-22 |
ID30432A (en) | 2001-12-06 |
EP1150672A1 (en) | 2001-11-07 |
MXPA01007388A (en) | 2002-07-22 |
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