MXPA96003341A - Use of 4-chloro-5- (imidazolin-2-ilamino) -6-metoxy-2-methyl pyrimid - Google Patents
Use of 4-chloro-5- (imidazolin-2-ilamino) -6-metoxy-2-methyl pyrimidInfo
- Publication number
- MXPA96003341A MXPA96003341A MXPA/A/1996/003341A MX9603341A MXPA96003341A MX PA96003341 A MXPA96003341 A MX PA96003341A MX 9603341 A MX9603341 A MX 9603341A MX PA96003341 A MXPA96003341 A MX PA96003341A
- Authority
- MX
- Mexico
- Prior art keywords
- nicotine
- symptoms
- ethanol
- drug
- withdrawal syndrome
- Prior art date
Links
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- 239000011701 zinc Substances 0.000 description 1
Abstract
The present invention fits into the fields of pharmacology and pharmaceutical chemistry and provides a method for the use of 4-chloro-5- (imidazoline-2-ylamino) -6-methoxy-2-methyl pyrimidine, for the treatment of the suppression of smoking, withdrawal symptoms caused by nicotine, opiates, ethanol, and combinations thereof, and for relieving appetite for tobacco, nicotine, apiaceous, ethanol, and combinations of same
Description
USE OF 4-CHLORINE-5- (IMIDAZOLIN-2-ILAMINO) -6-METOXY-2-METHYL PYYRIMIDINE
DESCRIPTION OF THE INVENTION
The present invention falls within the fields of pharmacology and pharmaceutical chemistry and provides a method for the use of 4-chloro-5- (imidazoline-2-ylamino) -6-methoxy-2-methylpyrimidine, for the treatment of smoking cessation, nicotine withdrawal syndrome, opiates, ethanol, and combinations thereof, and for relief of craving for tobacco, nicotine, opiates, ethanol, and combinations thereof . It is well known that chronic administration of nicotine, opiates, ethanol or combinations thereof results in tolerance and, over time, dependence. The use of tobacco, opiates, and ethanol is extremely widespread in many countries, despite knowledge of the adverse effects of its use. Many people who use tobacco habitually would like to stop using it but can not because they are addicted to the psychoactive drug that is the component of tobacco that produces dependence, nicotine, Benozit, N. In. J.
Med .. 319: 20. 1318-1330 (1988). Benowitz warns that nicotine can also contribute to various diseases, including cancer, heart disease, respiratory diseases and others REF: 22764 diseases, for which the use of tobacco is a risk factor, particularly in heart disease. Nicotine is present in cigarettes and other tobacco products that are smoked or chewed. These tobacco products cause addiction and are associated with diseases of the lung and heart, and other serious illness states. Strong campaigns against the use of tobacco have been carried out, and it is now known that the suppression of tobacco use brings with it many unpleasant withdrawal symptoms, including irritability, anxiety, restlessness, lack of concentration , the daze, the insomnia, the tremors, the increase of the sensation of hunger and the gain of weight, and, of course, an intense appetite for the tobacco. The utility of a few pharmaceutical agents for the treatment of nicotine dependence has been reported, including clonidine, an adrenergic agonist-a2, and alprazolam, a benzodiazepine agonist. Antagonists of receptors such as mecamylamine have also been used. A few psychotropic benzodiazepine drugs have been described for use in suppressing tobacco use, but their use is not widespread. Some drugs that affect serotonin have been described as non-smoking aids, particularly including buspirone, which has been described by West and Co, as a promising aid for people trying to quit tobacco use, Psvchopharmacolocry 104: 91- 96 (1991). Benowitz reports that the most effective treatments so far have been nicotine replacement therapy, using nicotine gum, or transdermal patches that release nicotine to slowly dissociate individuals from their addictions to nicotine and the use of derivatives. of tobacco containing nicotine. Desafotunadamente, the substitution therapy of the nicotine implies the administration of the psychoactive component of the tobacco. Nicotine replacement must be staggered, often resulting in nicotine withdrawal and subsequent relapse in the use of tobacco products. Nicotine replacement is generally accepted as the most effective when combined with treatments and psychological behavior modification training. There is a need for a therapy that has a profile of desirable side effects, which alleviates the symptoms of the withdrawal syndrome caused by nicotine, including long-term cravings for nicotine. Opioids are well-known psychoactive drugs, whose use induces tolerance and dependence on the psychoactive drug that is being administered. Drug abuse and dependence, specifically opioids, are observed with concern throughout the world. The symptoms of the withdrawal syndrome caused by stopping opioid use vary greatly in intensity depending on numerous factors, including the dose of opioid used, the extent to which continued use of the opiate affects the CNS, the duration of chronic use, and the speed at which the opiate is eliminated from the receptors. These withdrawal symptoms include cravings, anxiety, dysphoria, yawning, perspiration, lacrimation, rhinorrhea, restlessness and interruption of sleep, irritability, dilation of the pupils, pain in the bones, back and muscles, piloerection, flushing of heat and cold, nausea, vomiting, diarrhea, weight loss, fever, increase in blood pressure, pulse and respiratory rate, nervous movement of muscles and shaking of the lower extremities. Although oral opioids are relatively non-toxic, chronic use is associated with secondary endocrine abnormalities, constipation and some sleep disturbances. However, the life expectancy of opiate addicts is significantly reduced due to overdose, drug-related infections, suicide and homicide. Medical complications associated with opioid injection include a variety of pathological changes in the CNS including degenerative changes in the lenticular nucleus, necrosis of spinal gray matter, transverse myelitis, amblyopia, plexitis, peripheral neuropathy, Parson's syndrome, intellectual impairment , personality changes, and pathological changes in muscles and peripheral nerves. Skin and systemic organ infections are also common, including staphylococcal pneumonitis, tuberculosis, endocarditis, septicemia, viral hepatitis, human immunodeficiency virus (HIV), malaria, tetanus, and osteomyelitis. Pharmaceutical agents used for the treatment of opioid dependence include methadone, which is an opioid, and opioid antagonists, primarily naloxone and naltrexone. It has been shown that clonidine suppresses some elements of opioid suppression but has side effects of hypotension and sedation, which can be quite extreme. The treatment and psychological training for the modification of therapies are frequently used jointly in association with pharmaceutical agents. There is a need for a therapy that has a more desirable side effect profile to alleviate the symptoms of withdrawal syndrome caused by opiates. Ethanol is probably the sedative most frequently used in most cultures and one of the main causes of morbidity and mortality. Repeated ingestion of large amounts of ethanol can affect almost every organ system in the body, particularly the gastrointestinal tract, the cardiovascular system, and the peripheral and central nervous systems. Gastrointestinal effects include gastritis, stomach ulcers, duodenal ulcers, liver cirrhosis and pancreatitis. In addition there is an increased proportion of cancer of the esophagus, stomach and other parts of the gastrointestinal tract. Cardiovascular effects include hypertension, cardiomyopathy and other myopathies, significantly elevated levels of triglycerides and low density lipoprotein cholesterol. These cardiovascular effects contribute to a marked increase in the risk of heart disease. Peripheral neuropathy can be evidenced by muscle weakness, paraesthesia and decreased peripheral sensation. Central nervous system effects include cognitive deficits, degenerative changes of severe memory impairment in the cerebellum, and persistent amnestic disorders induced by ethanol in which the ability to encode new memory is severely impaired. Generally, these effects are related to the deficiency of vitamins, specifically vitamin B. Individuals with ethanol dependence show symptoms and physical changes that include dyspepsia, nausea, swelling, esophageal varices, hemorrhoids, tremors, instability while walking, insomnia, dysfunctions erectile, decreased testicular size, femineizante effects associated with reduced levels of testosterone, miscarriage and fetal alcohol syndrome. Symptoms associated with the suppression of ethanol include nausea, vomiting, gastritis, hematemesis, dry mouth, bloated complexion and full of spots, and peripheral edema. The generally accepted treatment of withdrawal symptoms caused by ethanol and diseases consists in the administration of a mild tranquilizer such as chloridiazephoxide. Usually, vitamins are also administered, specifically vitamin B. Optionally, magnesium sulfate and / or glucose is also administered. Nausea, vomiting and diarrhea are treated symptomatically at the discretion of the attending physician. Disulfiram can also be administered to help maintain abstinence. If etatanol is consumed with disulfiram, the accumulation of acetaldehydes produces nausea and hypotension. There is a need for an effective therapy for the relief of symptoms and states resulting from the withdrawal syndrome caused by ethanol having a more desirable side effect profile. There is a definite need for a clear therapy for the withdrawal syndrome produced by the substance abuse by a pharmaceutical agent that alleviates the symptoms of elimination and states produced by the withdrawal syndrome that is not by itself an agent of addition as it happens with nicotine and methadone; a receptor antagonist such as naloxone and naltrexone that induces or exacerbates the symptoms and conditions caused by the withdrawal syndrome; or an enzyme inhibitor that induces or exacerbates the symptoms and conditions caused by the withdrawal syndrome; and have an acceptable side effect profile. Surprisingly, applicants have discovered that 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine may be useful for the treatment of symptoms and conditions induced by the cessation of use or the appearance of the Nicotine withdrawal syndrome and tobacco products, opioids, or ethanol and combinations thereof. The present claimed invention provides a method for the inhibition of one or more symptoms or a state resulting from the cessation of the use or the application of withdrawal syndrome of tobacco, nicotine, opiates, ethanol or combinations thereof consisting in the administration of an effective amount of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine or a pharmaceutically acceptable salt thereof to a mammal in need of this treatment. The invention also provides a method of assisting mammals using tobacco, nicotine, opiates, ethanol or combinations thereof to stop or reduce their use, as well as a method to prevent a mammal that has stopped or reduced the use of tobacco, nicotine, opiates, ethanol or combinations thereof relies on their use, which comprises administering to said mammals an effective amount of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine or a pharmaceutically acceptable salt thereof. Substance dependence (nicotine, opiates and ethanol) is an accumulation of physiological, behavioral and cognitive symptoms that demonstrate that there is a continued use of the substance in spite of the significant problems related to the substance. There is a model of repeated self-administration that results in tolerance, appearance of withdrawal syndrome and compulsive behavior of taking the substance. Tolerance is the need for significantly increased amounts of the substance to achieve the desired effect, or a markedly diminished effect with the continued use of the same amount of substance. Generally, abstinence syndrome is a behavior change, which has cognitive and physiological components, that occur when the tissue or blood concentrations of a substance decrease in an individual who has maintained a prolonged use of the substance. After the development of withdrawal symptoms it is likely that the individual will take the substance to alleviate or avoid these symptoms. The compound 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine (moxonidine) is known and described in U.S. Patent No. 4,323,570 which is incorporated herein by reference in its entirety. As used herein, the term "mammal" means the class of higher vertebrate mammals. The term "mammal" includes, but is not limited to, a human. The term "treatment" as used herein includes the therapeutics and prophylaxis of the named symptoms and states and the improvement or elimination of the states once they have been established. The term "opioid", as used herein, means any natural opioid, synthetic and semi-synthetic exogenous substance that binds to one or more subtypes of opioid receptors and produces agonist action. The three subtypes of known opiate receptors include mu, kappa and delta. Examples of opiates include opium, morphine, heroin, codeine, pentazocine, buprenorphine, meperidine, butorphanol, feutanil, nalbuphine, hydromorphone, oxycodone, oxymorphone, and methadone.
The term "withdrawal syndrome" or "cessation and onset of withdrawal syndrome", as used herein, shall refer to the symptoms and conditions resulting from: decreased or discontinuous administration and use of tobacco products, diminished and discontinuous administration and use of nicotine, diminished or discontinuous administration and use, injectable or oral, of one or more opioids, diminished and discontinuous administration and use of ethanol, and any combination of two or more of these. The diseases and symptoms of nicotine withdrawal syndrome, opiates, and ethanol are characterized in the DSM-IV. Diasnostic and Statistical Manual of Mental Disorders, fourth edition (1994). The DSM-IV was prepared by the Nomenclature and Statistical Operations Group of the American Psychiatric Association, and provides a clear description of the diagnostic categories. Experts in the field will recognize that there are alternative nomenclatures, nosologies and classification systems for pathological psychological diseases and that these systems develop with scientific medical progress.
The criterion of dependence of a substance as set forth in the DSM-IV is a substance use model, which leads to clinically significant impairment or, as manifested in at least three of the following selected groups, occurring in any moment throughout the same twelve-month period: (1) Tolerance defined well as (a) need for substantially increased amounts of substance to achieve the desired effect; or (b) effect substantially decreased by the continued use of the same amount of substance; (2) withdrawal syndrome, demonstrated either as (a) abstinence syndrome characteristic of a specific substance; or (b) the same or a compound closely related to it taken to avoid or alleviate the symptoms of the withdrawal syndrome; (3) the substance is frequently taken in larger quantities or over a longer period than was intended; (4) there is a persistent appetite or useless efforts to stop using the substance or control its use; (5) a lot of time is spent on activities in order to obtain the substance, use it or recover from its effects; (6) important social, leisure or occupational activities are abandoned or reduced as a result of the use of the substance, and (7) the use of the substance is continued despite knowledge of the existence of a psychological or physical problem. recurrent or persistent that has probably been caused or exacerbated by the substance. Substance dependence may be accompanied by physiological dependence; that is, evidence of tolerance or abstinence syndrome is present, or without physiological dependence if tolerance or withdrawal syndrome is not evident.
Four of the states include remission. These types of referrals are based on the time interval elapsed since the dependencies cease and if there is a continued presence of one or more of the symptoms included in the dependency criteria. The qualifier "early complete remission" is used when no symptoms of dependency have been found for at least one month but less than twelve months. The qualifier "early partial remission" is used when one or more symptoms of dependence have been found during at least one month but less than twelve months, but all dependency criteria have not been met. The term "sustained complete remission" is used when none of the symptoms of dependence have been found at any time during a period equal to or greater than twelve months. The term "sustained partial remission" is used if symptoms of dependence have not been found for a period equal to or greater than twelve months but one or more symptoms of dependence have been met at some time. The qualifier "agonist therapy" is used if the subject is subject to prescribed agonist medication and no symptoms of dependence have been found for that class of medication for at least the last month. It also applies to those individuals who are being treated for dependence using a partial agonist.
The term "in a controlled environment" is used if the subject is in an environment where access to substances of abuse is restricted and no symptoms of dependency have been found for at least the last month. In the abstinence syndrome, the essential characteristic is the development of a change of specific behavior of the substance with concomitant cognitive and physiological circumstances, this is due to the cessation or to the considerable and prolonged reduction of the use of the substance. The specific symptoms of the substance cause clinically significant impairments in the field of social, occupational and other important activity areas. These symptoms are not due to a general medical condition and are not better explained by another disorder or mental disorder. Generally, withdrawal syndrome, although not necessarily, is associated with substance dependence. Individuals with withdrawal symptoms tend to readministration of the substance to reduce these symptoms. Withdrawal syndrome develops when doses of the substance are reduced or eliminated. Therefore, the term "cessation or onset of withdrawal syndrome" will include, but is not limited to, the following conditions characterized in the DSM-IV: nicotine suppression; Nicotine-related disorders not otherwise specified; nicotine dependence with physiological dependence; nicotine dependence without physiological dependence; nicotine dependence with early complete remission; nicotine dependence with early partial remission; nicotine dependence with sustained complete remission; nicotine dependence with sustained partial remission; nicotine dependence with agonist therapy; opioid suppression; disorders related to opiates not otherwise specified; opioid dependence with physiological dependence; opioid dependence without physiological dependence; opioid dependence with early complete remission; opioid dependence with early partial remission; opioid dependence with sustained complete remission; opioid dependence with sustained partial remission; opioid dependence with agonist therapy; dependence on opiates in a controlled environment; ethanol suppression; ethanol dependence with physiological dependence; ethanol dependence without physiological dependence; ethanol dependence with early complete remission; dependence on ethanol with early partial remission; suppression of ethanol with sustained complete remission; suppression of ethanol with sustained partial remission; suppression of ethanol with agonist therapy; Suppression of ethanol in a controlled environment. The discontinued use of nicotine-containing tobacco products results in the onset of states caused by the nicotine withdrawal syndrome. Individuals generally suffer from the symptoms of nicotine withdrawal syndrome as a consequence of the discontinuous use of tobacco in any form, including, but not limited to, smoking a cigarette, cigar, or pipe tobacco, or oral or intranasal tobacco ingestion. or the chewing of this one. Oral or intranasal ingestion includes, but is not limited to, sucking or chewing tobacco. Symptoms that occur within twenty-four hours of cessation of nicotine use or reduction of the amount of nicotine used include dysphoria, depression; daze; insomnia, irritability, frustration or anger; anxiety, nervous tremor; difficulty of concentration; restlessness; decreased heart rate; increase in appetite or weight gain; and the appetite for tobacco or nicotine. Frequently these symptoms cause deterioration or clinically significant alterations in the field of social, occupational and other important activity areas. The present invention is more preferably used to alleviate one or more symptoms attributed to the nicotine withdrawal syndrome when said symptoms are not due to a general medical condition and do not have a better explanation due to any other medical alteration. The present method is also useful for those who have substituted or partially substituted the use of tobacco by the use of a nicotine replacement therapy. A) YesThese patients can be helped to reduce or even completely eliminate their dependence on nicotine in all its forms. The reduction or discontinuation of opioid administration, usually self-administration, by injection or orally, through intranasal administration or by smoking, results in the presence of a characteristic opioid withdrawal syndrome state. This state of withdrawal syndrome is also caused by the administration of an opioid antagonist such as naloxone or naltrexone after the use of the opiate. The opioid withdrawal syndrome is characterized by symptoms that are generally opposite to the opiate agonist effects. These symptoms include anxiety; restlessness; muscle pain, often of the back and legs; opiate cravings; irritability and increased sensitivity to pain; dysphoric humor; nausea or vomiting; lacrimation; runny nose dilation of the papillae; piloerection; sweating diarrhea; yawns fever and insomnia. When dependence is due to short-acting opioids, such as heroin, symptoms of withdrawal syndrome occur between six to twenty-four hours after the last dose, whereas if it is due to long-acting opioids, such as methadone, Symptoms may take two to four days to arise. Frequently, these symptoms cause deterioration or clinically significant alterations in the field of social, occupational and other important activity areas. The present invention is most preferably used to alleviate one or more symptoms attributed to the opioid withdrawal syndrome when said symptoms are not due to a general medical condition and do not have a better explanation due to any other medical alteration. The discontinuation or reduction of the use of ethanol (content in beverages) results in the onset of symptoms due to the ethanol withdrawal syndrome. The states derived from the ethanol withdrawal syndrome are characterized by symptoms that begin with an acute decrease in the concentration of ethanol in the blood within four to twelve hours after the use of ethanol has been reduced or stopped. Symptoms include an appetite for ethanol; autonomic hyperactivity (sweating or pulse greater than 100); trembling hands; insomnia; sickness; vomiting; transitory auditory, tactile and visual hallucinations; psychomotor agitation; anxiety and attacks of epilepsy fully developed. These symptoms cause deterioration or clinically significant alterations in the field of social, occupational and other important activity areas. The present invention is more preferably used to alleviate one or more symptoms attributed to the ethanol withdrawal syndrome when said symptoms are not due to a general medical condition and do not have a better explanation due to any other medical alteration. The method of the present invention is preferably administered in conjunction with and / or a behavioral and / or educational modification program to increase the continued abstinence from tobacco, opiates, ethanol or other combinations thereof. The method of the present invention is also highly beneficial for these programs by alleviating the suffering experienced by the withdrawal syndrome caused by nicotine, opiates and ethanol throughout these programs. Therefore, programs can be more effective focused on behavioral and educational modification objectives, also reducing the incidence of incomplete programs. The compound 4'-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine is generally prepared as described in U.S. Patent No. 4,323,570. Preferably, 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine is prepared in the following manner.
Hydrochloride
H 4 * H3C - C, HC1 acetamidine
Diethyl malonate
4, 6-Dihydroxy-2-methylpyrimidine
-H2N03, CH3COOH (pyrolysis)
4,6-Dihydroxy-2-methyl-5-nitropyrimidine OH
4, 6 -Dichloro-2-methyl-5-nitropyrimidine
, Raney-Ni
gold-2
2-one
N- (1-acetylimidazolin-2-N- < N-iliden) -4,6-dichloro-2-methyl-Ac 5 -pyridinamine
4-Chloro-N- (imidazolidin-2-ylidene) -6-methoxy-2-methyl-5-pyrimidinamine The N-acetylimidazolin-2-one is prepared by reaction of acetic anhydride with 2-imidazolidone at room temperature. The reaction mixture is heated between 80 ° C and 100 ° C for 90 minutes and then cooled from about 10 ° C to about -10 ° C to provide N-acetylimidazolin-2-one. The first intermediate, 4,6-dihydroxy-2-methylpyrimidinamine, is synthesized by preparing sodium ethoxide in situ from sodium and an aqueous ethanol under nitrogen. Diethyl malonate and acetamidine hydrochloride are added and the reaction mixture is heated to boiling for 2 to 5 hours to ob 4,6-dihydroxy-2-methylpyrimidine. The second intermediate, 4,6-dihydroxy-2-methyl-5-nitropyrimidine, is synthesized by slow addition of 4,6-dihydroxy-2-methylpyrimidine to a reaction mixture of nitric acid from pyrolysis in acetic acid. Once the addition of 4,6-dihydroxy-2-methylpyrimidine has been completed, the reaction mixture is stirred for one and a half to two hours to ob 4,6-dihydroxy-2-methyl-5-nitropyrimidine. After the nitration, phosphorus oxychloride (POCl3) and 4,6-dihydroxy-2-methyl-5-nitropyrimidine are combined by stirring. Diethyl aniline is added dropwise to this mixture at a rate such that the temperature of the reaction mixture is mained below about 40 ° C. After the addition is complete the reaction mixture is refluxed for one to three hours and then distilled under vacuum to ob the intermediate tert, 4,6-dichloro-2-methyl-5-nitropyrimidine. The third intermediate, 4,6-dichloro-2-methyl-5-nitropyrimidine is hydrogenated over Raney-Ni, as a 10% to 30% solution in toluene to ob the corresponding compound, 6-dichloro-2-methyl- 5-aminopyrimidine, as an intermediate room. The fifth intermediate, N- (l-acetylimidazolin-2-ylidene) -4,6-dichloro-5-pyrimidinamine, is prepared by combining phosphorus oxychloride, N-acetylimidazolin-2-one and 5-amino-4,6. - Dichloro-2-methylpyrimidine, and it is heated to boiling for 2 to 4 hours, then it is cooled while stirring to room temperature. The final product, 4-chloro-N- (imidazolin-2-ylidene) -6-methoxy-2-methyl-5-pyrimidinamine is synthesized by preparing sodium methoxide in situ from anhydrous methanol and sodium. The fifth intermediate, N- (1-acetylimidazolin-2-ylidene) -4,6-dichloro-2-methyl-5-pyrimidinamine, is added and the reaction mixture is boiled. 15 minutes to one hour after the reaction mixture is boiled, additional sodium methoxide is added and the reaction mixture is boiled for 15 minutes to one hour to provide 4-chloro-N- (imidazolin-2-) yliden) -6-methoxy-2-methyl-5-pyrimidinamine. The obing of several intermediates is carried out by standard techniques well known to those skilled in the art. The various reactants and reagents used in this synthesis are commercially available or are readily prepared from commercially available material by standard methods well known to those skilled in the art. It will be appreciated that the compound of the present invention can be isolated per se or can be converted to an acid addition salt using conventional methods. By the term "effective dose" is meant an amount of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine, or a pharmaceutically acceptable salt thereof, which will decrease or alleviate one or more symptoms or conditions resulting from the cessation or onset of tobacco withdrawal syndrome, nicotine, opiates, ethanol and combinations thereof. The compound of the present invention is an imidazoline-Il ligand that demonstrates substantial selectivity for receptors II on a2 adrenergic receptors. In saturation binding experiments in the rostral-bovine ventrolateral marrow (bovine RVLM), moxonidine exhibits a selectivity value (ki in location a2 in uM / Ki in locations II in uM) greater than 20 and preferably greater than 30X, where Ki it is the inhibitory affinity constant. Of course, Ki is inversely proportional to affinity, so lower Ki values indicate a higher affinity. Therefore, at the higher selectivity value, the compound is more selective. In contrast, the selectivity value of clonidine in bovine RVLM is less than 4. See Ernsberger et al. , J. Pharmacol. EXP. Ther. , 264. 172-182 (1993) for more details on the experimental protocol and results. The dose of the compound to be administered, in general, is from about 0.001 to about 10.0 mg / day; Normally, the daily dose can be administered in a single dose or in divided doses, depending on the judgment of the physician in charge of the case. A more preferred dose range is from about 0.002 to about 5.0 mg / day; Other dosage ranges that may be preferred in certain circumstances are from about 0.005 to about 2.0 mg / day; from about 0.1 to about 1.0 mg / day; from about 0.05 to about 0.8 mg / day; and a particularly preferred range is from about 0.05 to about 0.06 mg / day. It will be understood that the dose for a given patient will always be established at the discretion of the attending physician, and that the dose is subject to modification depending on the size of the patient, the thin or obese nature of the patient, the characteristics of the particular compound chosen, the intensity of the patient's habit of tobacco, opioids, ethanol or other combinations thereof, of the intensity of the symptoms of the patient's withdrawal syndrome, and of psychological factors that may affect the physiological responses of the patient. The drugs are almost always formulated in pharmaceutical dosage forms in order to provide an easily controllable dosage of the drug and to provide the patient with a presentable and easily manageable product. The present compound is capable of being formulated into conventional pharmaceutical dosage forms including capsules, tablets, inhalers, injectable parenteral solutions and suppositories. Nomally, the oral dosage forms, specifically tablets and capsules, are the most convenient for the patient and normally preferred. Liquid suspensions of formerly popular pharmaceutical preparations have become less popular and are rarely used, but the present compounds are fully available as such products if desired. While it is possible to administer 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine directly, it is preferably employed in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier, diluent or excipient and compound. Such formulations will contain from about 0.01% to about 99% of the compound. In the preparation of the formulations of the present invention, the active ingredient will normally be mixed with at least one vehicle, or diluted with at least one vehicle or included in a vehicle which may be in the form of a capsule, sachet, paper or other container using conventional techniques and procedures for the preparation of pharmaceutical formulations. When the vehicle serves as a diluent, it can be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active ingredient. In this way, the formulations can be presented in the form of tablets, granules, pills, powders, pills, sachets, capsules, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium) and gelatin capsules hard and soft. Examples of suitable carriers, diluents and excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, liquid paraffin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, gum tragacanth, gelatin, syrup, hypromellose, methyl and propyl hydroxybenzoates, vegetable oils, such as olive oil, injectable organic esters such as ethyl oleate, talc, magnesium stearate, water and mineral oil. The formulations may also include wetting agents, lubricants, emulsifiers and suspending agents, preservatives, sweetening agents, perfuming agents, stabilizing agents or flavoring agents. The formulations of the invention can be formulated in such a way as to provide immediate or non-immediate release of the active ingredient, by methods well known in the art.
Preferably, the formulations of the present invention will be formulated to obtain a non-immediate release of the active ingredient by transdermal or oral administration.
In the non-immediate release dosage forms, the release of the drug from its dosage form is the rate-limiting step in the kinetic path of release-absorption-elimination. This is distinguished from the immediate release dosage forms in which the absorption of the drug through the biological membrane is the rate limiting step. The non-immediate release systems have been divided into four categories: (1) delayed release;
(2) sustained release; (3) release in a specific place; and (4) release in the receiver. Generally, delayed release systems are those that employ repetitive intermediate dosages of a drug from one or more immediate release units incorporated in a single dosage form. Examples of delayed release systems include repeat-action tablets and enteric coated capsules and tablets in which delayed release is achieved by a barrier coating. Sustained release systems include both controlled release and prolonged release. Generally, sustained release systems include any drug delivery system that achieves a slow release of the drug over a prolonged period of time. When the system maintains constant levels of drug in the blood or tissue, it is considered a controlled release system. When the system extends the duration of the action beyond that provided by a conventional release system, it is considered a prolonged release system. The delivery systems in the recipient and at a specific location refer to the transport of the drug directly to a target area, to a desired biological location. In the case of a release in a specific place, an objective is a particular organ or tissue. Similarly, in the case of release in the recipient, the target is the particular receptor of a drug within the particular organ or tissue. Typical oral forms of non-immediate release include diffusion and dissolution systems. In diffusion systems, the rate of drug release is determined by its diffusion through a water-insoluble polymer. Normally there are two types of diffusion devices, reservoir-type devices in which a drug core is surrounded by a polymer membrane; and matrix-type devices in which the dispersed or dissolved drug is substantially and uniformly distributed in an inert polymer matrix. In actual practice, many systems that use diffusion may also depend to some extent on dissolution to determine the rate of release. The common practice used for the development of reservoir-type systems includes the microencapsulation of drug particles and the compressive coating of whole tablets or particles. Frequently, the microencapsulated coated particles form a system in which the drug is contained in the coating film as well as in the core of the microcapsule. The release of the drug typically includes a combination of dissolution and diffusion with the solution being the process that controls the rate of release. The material commonly used as a barrier coating membrane, alone or in combination, includes hardened gelatin, ethyl cellulose and hypromellose, polyhydroxymethacrylate, hydroxypropylcellulose, vinyl polyacetate, and various waxes. In matrix-type systems, the three main types of materials frequently used in the preparation thereof include insoluble plastics, hydrophilic polymers, and fatty compounds. The plastic matrices that are used include methyl acrylate-methyl methacrylate, poly (vinyl chloride) and polyethylene. Hydrophilic polymers include hypromellose, hydroxypropylcellulose and sodium carboxymethylcellulose. The fatty compounds include various waxes such as carnauba wax and glyceryl tristearate. The preparation of these matrix-type systems is carried out by methods well known to those skilled in the art. These methods of preparation generally consist of mixing the drug with the matrix material and compressing the mixture into tablets. In wax matrices, the drug is generally dispersed in molten wax, then coagulated, granulated and compressed into cores. As in other non-immediate systems, it is common for a portion of the drug to be available immediately as a first dose and the rest to be released in a sustained manner. This is generally carried out in the matrix-type system by placing a first dose in a coating on the tablet. The coating can be applied by compressive coating or a conventional coating suspension. Dissolution systems are generally products that have a reduced dissolution rate where the drug is highly soluble. Various approaches to achieve a slow dissolution rate include the preparation of a suitable salt or derivative of the active agent, by coating the drug with a slowly dissolving material, or by incorporating the drug in a tablet with a slowly dissolving vehicle. The encapsulated solution systems are prepared either by coating particles or drug granules with slowly soluble polymers of different thicknesses or by microcapsulation. The most commonly used microencapsulation method is coacervation, which involves the addition of a hydrophilic substance to a colloidal dispersion. The hydrophilic substance, which acts as a coating material, is selected from a wide variety of synthetic and natural polymers including rubber, lacquers, waxes, starches, acetate, phthalate or cellulose butyrate, polyvinylpyrrolidone, and poly ( vinyl chloride). Once the coating material is dissolved, the drug inside the microcapsule is immediately available for dissolution and absorption. The release of the drug, therefore, can be controlled by adjusting the thickness and speed of dissolution of the coating. For example, the thickness can be varied from less than 1 mm to 200 mm by changing the amount of coating material from about 3% to about 30% by weight of the total weight. By using different thicknesses, usually 3 or 4, the active agent will be released at different predetermined times to provide a delayed release effect. The coated particles can be compressed directly into tablets or placed inside capsules. Matrix-type delivery systems are prepared by compressing the drug with a slow dissolving polymeric vehicle in a tablet. There are generally two methods for the preparation of the drug-polymer particles, freezing and aqueous dispersion methods. In the freezing method, the drug is mixed with a polymer or wax and either cooled or cooled and sieved or spray frozen. In the aqueous dispersion method, the drug-polymer mixture is simply sprayed or placed in water and the resulting particles are collected. Osmotic systems are also available when osmotic pressure is used as a force directed to the release of a drug. Such systems generally consist of a drug core surrounded by a semipermeable membrane containing one or more orifices. The membrane allows the diffusion of water into the core, but does not allow the release of the drug except through the holes. Examples of materials used as semipermeable membranes include polyvinyl alcohol, polyurethane, cellulose acetate, ethylcellulose, and poly (vinyl chloride). Another system consists of ion exchange resins. These resins are water-insoluble crosslinked polymers containing salt-forming groups at positions that repeat along the polymer chain. The active agent is bound to the resin by repeated exposure of the resin to the drug in a chromatographic column, or by prolonged contact of the resin with a solution of the drug. The release of the drug from the drug-resin complex depends on the ionic environment; that is, the pH and the concentration of the electrolyte in the gastrointestinal tract, as well as the specific properties of the resin. The drug molecules attached to the resin are released by exchange with suitably charged ions in the gastrointestinal tract followed by infusion of the free drug molecule out of the resin. Generally, the rate of diffusion is controlled by the diffusion area, the link of the diffusion path, and the degree of crosslinking in the resin. A modification of the release rate can then be achieved by coating the drug-resin complex. The most common types of dosage forms used in non-immediate parenteral release therapies are intramuscular injections, implants for subcutaneous tissues and other body cavities, and transdermal devices. Generally, intramuscular injections involve the formation of a dissociable complex of a drug with another molecule. In this regard, the drug-molecule complex serves as a reservoir at the injection site for the release of the drug into the surrounding tissues. Examples of macromolecules include biological polymers such as antibodies and proteins or synthetic polymers such as polyvinylpyrrolidone, and polyethylene glycol. They can also form complexes between drugs and small molecules. When the drug molecule is larger in relation to the complexing agent, the association constant will be higher and the complex more stable. Examples of smaller molecules include zinc, optionally suspended in a gelatin solution or in an oil solution. An alternative dosage form for an intramuscular injection is an aqueous suspension. A stable suspension of active ingredient can be obtained by varying the viscosity and the particle size. Another common practice aimed at decreasing the rate of dissolution is the elimination of the saturation solubility of the drug. This is carried out by the formation of less soluble salts and prodrug derivatives and by using polymorphic crystalline forms of the active principle.
Another possibility is to use oil solutions and suspensions. As will be well appreciated by those skilled in the art, those drugs that have an appreciable oil solubility and the desired splitting characteristics are the most suitable. Examples of oils that can be used for intramuscular injection include sesame, olive, peanut, corn, almond, cottonseed and castor oil. In oily suspensions, the drug particles must first be dissolved in the oil phase and then divided in the aqueous medium. Oil-in-water or water-in-oil emulsions can also be used. The implants consist of a polymeric barrier-drug device that is inserted subcutaneously or in various body cavities. The polymeric material that is used must, of course, be biocompatible and non-toxic being usually chosen from among hydrogels, silicones, polyethylenes, ethylene-vinyl acetate copolymers and biodegradable polymers. Generally hydrogels are a polymeric material that shows the ability to swell in water and retain more than 20% of the water in its structure but will not dissolve in water. Low molecular weight substances are capable of diffusing through hydrogels. Specific examples of hydrogels include polyhydroxyalkyl methacrylate, polyacrylamide and polymethacrylamide, polyvinylpyrrolidone, polyvinyl alcohol and various polyelectrolyte complexes. Other additional systems include subcutaneous and intravaginal devices. The percutaneous absorption of the drug, usually referred to transdermal systems, generally includes micropore membranes as a barrier controlling the rate of release. Micropore membranes are films with different thicknesses and pore sizes that range from several microns to a few angtroms. Examples of construction materials of these membranes include regenerated cellulose, acetates and cellulose nitrates, cellulose triacetate, polypropylene, polycarbonate, and polytetrafluoroethylene. The barrier properties of these films depend on the preparation method, the means with which the pores are filled, the pore diameter, the porosity percentage and the tortuosity. In U.S. Patent No. 4,201,211, an example of a transdermal system is described. Delivery systems with transport to a specific site include nanoparticles and liposomes. Nanoparticles are examples of systems known as colloidal drug release system. Other members of this group include microcapsules, nanocapsules, macromolecular complexes, polymeric globules, microspheres and liposomes. Generally, a nanoparticle is a particle that contains the dispersed drug with a diameter of 200-500 nm. The materials used for the preparation of nanoparticles are non-toxic, biodegradable and sterilizable. Some examples include albumen, ethylcellulose, casein and gelatin. They are usually prepared by procedures similar to the coacervation method of microencapsulation. The liposomes, generally, are phospholipids that when dispersed in aqueous medium swell, hydrate and form multilamellar concentric bilayer vesicles with layers of aqueous medium separating the lipid bilayers. Phospholipids can also form a variety of structures that are not liposomes when dispersed in water based on the molar lipid-water ratio. At low ratios, the liposome is the preferred structure. The actual physical characteristics of liposomes depend on the pH, the ionic strength and the presence of divalent cations. They show low hypermeability to ionic and polar substances but at high temperatures they undergo a transition - which alters their permeability. Polar drugs are trapped in aqueous spaces and nonpolar (apolar) drugs bind to the lipid bilayer of the vesicle. Polar drugs are released when the bilayer is broken or by permeation, whereas apolar drugs remain attached to the bilayer until it is altered by temperature or exposure to lipoproteins. The liposome acts as a vehicle for the active agent. Depending on the method of administration, the formulations for the treatment of the states caused by the nicotine withdrawal syndrome, the opiates, the ethanol and the combinations thereof, can be formulated as tablets, capsules, injectable solutions for parenteral use, gels or suspensions of transdermal release, suspensions or elixirs for oral use or suppositories. Preferably the compositions will be formulated in a single dosage form each containing from 0.01 to 0.04 mg, generally from 0.05 to 0.3 mg of active ingredient. The term "single dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in relation to the desired daily or divided dose, in association with a suitable pharmaceutical vehicle, diluent or excipient thereof. When a sustained release formulation is desired, the single dosage form may contain from 0.01 to 2.0 mg of active ingredient. A preferred formulation of the invention is a non-immediate release or transdermal patch having from 0.01 to 2.0 mg or 0.05 to 2.0 mg of active ingredient together with a pharmaceutically acceptable carrier thereof. In order to illustrate the operation of this invention, the following examples of formulations are provided. The examples are illustrative only and are not intended to limit the scope of the invention. FORMULATION 1 Hard gelatine capsules prepared using the following ingredients:
The above ingredients are mixed and filled into hard gelatine capsules in 240 mg cations.
FORMULATION 2 Capsules containing 10 mg of drug are prepared as follows:
The active principle, the cellulose, the starch and the magnesium stearate are mixed, they are passed through a U.S. of nG of 45 mesh and are introduced in a hard gelatin capsule. FORMULATION 3 Capsules containing 10 mg of active substance are prepared as follows:
The above ingredients are mixed vigorously and placed in an empty gelatin capsule. FORMULATION 4 Tablets containing 10 mg of active substance are prepared as follows:
The active principle, starch and cellulose are passed through a U.S. of No. 45 mesh, and mix vigorously. The polyvinylpyrrolidone solution is mixed with the resultant powders which are passed through a U.S. sieve of mesh size 14. The granulate thus obtained is dried at 50-60 ° C and passed through a U.S. of mesh size 18. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a U.S. sieve, are then added. 60 mesh size, to the granulate that, after being mixed, is compressed in a compression machine to obtain a 100 mg tablet weight. FORMULATION 5 A tablet can be prepared using the ingredients indicated below:
The components are mixed and compressed to obtain tablets of 420 mg weight each. FORMULATION 6 Suspensions containing 5 mg of medication per 40 mL dose can be prepared as follows:
The medicament is passed through a U.S. sieve. 45 mesh size and mixed with the sodium carboxyhiprolose and syrup to form a soft paste. The benzoic acid solution, the aroma and the color are diluted with water and added while stirring. Then water is added in sufficient quantity to obtain the required volume. The usefulness of the compound in the treatment of a disease produced as a result of the cessation of use or the appearance of the nicotine withdrawal syndrome and the lack of sedative effect is supported by the following studies.
I. Auditory Startle Response Animals: Long Evans male rats (Harían Sprague Dawley, Columbus, Indiana) are kept individually in a controlled environment in a 12-hour light-dark cycle. The rats are allowed to freely access food (Purina Rodent Chow) and water. All treatment groups consist of 8 to 10 rats. ' Chronic nicotine treatment: Rats are anesthetized with isoflurane and Alzet osmotic minipumps are implanted subcutaneously (Alza Corporation, Palo Alto, California, Model 2 ML2). Nicotine ditartrate is dissolved in physiological saline. The pumps are filled with nicotine ditartrate (6 mg / kg base / day) or physiological saline. Twelve days after the implantation of the pumps, the rats are anesthetized and the pumps are removed. Observation of auditory startle response: The sensory motor reactions (response to auditory startle (peak amplitude, Vraax)) of the individual rats are recorded using starter cameras from San Diego Instruments (San Diego, California). The startle sessions consist of a 5-minute adaptation period at the level of background noise of 70 +/- 2dBA immediately followed by 25 presentations of auditory stimuli (120 +/- 2 dBA of noise, 50 minutes of duration) presented to intervals of 8 seconds. The amplitudes of the peaks caused by the start are averaged for the 25 stimulus presentations per session. The response to auditory startle is evaluated daily at 24 hour intervals on days 1, 2 and 3 after the nicotine suppression. The compound 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine is administered subcutaneously in 3 doses approximately 15 minutes before the startle assay each day. Clonidine was also analyzed. Ambulatory activity response: Spontaneous activity of Long Evans male rats was recorded using Multi-Variax activity monitors (Columbus Instruments, Columbus, Ohio). The interruptions of three individual infrared photocells were recorded by computer. The activity counts were accumulated at 15 minute intervals during the hour immediately following the administration of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine (0.01, 0.1, 1 mg / kg, sc), clonidine (0.1, 0.3, 1.0 mg / kg, sc), or saline control. The ambulatory activity records represent the sum of the interruptions of the individual emissions in a representative time interval. Results: As illustrated in Tables 1, 2, 3 and 4, the subcutaneous administration of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine (Moxonidine) 15 minutes before the test of Startle significantly attenuated the effects of nicotine suppression on the auditory startle reflex. The compounds were as follows: A. Moxonidine B. Clonidine
Table 1
* Significantly different from the nicotine / saline control, p < 0.05.
Table 2
* Significantly • different from saline / saline solution control, p < 0.05.
Table 3 Acute effect
* Significantly different from saline control, p < 0.05. Table 4 Acute effect
* Significantly different from saline control, p < 0.05.
Table 5 Spontaneous Activity Levels (Counting)
* Significantly different from vehicle control, p
< 0.05. As can be seen in Table 2 above, clonidine administered subcutaneously effectively effectively reduces the rise in startle reactivity usually observed in rats that have experienced the withdrawal syndrome caused by nicotine. The ED50 for clonidine administered subcutaneously in this model is approximately 0.0004 mg / kg. Treatment with moxonidine prior to the startle test during nicotine suppression also effectively blocks the hyperreactivity that is commonly observed (ED50 about 0.00007 mg / kg, see Table 1 above). These data indicate that moxonidine may be useful as an aid to smoking cessation and nicotine withdrawal in mammals at unexpectedly lower and more significant doses than clonidine. Since the effects observed in the auditory startle could be partially produced as a result of drug-related sedation or the inability to respond to startle, the rats were evaluated to determine the comparative effects of moxonidine and clonidine on locomotor activity and response to startle in animals not dependent on nicotine. The results of the activity assay for clonidine and moxonidine are shown in Table 5. As can be seen, clonidine reduced the ambulatory activity significantly at doses = 0.03 mg / kg. Moxonidine also reduced ambulatory activity but a dose of 1 mg / kg was necessary to cause a reduction in ambulatory activity similar to the reduction observed with the 0.03 mg / kg dose of clonidine. Both compounds also reduce the auditory startle response (see Tables 3 and 4) at doses that are equivalent to the doses that reduce ambulation. Again, clonidine is more potent than moxonidine in reducing the baseline response to startle. These data indicate that clonidine produces sedation and interferes with the response to doses more than 30 times lower than moxonidine. Table 6 Comparison of moxonidine and clonidine
Clonidine is able to reduce the reflex to the acoustic startle increased by the nicotine withdrawal syndrome. However, clonidine also produces sedation side effects at doses that are less than 100 times higher than ED50 in the nicotine withdrawal syndrome trial. This limited separation between efficacy and side effects for clonidine in the rat parallels its narrow therapeutic window in smoking cessation treatment and nicotine withdrawal in man. Moxonidine is more potent than clonidine in the nicotine elimination test and produces sedation side effects only at doses greater than ten thousand times higher than ED50 in the nicotine elimination test. Therefore, moxonidine will have good efficacy as an aid to smoking cessation and in the treatment of nicotine withdrawal syndrome without producing the side effects observed with clonidine. The following studies support the utility of the compound for the treatment of a disease caused by cessation of use and the appearance of the opiate withdrawal syndrome. Materials Dependence and Opiate Withdrawal Syndrome Opioid dependence was induced in Sprague-Dawley male mice (Charles Rives, 250-350 g) by s.c. of morphine boluses. They were implanted under halothane anesthesia two boluses daily (75 mg of morphine per bolus) for two days. Withdrawal syndrome was induced 48 hours after the last bolus group was implanted; all four boluses were removed 1 hour before causing the withdrawal syndrome. Elimination was induced by administration of the opiate antagonist naltrexone hydrochloride (10 mg / kg; Sigma) s.c. Behavioral estimates To evaluate the behavior caused by the opiate withdrawal syndrome, animals were studied in transparent plexiglass cages (45.72 x 25.40 x 20.32 centimeters). The animals remained in these cages throughout the study. The animals were adapted to the cages for fifteen minutes and pretreated with moxonidine or saline (1 ml / kg s.d.). Naltrexone was administered fifteen minutes after pretreatment. Previously, eleven identified characteristic behaviors of rats with the withdrawal syndrome were evaluated (see Himmelsback et al., 1935; Way et al., 1969; Wei, 1963; Blásig et al., 1973; Aceto et al., 1986). The absolute frequency of 7 episodic behaviors was recorded and the result was calculated based on multiples of five incidents (0 = no incident, 1 = 1-5 incidents, etc). The behaviors recorded in this way included: teeth grinding (separated by at least 3s), jumping, shaking, twisting, diarrhea, digging and erections. Similarly, chewing movements (with nothing in the mouth) were recorded in multiples of one hundred incidences. Three behaviors caused by withdrawal syndrome could not be defined in specific episodes and the severity thereof was evaluated during the predefined support points on a four-point scale: 0 = absence; 1 = mild; 2 = moderate; 3 = marked. The behaviors estimated in this way were lacrimation, ptosis and salivation. At the end of the estimation period the weight loss was determined (one hour after the administration of naltrexone) and the result was calculated based on multiples of 5 g (0 = no loss, 1 = 1-5 g; = 6-10 g, 3 = 11-15 g, etc.).
Table 7
* Significantly different from saline control, P < 0.05. It is noted that. in relation to this date, the best method known by the applicant to bring the aforementioned invention into practice is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (5)
1. The use of 4-chloro-5- (imidazolin-2-ylamino) -6-methoxy-2-methylpyrimidine, or a pharmaceutically acceptable salt thereof, for the treatment of symptoms or conditions caused as a result of cessation of use or emergence of tobacco withdrawal syndrome, nicotine, opioids, ethanol or other combinations thereof.
2. The use of claim 1, for the treatment of symptoms or conditions caused as a result of cessation of use or the occurrence of the withdrawal syndrome of tobacco or nicotine.
3. The use of claim 1, for the treatment of symptoms or conditions caused as a result of cessation of use or the occurrence of the opioid withdrawal syndrome.
4. The use of claim 1, for the treatment of symptoms or conditions caused as a result of cessation of use or the occurrence of ethanol withdrawal syndrome.
5. The use of an I1 gonist or a pharmaceutically acceptable salt thereof having a selectivity value of receptor I1 to receptor a2 greater than 20, for the inhibition of the symptoms or states evoked as a consequence of the cessation of use or the appearance of the tobacco withdrawal syndrome, nicotine, opioids, ethanol or other combinations thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US234195P | 1995-08-15 | 1995-08-15 | |
US002341 | 1995-08-15 |
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MX9603341A MX9603341A (en) | 1997-07-31 |
MXPA96003341A true MXPA96003341A (en) | 1997-12-01 |
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