WO1990000896A1

WO1990000896A1 - USE OF BENZO(g)QUINOLINES IN TREATMENT OF NICOTINE ADDICTION

Info

Publication number: WO1990000896A1
Application number: PCT/EP1989/000814
Authority: WO
Inventors: John Harry Gogerty
Original assignee: Sandoz Ag; Sandoz-Patent-Gmbh
Priority date: 1988-07-22
Filing date: 1989-07-13
Publication date: 1990-02-08
Also published as: IT1232158B; AU3879789A; IT8948215A0; FR2634379A1

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; R¿4¿ is -COOH, -CH¿2?OR5, -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

Use of benzo(g)quinolines in treatment of nicotine addiction

The present invention relates to a new use of benzo[g]quinolines.

More particularly the present invention relates to the use of benzo[g]quinolines as defined below, for treating nicotine

addiction, in particular for treating withdrawal symptoms in

patients undergoing treatment for nicotine abuse and for reducing craving for nicotine while smoking behaviour is allowed or

preventing craving for nicotine after withdrawal.

Especially the present invention relates to the use of said

benzo[g]quinolines for controlling tobacco consumption, e.g.

smoking, in particular for treating craving or withdrawal

symptoms in patients undergoing treatment for reducing or

stopping tobacco consumption, e.g. smoking, and for preventing need for tobacco after withdrawal.

Tobacco use and smoking in particular has become recognized over the last few decades as a major medical and social problem. This includes not only cigarette smoking, but also cigar and pipe

smoking and smokeless tobacco use including chewing tobacco and snuff. Because of the medical problems associated with its use, the majority of tobacco users would like to stop or at least reduce the amount of tobacco consumed each day. In addition to the medical problems, there are also restrictions now relating to smoking in the work place and in public areas, which also require smokers to exercise considerably greater control over their smoking habits. However, many people find it virtually

impossible, especially in the case of cigarettes, to control their tobacco habit. When a person, for example, has stopped smoking cigarettes completely, there is in most cases a

continuous craving, and if that person tries to alleviate the craving by smoking even just one cigarette, he or she very quickly returns to his or her original level of consumption. Similarly, if one tries to cut down on the amount of tobacco used, such as the number of cigarettes smoked each day, the craving increases in intensity, and the smoker soon returns to the former level of use. Prior to this invention, available therapies generally have failed to support long term abstinence and tobacco users, especially smokers, have had to rely on will power to manage their tobacco habit. There was no recognized therapeutic intervention which permitted the users to control effectively their craving or use of tobacco.

In the present invention, it has been found that nicotine addiction, in particular smoking, especially cigarette smoking, can be controlled by administering to a human nicotine abuser a benzo[g]quinoline 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 C_1-4alkyl;

R₄ is -COOH, -CH₂OR₅, -CH₂CN, -CON(R₆)R₇, -CH₂SR₈, -NHSO₂N(R₉ )R₁₀ or -NHCON(R₉)R₁₀,

R₅ is hydrogen or C_1-3alkyl,

R₆ is hydrogen or C_1-3alkyl and

R₇ is hydrogen, C_1-3alkyl, 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 C_1-4alkyl or pyridyl, said pyridyl being optionally substituted by halogen, methyl or methoxy, and

R₉ and R₁₀ are each independently hydrogen or C_1-3 alkyl or

together are -(CH₂)₄- or -(CH₂)₅-, or a physiologically-hydrolysable and -acceptable ester thereof, in free or in pharmaceutically acceptable salt form, in an amount which is effective in reducing or eliminating the craving for nicotine when cutting down on smoking or stopping completely.

In formula I the following significances as well as combinations thereof are preferred:

1. R₁ and R₂ are independently hydrogen or hydroxy. Most

preferably one is hydrogen and the other is hydroxy.

2. _R3 is C_1-4alkyl, especially n-propyl. 3. R₄ is other than -COOH and is especially -CON(R₆)R₇, -CH₂SR₈, -NHSO₂N(R₉)R₁₀ or -NHCON(R₉ )R₁₀, more especially -CH₂SR₈ or -NHSO₂N(R₉)R₁₀, most especially -NHSO₂N(R₉ )R₁₀.

4. R₅ is hydrogen.

5. R₆ is hydrogen and R₇ is pyridyl optionally substituted by halogen, methyl or methoxy; especially pyridyl optionally mono-substituted by halogen, methyl or methoxy; more especially 3-pyridyl mono-substituted in the para position by methoxy.

6. R₈ is C_1-4alkyl, especially methyl.

7. R₉ is hydrogen or C_{1- 4}alkyl; especially C_1-4alkyl; in particular ethyl, and R₁₀ is hydrogen or C_1-4alkyl; especially C_1-4 alkyl; in particular ethyl.

One group of compounds in accordance with the present invention comprises benzo[g]quinolines of formula I as defined above, wherein

R₁ and R₂ are both hydroxy or both methoxy or one of R₁ and R₂ is hydrogen and the other is hydroxy or methoxy,

R₃ is C_1-4alkyl,

R₄ is -CH₂OH, -CH₂CN, -CON(R₆)R₇, -CH₂SR₈, -NHSO₂N(R₉)R₁₀ or

-NHCON(R₉)R₁₀,

R₆ is hydrogen or C_1-3alkyl,

R₇ is pyridyl optionally substituted by halogen, methyl or

methoxy and

R₈, R₉ and R₁₀ have the meanings given for formula I, as well as the physiologically-hydrolysable and -acceptable esters thereof. A second group of compounds in accordance with the present invention comprises benzo[g]quinolines of formula I as defined above,

wherein

R₁, R₂ and R₃ have the meanings given for formula I,

R₄ is -COOH, -CH₂OH, -CH₂CN, -CON(R₆)R₇, -CH₂SR₈, -NHSO₂N(R₉ )R₁₀ or -NHCON(R₉)R₁₀, and

R₆, R₇, R₈, R₉ and R₁₀ have the meanings given for formula I, as well as the physiologically-hydrolysable and -acceptable esters thereof.

A further group of compounds in accordance with the present invention comprises benzo[g]quinolines of formula I as defined above, wherein one of R₁ and R₂ is hydrogen and the other is hydroxy or methoxy, and R₃ through R₁₀ have the meanings given for formula I, as well as the physiologically-hydrolysable and -acceptable esters thereof.

The preferred compound of formula I in the present invention is N,N-diethyl-N'-[(3α,4aα,10aα)-1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-propylbenzo[g]quinolinyl-3-yl]sulfamide in free or in pharmaceutically acceptable salt form, preferably in form of the hydrochloride which has the formula

This compound, referred to as CV below, and the remaining compounds of formula (I) are known, and their preparation and uses are described in USP 4,565,818, the contents of which are incorporated herein by reference.

The amount of compound of formula (I) administered will vary depending on the compound used and the individual undergoing treatment. It has been found, however, that good results are obtained in the majority of cases with daily dosages in the lowest range utilized for the compounds known indications. The compounds are generally administered in individual dosages ranging from about 0.01 milligram to about 100 milligrams per day. The preferred compound CV is administered at doses of from about 0.01 to about 1.0 milligram per day, although higher doses may be required by some individuals to control their tobacco habit. In most cases, however, it is administered in unit doses of about 0.01 to about 0.5 milligram 2 to 4 times daily, preferably two times daily conveniently at mealtime, especially at breakfast, and at bedtime. Normally, the initial dose of CV is about 0.01 to 0.1 milligram, preferably about 0.02 to 0.05 milligram, once a day for one week. The dosage is then gradually increased to about 0.05 to 0.5 milligram 2 times a day or as needed.

When appropriate, the compound of formula I used in the invention may be employed in free base form or in ester form or in pharmaceutically acceptable salt form. The preferred compound as indicated above is preferably used in the form of the hydrochloride salt. Generally, the activities of such esters and salt forms will be of the same order as that of the corresponding free base form, and references to compounds in the free base form

throughout the specification and claims are to be understood as including known salt forms. The active ingredient of the invention may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, or parenterally as solutions, e.g., a sterile injectable aqueous solution. Tablets may contain the active ingredients in admixture with conventional pharmaceutically acceptable

excipients, e.g., inert diluents and granulating, disintegrating and lubricating agents. The tablets or the active ingredient may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredients in admixture with any of the conventional excipients utilized in the preparation of such compositions. Capsules may contain the active ingredients alone or admixed with an inert solid diluent. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about 90 % of the active ingredients in combination with the carrier or adjuvant.

Thus the present invention further provides a pharmaceutical composition which incorporates a compound of formula I for use in the treatment of nicotine addiction.

The effect of CV versus placebo on the smoking behavior of 150 healthy moderate to heavy smokers is assessed in a doubleblind randomized parallel group over a period of four months followed by a six-month evaluation of abstinence without pharmacological intervention. The subjects undergo a standard physical examination and complete a background smokers profile (Addictive Behaviors, 8: 253 - 261, 1983) before the study begins. They also complete the Schneider's Smoker Complaint Scale and Hopkin's Symptom Checklist (Psychopharmacology, 81: 43 - 44, 1984;

Behavioral Science, 19: 1 - 15, 1974) after not smoking for 48 hours prior to their next visit. Saliva nicotine levels and expired air carbon monoxide levels are measured at that time and at each subsequent visit. Those subjects who qualify for the study resume normal smoking behaviour for seven days and are then randomized into three treatment groups. The first group receives 0.025 mg per day of CV, doubled each weak to a maximum of 0.20 mg per day after three weeks and then continuing at this dose for the remaining thirteen weeks on medication. The second group also receives 0.025 mg per day of CV, doubling each week to a maximum of 0.4 mg per day after four weeks and continuing at this dose for the remaining twelve weeks on medication. The third group receives the placebo. After the first week, the three groups receive half the dosage or placebo at breakfast and the other half or placebo at bedtime. During the first four weeks, the subjects are allowed to continue smoking as they choose. After the fourth week, each subject is instructed to stop smoking, if they have not already done so. The subjects return weekly for testing during the first eight weeks of the study and then once a month for the next eight weeks. At week sixteen, the subjects stop taking medication and return on a monthly basis for testing until the 40th week of the study. The 0.20 to 0.40 mg dosage of CV per day is found to be indicated for controlling tobacco use and reducing or stopping cigarette smoking.

Capsules containing the ingredients indicated below are prepared by conventional techniques and are useful in controlling tobacco use at a dose of one or two capsules two to four times a day.

Ingredients

Weight (mg)

CV 0.0273 ¹ 0.0546 ² 0.1092 ³

Silicon dioxide, colloidal 1.5 1.0 0.7

Hydroxypropylmethylcellulose 1.0 2.0 4.0

Magnesium stearate 3.0 3.0 3.0

Lactose 125.0 125.0 125.0

Maize starch 169.4727 168.9454 167.1908

Fill weight 200.0 300.0 300.0

¹ Equivalent to 0.025 mg of CV

² Equivalent to 0.05 mg of CV

³ Equivalent to 0.10 mg of CV

Sufficient CV for the desired number of capsules is dissolved in 94 % ethanol water and this solution is mixed with a portion of the maize starch and lactose, dried and then mixed with the remaining ingredients. The final mixture is filed into number 1 blue capsules. Similarly, compositions for enteral and parenteral administration can be prepared by conventional processes.

The present invention also provides a method of treating nicotine addiction, particularly for treating withdrawal symptoms in patients undergoing treatment for nicotine abuse and for preventing craving for nicotine after withdrawal, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula I.

Moreover the present invention provides the use of a compound of formula I for the manufacture of a pharmaceutical composition for the treatment of nicotine addiction.

Claims

WHAT WE CLAIM IS:

1. The use of a compound 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 C_1-4alkyl;

R₄ is -COOH, -CH₂OR₅, -CH₂CN, -CON(R₆)R₇, -CH₂SR₈,

-NHSO₂N(R₉)R₁₀ or -NHCON(R₉ )R₁₀,

R₅ is hydrogen or C_1-3alkyl,

R₆ is hydrogen or C_1-3alkyl and

R₇ is hydrogen, C_1-3alkyl, 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-,

R₉ and R₁₀ are each independently hydrogen or C_{1- 3}alkyl or together are -(CH₂)₄- or -(CH₂)₅-,

or a physiologically-hydrolysable and -acceptable ester thereof, in free or in pharmaceutically acceptable salt form,

for the treatment of nicotine addiction.

2. The use of a compound according to claim 1, for the manufacture of a pharmaceutical composition for the treatment of nicotine addiction.

3. A method of treating nicotine addiction in a subject in need of such treatment, which comprises administering to such subject an effective amount of a compound according to claim 1.

4. A pharmaceutical composition which incorporates as active agent a compound according to claim 1, for use in the treatment of nicotine addiction.

5. A pharmaceutical composition according to claim 4, for

controlling tobacco consumption.

6. A pharmaceutical composition according to claim 5, for

stopping or reducing smoking.

7. A pharmaceutical composition according to any one of

claims 4 to 6, in which the active agent is a compound of formula I wherein

R₃ is C_1-4alkyl,

R₄ is -CH₂OH, -CH₂CN, -CON(R₆)R₇, -CH₂SR₈, -NHSO₂N(R₉ )R₁₀ or -NHCON(R₉)R₁₀,

R₆ is hydrogen or C_1-3alkyl,

R₇ is pyridyl optionally substituted by halogen, methyl or methoxy and

R₈, R₉ and R₁₀ have the meaning given for formula I, or a physiologically-hydrolysable and -acceptable ester thereof, in free or pharmaceutically acceptable salt form.

8. A pharmaceutical composition according to any one of claims 4 to 6, in which the active agent is a compound of formula I wherein

R₁, R₂ and R₃ have the meaning give_{n for formula I,}

R₄ is -COOH, -CH₂OH, -CH₂CN, -CON(R₆)R₇, -CH₂SR₈,

-NHSO₂N(R₉)R₁₀ or -NHCON(R₉)R₁₀, and

R₆, R₇, R₈, R₉ and R₁₀ have the meaning given for formula I, or a physiologically-hydrolysable and -acceptable ester thereof, in free or pharmaceutically acceptable salt form.

9. A pharmaceutical composition according to any one of

claims 4 to 6, in which the active agent is N,N-diethyl- N'-[(3α,4aα,10aα)-1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy- 1-propylbenzo[g]quinolinyl-3-yl]sulfamide in free or in pharmaceutically acceptable salt form.

10. A pharmaceutical composition according to claim 9,

containing 0.01 to 0.5 milligram of the active agent per unit dose.