Eield_of-±ejLαi-£iιtiQn The present invention relates to a new use of certain pyridyl- and pyrimidylpiperazines substituted in the 1 -position of the piperazine ring with an arylalkyl, an aryloxyalkyl or an arylthioalkyl group in the treatment of substance abuse disorders. More particularly, this invention relates to the amelioration of withdrawal symptoms and to modify drug- seeking behav- iour.

Background of the invention

Drug dependency is extremely difficult to escape. This is true whether the dependency is one based on ethanol, amphetamine, barbiturates, ben- zodiazepines, cocaine, nicotine, opioids, and phencyclidine or the like. There is thus a need for an agent decreasing or overcoming such addiction and, if possible reducing or eliminating the symptoms related to the withdrawal of such drugs or substances of abuse.

Different classes of neuronal receptors and neurotransmitters in the brain have been implicated in the complex mechanisms underlying for ex- ample the compulsive drinking of alcohol. Experimental findings have fa¬ voured the opioid, dopaminergic, serotonergic, and benzodiazepine receptor subtypes.

Based upon a large number of genetic and pharmacological studies, serotonin (5-HT) containing neurones in the limbic-midbrain and limbic- forebrain pathways are seemingly involved, in part, in the fundamental mechanisms underlying for example alcohol drinking.

Buspirone (The Merck Index 11 th Ed., No. 1493), a partial 5-HT1A ago¬ nist, has been found to be effective for the treatment of anxiety. Buspirone was reported to attenuate significantly the consumption of alcohol by mon- keys. In a clinical trial comparing buspirone to placebo in alcohol-dependent

individuals, there was a lower drop-out rate in the buspirone-treated group, which also reported fewer signs of craving.

Amperozide (The Merck Index 11th Ed., No. 612), a 5-HT2 antagonist, was reported to significantly attenuate the intake of alcohol in rats without affecting neither consumption of food nor level of body weight (Myers et al., Pharmacol. Biochem. Behav.43:661-667, 1992). Also the bisρhenylalkyl-2- pyridinyl-piperazine derivative FG5893 was reported to have a similar am- perozide-like action (Singh et al., Alcohol 10:243-248, 1993). Summary of the invention It has now surprisingly been found that the compounds of general for¬ mula (I)

and the pharmaceutically acceptable acid addition salts thereof, wherein

Rl is either halogen or hydrogen and R2 is halogen; X is CH2, O or S;

R3 and R4 are the same or different and selected from hydrogen or lower alkyl; n is 2 or 3;

A is selected from the following pyrimidyl- or pyridyl-groups:

wherein

R5 is selected from hydrogen, lower alkyl or halogen;

R6 and R7 are the same or different and selected from hydrogen, lower alkyl, halogen, lower alkoxy, hydroxy, cyano, nitro, trifluoromethyl, COOR8, CONR9R10 or COB; wherein

R8 is hydrogen or lower alkyl;

R9 and RIO are the same or different and selected from hydrogen, lower alkyl and cycloalkyl;

B is selected from

wherein m is 1, 2, 3, or 4; Rl 1 is selected from hydrogen or lower alkyl, and when used in the foregoing definitions the term lower alkyl is meant to include straight and branched hydrocarbon groups having from 1 to 5 carbon atoms; cycloalkyl is meant to include cyclohydrocarbon groups having from 3 to 8 carbon atoms; lower alkoxy is meant to include straight and branched alkoxy groups having from 1 to 5 carbon atoms; halogen is meant to include F, CI and Br, are unexpectedly effective and specific in the treatment of individuals addicted to drugs or substances of abuse, suffering from symptoms related to withdrawal of such drugs or substances. This finding opens up a new method of treating dependence on drugs, such as alcohol, hallucinogens, mi¬ nor tranquillisers, nicotine, opiates, and stimulants.

The aforementioned term "pharmaceutically acceptable acid addition salt" is meant to comprise these salts obtained by treating the base form of the active ingredients of formula (I) with appropriate acids, such as, for ex-

ample, inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, and phosphoric acid, or organic acids, e.g. acetic acid, pro- panoic acid, glygolic acid, lactic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, and pamoic acid. Conversely, the salt form can be converted into the free base form by treatment with alkali.

The compounds of formula (I) as such as well as their use in other areas of medicine are known from the prior art (see US Pat. No. 5,034,390, which is hereby incorporated by reference).

The preferred substances of the present application have a monoaryl- butyl side chain. The substances according to WO 93/20821 though have a diarylbutyl side chain. This chemical difference cause a significant difference in pharmacological effect for the respective substances - see below under Examples, Table 2. DetailpH Hpςrriprion of fhp invpntion Twenty years of research has consistently demonstrated that drugs or substances that are abused by man are usually self-administered by labora¬ tory animals. Ethanol, amphetamine, barbiturates, benzodiazepines, cocaine, nicotine, opioids, and phencyclidine and the like are just a few examples of substances abused by man and self-administered in animal models. The value of animal models for investigating the pharmacological and behav¬ ioural mechanisms underlying drug dependence has been repeatedly demonstrated. In fact, the animal models are our only recourse for the in¬ vestigation of compounds to ameliorate or modify drug-seeking behaviour. In relation to this there is considerable experimental evidence supporting that a commonality in the mechanism of the addictive process itself exists in the brain stem which underlies the predilection to abuse the above men¬ tioned drugs.

Drug addiction includes two important characteristics, chronic com¬ pulsive or uncontrollable drug use and a withdrawal syndrome when use of drug is stopped. Studies have shown that a person dependent on alcohol of¬ ten coabuses other substances, for example cocaine. The subjective effects of

these two substances in a dependent individual may often appear to be more similar than they are different. Drugs of abuse have various effects on sev¬ eral neurotransmitters and systems, which ultimately interact to produce the feeling of well-being avidly sought by many individuals. This drive often eventually produces a dependence which has the associated social and medical consequences.

Biological theories of drug reinforcement have emerged that centre around the assumption that drugs of abuse including for example ethanol, cocaine, and nicotine directly or indirectly activate central "reward sub- strates", that mediate motivated behaviour and reinforcement. A substantial body of evidence implicates the mesocorticolimbic dopamine system in the mediation of acute effects of these drugs of abuse. Hence, there is consider¬ able evidence to suggest a common biological basis for reinforcement from ethanol and other drugs of abuse including cocaine and nicotine. The present invention relates to a method for treating substance abuse disorders by administering to a patient suffering from abuse a therapeuti¬ cally effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. Specifically the invention relates to the relief or prevention of a withdrawal syndrome resulting from addiction to a drug or substance of abuse and/or for the suppression of dependence on drugs or substances of abuse.

Repeated administration to a subject of certain drugs such as alcohol, hallucinogens, minor tranquillisers, nicotine, opiates, and stimulants can lead to physical and/or psychological dependence upon that drug or sub- stance. When the drug or substance of abuse is withdrawn from a dependent subject, the subject develops certain symptoms including sleep and mood disturbance and intense craving for the drug or substance of abuse. These symptoms may be collectively described as a withdrawal syndrome in con¬ nection with the present invention. Although drug treatments for substance abuse disorders are available, these remain largely ineffective and unspecific and, therefore, improvement

is needed. The anorexic and other effects of for example 5-HT reuptake blockers and buspirone constitute a major impediment to their considera¬ tion for clinical treatment. The compounds of formula (I) have been found to be both chemically and pharmacologically different from those drugs sug¬ gested hitherto for the treatment of drug dependence. Compounds of for¬ mula (I) represent a new and novel class of psychotropic agents by having high affinity for both 5-HT1A and 5-HT2 receptors and low to moderate 5-HT reuptake inhibiting properties.

A preferred compound is (l-[4-(p-fluorophenyl)-butyl]-4-(6-methyl-2- pyridinyl)-piperazine fumarate, hereinafter called Compound A. The follow¬ ing examples are intended to illustrate the present invention without limit¬ ing the scope thereof. Examples

The affinity for Compound A and other drugs acting on serotonergic re¬ ceptors was determined according to standard procedures. The results are presented in the below Table 1. Table 1

Drug affinity for serotonergic receptor suhtypps

^a ) Radioligand: ³ H-8-OH-DPAT Tissue: Hippocampus b) Radioligand ^H-Ketanserin Tissue: Cerebral cortex

^c ) Chemical name: l-[4-(p-fluorophenyl)-butyl]-4-(3-ethoxy-2- pyridinyl)-piperazine fumarate d) Chemical name: 2-[4-[4,4-bis(4-fluorophenyl)butyl]-l-piperazi- nyl]-3-pyridine-carboxylic acid methyl ester di¬ hydrochloride ethylat To demonstrate that the chemical differences between substances according to WO 93/20821 and the substances according to the present in¬ vention cause different pharmacological effects the [3HJ-5-HT uptake was evaluated. The results are presented in the below Table 2. Table 2

Uptake of [3H]-5-HT by synaptosomes from rat frontal cortex

IC50 is the drug concentration which inhibit the uptake by 50 %.

Effects of drugs on alcohol intake.

To further illustrate the useful pharmacological properties of com¬ pounds of formula (I) , the effect of Compound A administered systemati¬ cally was determined in alcohol preferring (P) rats. Because of its pattern of drinking, the P animal seems to represent a valid genetically based model to approximate the human condition of alcoholism (McBride et al., Alcohol 7:199-205, 1990; Lankford et aL, Pharmacol. Biochem. Behav. 8:293- 299,1991 ). After maximally preferred alcohol concentrations had stabilised for four days, Compound A in a dose of 2.5 and 10 mg/kg was administered twice a day over four consecutive days. Whereas control injections of saline

were without effect on alcohol consumption, during its administration both doses of Compound A significantly reduced the intake of alcohol in terms of both absolute g/kg and proportion of alcohol to total fluid intake. The high¬ est dose of Compound A reduced intake of alcohol by >40 %. During the five days following administration of Compound A, the alcohol intakes of the rats rebounded, however, still being significantly lower than those of the pre- treatment level. Further, each dose increased the ingestion of food and water above pre-treatment levels during the period of injection. After Compound A injections, food and water returned to pre-drug levels. The compounds of formula (I) and their acid addition salts are therefore indicated for use in amelioration of withdrawal symptoms and in modifying drug-seeking behaviour.

Effective quantities of the compounds of formula (I) and their acid ad¬ dition salts are preferably administered to a patient in need of such treat- ment according to usual routes of administration and formulated in usual pharmaceutical compositions comprising an effective amount of the active ingredient and a suitable pharmaceutically acceptable carrier. Such compo¬ sitions may take a variety of forms, e.g. solutions, suspensions, emulsions, tablets, capsules, and powders prepared for oral administration, patches for transdermal administration or sterile solutions for parental administration. A suitable daily dose for use in the treatment of substance abuse dis¬ orders is contemplated to vary between 0.1 mg/kg to about 10 mg/kg body weight, in particular between 0.1 mg/kg to 2 mg/kg body weight, depending upon the specific condition to be treated, the age and weight of the specific patient, and the specific patient's response to the medication. The exact in¬ dividual dosage, as well as the daily dosage, will be determined according to standard medical principles under the direction of a physician.

Various additives to enhance the stability or ease of administration of the drug are contemplated. The pharmaceutical composition may also con- tain additional therapeutically useful substances other than a compound of formula (I).