FR2634379A1 - THERAPEUTIC USE OF BENZO (G) QUINOLEINS FOR THE TREATMENT OF NICOTINE DEPENDENCE - Google Patents

Abstract

Benzo(g)quinolines of formula (I), wherein the rings A and B are trans-fused and wherein R1 and R2 are each independently hydrogen, hydroxy or methoxy, with the proviso that R1 and R2 may not both be hydrogen; R3 is hydrogen or C1-4 alkyl; R4 is -COOH, -CH2OR5, -CH2CN, -CON(R6)R7, -CH2SR8, -NHSO2N(R9)R10 or -NHCON(R9)R10, R5 is hydrogen or C1-3 alkyl, R6 is hydrogen or C1-3 alkyl and R7 is hydrogen, C1-3 alkyl, phenyl or pyridyl, said phenyl or pyridyl being optionally substituted by halogen, methyl or methoxy or R6 and R7 together are -(CH2)4-, -(CH2)5- or -(CH2)2-O-(CH2)2-, R8 is C1-4 alkyl or pyridyl, said pyridyl being optionally substituted by halogen, methyl or methoxy, and R9 and R10 are each independently hydrogen or C1-3 alkyl or together are -(CH2)4- or -(CH2)5-, are useful for the treatment of nicotine addiction.

Description

 The subject of the present invention is a new use in therapeutics for benzo [glquinoline.

 The invention relates to the therapeutic use of a benzolg] quinoline as defined below, for the treatment of nicotine dependence, in particular for the treatment of withdrawal symptoms in patients subjected to treatment against nicotine abuse and to reduce the need for nicotine in smokers or prevent withdrawal after withdrawal.

 The invention especially relates to the use of these compounds for controlling tobacco consumption, for example the action of smoking1 in particular for treating symptoms of need or withdrawal in patients subjected to a treatment intended to reduce or stop smoking. consumption of tobacco, for example the action of smoking, and to prevent the phenomenon of withdrawal after withdrawal.

 In recent decades, tobacco and cigarettes in particular have been recognized as major medical and social problems. This does not only concern cigarettes, but also cigars and pipes, as well as snuff and chewing tobacco. Because of the medical problems associated with its use, most tobacco users would like to quit smoking or at least reduce the amount of tobacco consumed daily.

In addition to medical problems, there are restrictions on smoking at work and in public places, such as restaurants and shopping malls, which means that smokers have to make a considerably greater effort to control their smoking. However, many people, especially those who smoke cigarettes, find it almost impossible to control their tobacco use. If a person, for example, has completely stopped smoking cigarettes, they will very often experience a phenomenon of continual withdrawal and if this person tries to calm this lack by smoking only one cigarette, they will soon resume their habitual consumption. , if a person tries to reduce his consumption of tobacco, like for example the number of cigarettes smoked per day, the phenomenon of withdrawal increases in intensity and the smoker quickly resumes his old habits. Before this invention, the available therapeutic treatments generally did not allow long-term abstinence and tobacco users, in particular smokers, could only count on their will to control their dependence on tobacco. There was no recognized therapy allowing them to effectively control their need or their consumption of tobacco.

dans laquelle les cycles A et B sont à jonction trans et
R1 et R2 signifient chacun, indépendamment l'un de
l'autre, l'hydrogène ou un groupe hydroxy ou mé
thoxy, R1 et R2 ne devant pas signifier tous les
deux l'hydrogène,
R3 signifie l'hydrogène ou un groupe alkyle en C1 -C4
R4 signifie -COOH, -CH20Rs, -CH2CN, -CON(R6)Rv,
-CH2SR11 -NHSO2N(R9)R10 ou -NHCON(Rg)Rlo,
R5 signifie l'hydrogène ou un groupe alkyle en
C1-C3, signifie l'hydrogène ou un groupe alkyle en
C1-C3, et
R7 signifie l'hydrogène ou un groupe alkyle en
C1-C31 phényle ou pyridyle, ledit groupe phényle
ou pyridyle étant éventuellement substitué par de
l'halogène ou par des groupes méthyle ou méthoxyou et et R7 signifient ensemble -(CH2)4-, -(CH2)5- OU
-(CH2 )2-O-(CH2 )2-,
Ra signifie un groupe alkyle en C1 -C4 ou pyridyle,
ledit groupe pyridyle étant éventuellement sub
stitué par de l'halogène ou par des groupes
méthyle ou méthoxy, et
Rg et R10 signifient chacun, indépendamment l'un de
l'autre, l'hydrogène ou un groupe alkyle en C1 -C3
ou signifient ensemble -(CH2)4- ou -(CH2)5-, ou un ester physiologiquement hydrolysable et physiologiquement acceptable de ce composé, sous forme libre ou sous forme d'un sel pharmaceutiquement acceptable, en une quantité efficace pour réduire ou éliminer la dépendance à la nicotine lors d'une réduction ou d'un arrêt complet de la consommation de tabac.The Applicant has now found that the dependence on nicotine, in particular for smokers, especially cigarette smokers, can be controlled by administering to the heavy nicotine users a benzo [g] quinoline of formula I

in which cycles A and B are at trans junction and
R1 and R2 each mean, independently of one of
the other, hydrogen or hydroxy or me
thoxy, R1 and R2 should not mean all
two hydrogen,
R3 signifies hydrogen or a C1-C4 alkyl group
R4 means -COOH, -CH20Rs, -CH2CN, -CON (R6) Rv,
-CH2SR11 -NHSO2N (R9) R10 or -NHCON (Rg) Rlo,
R5 signifies hydrogen or an alkyl group
C1-C3, signifies hydrogen or an alkyl group in
C1-C3, and
R7 signifies hydrogen or an alkyl group
C1-C31 phenyl or pyridyl, said phenyl group
or pyridyl being optionally substituted with
halogen or by methyl or methoxyou groups and and R7 together signify - (CH2) 4-, - (CH2) 5- OR
- (CH2) 2-O- (CH2) 2-,
Ra signifies a C1-C4 alkyl or pyridyl group,
said pyridyl group being optionally sub
halogenated or by groups
methyl or methoxy, and
Rg and R10 each signify independently of one of
the other, hydrogen or a C1-C3 alkyl group
or mean together - (CH2) 4- or - (CH2) 5-, or a physiologically hydrolyzable and physiologically acceptable ester of this compound, in free form or in the form of a pharmaceutically acceptable salt, in an amount effective for reducing or eliminating nicotine dependence during a reduction or a complete cessation of tobacco consumption.

In formula I, the following meanings and their combinations are preferred: 1. R1 and R2 each mean, independently of one of
the other, hydrogen or a hydroxy group. More
preferably, one of the symbols means hydro-
gene and the other signifies a hydroxy group.

2. R3 means a C1-C4 alkyl group, especially
an n-propyl group.

3. R4 has a meaning other than -COOH and means
preferably -CON (R6) R7, -CH2SRs, -NHS02N (Rg) Rlo
or -NHCON (R9) R10, more preferably -CH2SRS or
-NHSO2N (R9) R10, especially -NHS02N (Rg) Rlo.

4. R5 means hydrogen.

5. R6 means hydrogen and R7 means a group
pyridyle optionally substituted by halogen
or by methyl or methoxy groups, preferably
requires a possibly monosub pyridyl group
substituted by halogen or by a methyl group or
methoxy, more preferably a 3-pyridyl group
monosubstituted in para position by a me group
thoxy.

6. R8 means a C1-C4 alkyl group, especially
a methyl group.

7. Rg signifies hydrogen or an alkyl group
C1 -C41 preferably a C1-C4 alkyl group,
more preferably an ethyl group, and Rlo signi
hydrogen or a C1-C4 alkyl group,
especially a C1-C4 alkyl group, in part
an ethyl group.

A group of compounds according to the invention comprises the benzo [glquinolines of formula I as defined above, in which
R1 and R2 both signify hydroxy or
methoxy or one of the symbols R1 and R2 means
hydrogen and the other one is hydroxy
or methoxy,
R3 signifies a C1-C4 alkyl group,
R4 means -CH2OH, -CH2CN, -CON (R6) Rv, -CH2SRE,
-NHSO2N (R9) R10 or -NHCON (R9) R10,
R6 means hydrogen or C1-C31 alkyl
R7 signifies an optionally substituted pyridyl group
killed by halogen or by methyl groups or
methoxy and R "R9 and Rlo have the meanings indicated for the
formula I, as well as their physiologically hydrolysable and physiologically acceptable esters.

A second group of compounds according to the invention comprises the benzo [g] quinolines of formula I as defined above, in which
R1, R2 and R3 have the meanings indicated for the
formula I,
R4 means -COOH, -CH20H, -CH2CN, -CON (R6) R71
-CH2SR "-NHSO2N (Rg) Rlo or -NHCON (Rg) Rlo, and R61 R7, R8, R9 and R1o have the meanings indicated
for formula I, as well as their physiologically hydrolysable and physiologically acceptable esters.

Another group of compounds according to the invention comprises the benzolg] quinolines of formula I as defined above, in which one of the symbols R1 and R2 signifies hydrogen and the other signifies a hydroxy or methoxy group, and the symbols
R3 to Rlo have the meanings indicated for formula I, as well as their physiologically hydrolysable and physiologically acceptable esters,
The preferred compound of formula I according to the invention is N, N-diethyl-N '- [(3a, 4aa, 10aa) - 1,2,3,4,4a, 5,10, 10a-octahydro-6- hydroxy-1-propyl-benzo [g] quinoline-3-yl] sulfamidet in free form or in the form of a pharmaceutically acceptable salt, preferably in the form of the hydrochloride of formula

 This compound, hereinafter referred to as CV, and the other compounds of formula I are known and are described in US Pat. No. 4,565,818, the content of which is incorporated in the present application by way of reference.

 The amount of compound of formula I to be administered will depend on the active substance and the treatment followed. However, it has been found that good results are obtained in the majority of cases with daily doses corresponding to the minimum doses used for the known indications of these compounds. The compounds will generally be administered in daily doses of between about 0.01 and 100 mg. The preferred CV compound is administered in doses of between about 0.01 and about 1.0 mg per day, although higher doses may be necessary for some patients in order to control their smoking. In most cases, the compound CV is administered in the form of unit doses each containing from approximately 0.01 to approximately 0.5 mg of active substance, 2 to 4 times a day, preferably 2 times a day, advantageously at mealtimes, especially at breakfast lunch, and at bedtime. Normally, the dose of CV is initially between approximately 0.01 and 0.1 mg, preferably between approximately 0.02 and 0.05 mg, once a day for 1 week. The dose is then gradually increased to approximately 0.05 to 0.5 mg twice a day or as needed.

 If necessary, the compound of formula I used according to the invention can be in the form of a free base, in the form of an ester or in the form of a pharmaceutically acceptable salt. The preferred compound referred to above is preferably used in the form of the hydrochloride. In general, such esters and such salts have an activity of the same order as. that of the corresponding free base and the references to the compounds in the form of the free base in the description and the claims must be understood as including the known salts.

 The active substance can be administered orally or parenterally, as it is or in combination with the usual pharmaceutical excipients. It can be administered orally in the form of tablets, dispersible powders, granules, capsules, capsules, syrups and elixirs, or parenterally in the form of solutions, for example in the form of a solution sterile aqueous injection. The tablets may contain the active substance in admixture with usual pharmaceutically acceptable excipients, for example inert diluents, granulating agents, disintegrants and lubricants. The tablets containing the active substance may be uncoated or coated according to techniques known for delay disintegration and absorption in the gastrointestinal tract and thus allow prolonged action. Likewise, suspensions, syrups and elixirs may contain the active substance in combination with any of the usual excipients used for the preparation of such compositions.

The capsules may contain the active substance alone or in combination with a solid inert diluent. The injectable compositions are formulated according to the usual methods. These pharmaceutical preparations can contain up to approximately 90% of active substance in combination with a vehicle or an adjuvant.

 The invention also relates to a pharmaceutical composition comprising a compound of formula I, for use in the treatment of nicotine dependence.

The effect of CV compared to placebo on the behavior of 150 healthy people divided into moderate to heavy smokers, was determined in a double-blind randomized study followed by a 6-month evaluation of abstinence without taking medication. Before the start of the study, these people are subjected to a medical examination and fill out a form concerning their smoking habits (Additive Behaviors, 8: 253-261, 1983). They also complete the following forms: "Schneider's Smoker Complaint Scale" and "Hopkin's
Symptom Cheklist "(Psychopharmacology, 81: 43-44, 1984; Behavioral Science, 19: 1-15, 1974), after having abstained from smoking during the 48 hours preceding the next visit. It is then measured and at each subsequent visit nicotine levels in saliva and carbon monoxide levels in exhaled air. The people chosen for the study resume normal smoking behavior for 7 days and are then divided into 3 groups and subjected to treatment The first group receives 0.025 mg per day of CV, the dose being doubled each week to reach a maximum of 0.20 mg per day after 3 weeks and receive this dose for the following 13 weeks of treatment. second group also receives 0.025 mg per day of CV, the dose being doubled each week to reach a maximum of 0.4 mg per day after 4 weeks and receive this dose during the following 12 weeks of treatment. upe receives the placebo.

At the end of the first week, the 3 groups receive half the dose or the placebo at breakfast and the other half or the placebo at bedtime.

During the first four weeks, they are allowed to smoke as they wish. After the fourth week, everyone is asked to quit smoking1 unless they have already done so. Study participants are subjected to a weekly examination for the first eight weeks of the study and then to a monthly examination for the following eight weeks. At the sixteenth week, people stop all medication and are subjected to a monthly examination until the 40th week of the study. A daily dose of CV between 0.20 and 0.40 mg is indicated to control tobacco consumption and reduce or stop smoking cigarettes.

 The capsules having the following composition are prepared according to the usual techniques and are useful for controlling tobacco consumption, the dose being from 1 to 2 capsules 2 to 4 times a day.

Corposition:
Weight (mg)
CV 0.0273 1 0.0546 2 0.1092 3
Colloidal silica 1.5 1.0 0.7
Hydroxypropylmethylcellulose 1.0 1.0 4.0
Magnesium stearate 3.0 3.0 3.0
Lactose 125.0 125.0 125.0
Corn starch 169.4727 169.9454 167.1908
Total weight 30u, 0 300.0 300.0 Equivalent to 0.025 mg of CV 2 Equivalent to 0.05 mg of CV 3 Equivalent to 0.10 mg of CV
In sufficient 94% aqueous ethanol, a sufficient quantity of CV is dissolved for the desired number of capsules and this solution is mixed with a portion of corn starch and lactose, dried and mixed with the other ingredients. The final mixture is poured into blue capsules. 1. By proceeding according to the usual methods, it is also possible to prepare compositions intended for administration by the enteral route or by the parenteral route.

 The invention further relates to the use of a compound of formula I-for the preparation of a medicament for the treatment of nicotine dependence.

Claims (10)

 1. The therapeutic use of a benzo [g] quinoline of formula I

 in which cycles A and B are at trans junction and R1 and R2 each mean, independently of one of  the other, hydrogen or hydroxy or me  thoxy, R1 and R2 should not mean all  two hydrogen, R3 signifies hydrogen or an alkyl group  C1-C4, R4 means -COOH, -CH2OR5, -CH2CN, -CON (R6) R7,  -CH2SR8, -NHSO2N (R9) R10 or -NHCON (R9) R10, R5 signifies hydrogen or an alkyl group  C1-C3, R6 signifies hydrogen or an alkyl group  Cl-C3, and R7 signifies hydrogen or an alkyl group  C1-C3, phenyl or pyridyl, said phenyl group  or pyridyl being optionally substituted with  halogen or by methyl or methoxy groups,  or R6 and R7 together mean - (CH2) 4-, - (CH2) 5- or - (CH2) 2-O- (CH2) 2-, R8 signifies a C1-C4 alkyl or pyridyl group,  said pyridyl group being optionally sub  formed by halogen or by groups  methyl or methoxy, and R9 and R10 each mean, independently of one of  the other, hydrogen or a C1-C3 alkyl group  or mean together - (CH2) 4- or - (CH2) 5-, or of a physiologically hydrolyzable and physiologically acceptable ester of this compound, in free form or in the form of a pharmaceutically acceptable salt, for the treatment of dependence nicotine.  2. A benzo [glquinoline of formula I as defined in claim 1, for use as a medicament for the treatment of nicotine dependence.  3. The use of a benzolg] quinoline of formula I as defined in claim 1, for the preparation of a medicament intended for the treatment of nicotine dependence.  4. A pharmaceutical composition comprising, as active substance, a benzo [g) quinoline of formula I as defined in claim 1, for use in the treatment of nicotine dependence.  5. A pharmaceutical composition according to claim 4, for controlling the consumption of tobacco.  6. A pharmaceutical composition according to claim 5, for suppressing or reducing the consumption of tobacco.  7. A pharmaceutical composition according to any one of claims 4 to 6, characterized in that the active substance is a compound of formula I in which R1 and R2 both signify hydroxy or  methoxy or one of the symbols R1 and R2 means  hydrogen and the other one is hydroxy  or methoxy, R3 signifies a C1-C41 alkyl group R4 means -CH2OH, -CH2CN, -CON (R6) R71 -CH2SR8,  -NHSO2N (Rg) Rlo or -NHCON (R9) R10, R6 signifies hydrogen or a C1-C3 alkyl group,  and R7 signifies an optionally substituted pyridyl group  by halogen or by a methyl or methoxy group and R6, R9 and Rlo have the meanings indicated in the  claim 1 for formula I, or a physiologically hydrolyzable and physiologically acceptable ester of this compound, in free form or in the form of a pharmaceutically acceptable salt.  8. A pharmaceutical composition according to any one of claims 4 to 6, characterized in that the active substance is a compound of formula I in which R1, R2 and R3 have the meanings indicated in the  claim 1 for formula I, R4 means -COOH, -CH2OH, -CH2CN, -CON (R6) Rv,  -CH2SR8, -NHSO2N (R9) R1o or -NHCON (R9) R10 and, R61 R71 R81 R9 and Rlo have the meanings indicated  to claim 1 for formula I, or a physiologically hydrolyzable and physiologically acceptable ester of this compound, in free form or in the form of a pharmaceutically acceptable salt.  9. A pharmaceutical composition according to any one of claims 4 to 6, characterized in that the active substance is N, N-diethyl-N 'l (3 t4a, 10a) -lt2344a, 5tl0,10a-octahydro-6 -hydroxy- 1-propyl-benzo [g] quinoline-3-yl] sulfonamide, in free form or in the form of a pharmaceutically acceptable salt.  10. A pharmaceutical composition according to claim 91 characterized in that it contains from 0.01 to 0.5 mg of active substance per unit dose.