Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-11-05
2001-04-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217040, C514S217060, C514S218000, C514S235800, C514S252140, C514S253010, C540S481000, C540S575000, C540S598000, C544S121000, C544S295000, C544S360000
Reexamination Certificate
active
06221858
ABSTRACT:
FIELD OF THE INVENTION
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 behaviour.
BACKGROUND OF THE INVENTION
Drug dependency is extremely difficult to escape. This is true whether the dependency is one based on ethanol, amphetamine, barbiturates, benzodiazepines, 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 example the compulsive drinking of alcohol. Experimental findings have favoured 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 11th Ed., No. 1493), a partial 5-HT1A agonist, has been found to be effective for the treatment of anxiety. Buspirone was reported to attenuate significantly the consumption of alcohol by monkeys. 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 bisphenylalkyl-2-pyridinyl-piperazine derivative FG5893 was reported to have a similar amperozide-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 formula (I)
and the pharmaceutically acceptable acid addition salts thereof, wherein
R1 is either halogen or hydrogen and R2 is halogen;
X is CH
2
, 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 R10 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;
R11 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, Cl 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, minor 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 example, inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, and phosphoric acid, or organic acids, e.g. acetic acid, propanoic 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 U.S. Pat. No. 5,034,390, which is hereby incorporated by reference).
The preferred substances of the present application have a monoarylbutyl 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.
DETAILED DESCRIPTION OF THE INVENTION
Twenty years of research has consistently demonstrated that drugs or substances that are abused by man are usually self-administered by laboratory 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 behavioural mechanisms underlying drug dependence has been repeatedly demonstrated. In fact, the animal models are our only recourse for the investigation 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 mentioned drugs.
Drug addiction includes two important characteristics, chronic compulsive or uncontrollable drug use and a withdrawal syndrome when use of drug is stopped. Studies have shown that a person dependent on alcohol often 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 several 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 substrates”, 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 considerable 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 therapeutically 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 substance. 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 connection with the present invention.
Although drug
Birch & Stewart Kolasch & Birch, LLP
McKenzie Thomas
Pharmacia & UpJohn AB
Shah Mukund J.
LandOfFree
Pyridyl-and pyrimidyl-piperazines in the treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pyridyl-and pyrimidyl-piperazines in the treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyridyl-and pyrimidyl-piperazines in the treatment of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2494731