WO2009097414A1 - Use of imidazolylalkyl-pyridines for the treatment of addictive disorders - Google Patents

Use of imidazolylalkyl-pyridines for the treatment of addictive disorders Download PDF

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WO2009097414A1
WO2009097414A1 PCT/US2009/032415 US2009032415W WO2009097414A1 WO 2009097414 A1 WO2009097414 A1 WO 2009097414A1 US 2009032415 W US2009032415 W US 2009032415W WO 2009097414 A1 WO2009097414 A1 WO 2009097414A1
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method
addiction
lower alkyl
pyridine
hydrogen
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PCT/US2009/032415
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French (fr)
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Christian Lavedan
Mihael H. Polymeropoulos
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Vanda Pharmaceuticals, Inc.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Abstract

The present invention relates to the use of certain azolylalkyl-pyridines to treat addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction, and/or nicotine addiction.

Description

USE OF IMIDAZOLYLALKYL-PYRIDINES FOR THE TREATMENT OF ADDICTIVE DISORDERS

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of co-pending U.S. Provisional Application No. 61/024,262, filed January 29, 2008, which is hereby incorporated herein in its entirety.

BACKGROUND OF THE INVENTION

(1 ) Technical Field

The present invention relates generally to the treatment of addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction and/or nicotine addiction comprising administering a therapeutically effective, nontoxic dose of imidazolylalkyl-pyridines and derivatives to a patient. The present invention also relates generally to the treatment of diseases wherein addictive disorder, psychoactive substance use disorder, intoxication disorder, inhalation disorder, alcohol addiction, tobacco addiction and/or nicotine addiction is a contributing factor or a complicating condition associated with another disease, disorder, or condition.

(2) Description of Related Art

Drug addiction is a complex brain disease. It is characterized by compulsive, at times uncontrollable, drug craving, seeking, and use that persist even in the face of extremely negative consequences. Drug seeking becomes compulsive, in large part as a result of the effects of prolonged drug use on brain functioning and behavior. For many people, drug addiction becomes chronic, with relapses possible even after long periods of abstinence

(http://teens.drugabuse.gov/drnida/drnida_brain1.asp). Drug abuse is a major public health problem that impacts society on multiple levels. Drugs take a tremendous toll on our society at many levels. This includes healthcare expenditures, lost earnings, and costs associated with crime and accidents. This is an enormous burden that affects all of society - those who abuse these substances, and those who don't. See, e.g., http://www.nida.nih.gov/about/welcome/aboutdrugabuse/magnitude/. Many of America's top medical problems (cancer, heart disease, HIV/AIDS) and social problems (drugged driving, diolence, dtress, child abuse) can be directly linked to drug abuse.

However, because of the addictive properties of drugs, most users find it very difficult to quit. The development of effective therapies for the prevention of self- administration of addictive drugs, relapses, and the attenuation of withdrawal syndrome is of particular importance.

A key molecular player in the biology of addiction is dopamine, a neurotransmitter released by neurons in the brain. Because dopamine provides feelings of enjoyment, it is commonly associated with the pleasure system of the brain. Dopamine is released by naturally-rewarding experiences such as food, sex, use of certain drugs and other stimuli that become associated with them. Excess dopamine in the brain often creates rewarding feelings and sometimes even euphoria. Many drugs, especially amphetamines and cocaine, trigger the release of dopamine.

One treatment approach to addiction is the use of smaller doses of the addictive drug, which can suppress withdrawal and prevent craving, such as the use of nicotine patches for tobacco users. Another approach is the use of substitute therapies where the feeling of reward is provided by a safer and less addictive drug, such as the administration of methadone to individuals addicted to an opiate (e.g., heroin), or Naltrexone to individuals with a narcotic or alcohol addiction.

SUMMARY OF THE INVENTION

The present invention relates to the use of certain imidazolylalkyl-pyridines as compounds to treat or prevent addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, eating disorders, alcohol addiction, tobacco addiction and/or nicotine addiction. Such disorders are herein collectively referred to as "addictive disorders" and include any abnormal addictive behaviors that are ameliorated by enhanced dopamine activity. In illustrative uses, the addictive disorder is one in which the subject is addicted to an addictive substance.

More particularly, the present invention relates to such uses of compounds of formula I,

Figure imgf000005_0001
wherein Ri is hydrogen, lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl, R2 and R3 independently of one another are hydrogen or lower alkyl, R4 is hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen with an atomic number of 9 to 35, in free base or acid addition salt form, and the bridge between the pyridine and the imidazole, illustrated as methylene, is methylene or ethylene.

A particular aspect of the invention provides a method of treating at least one symptom of withdrawal from an addictive substance in an individual that comprises administering to the individual an effective amount of an imidazolylmethyl-pyridine of formula 1.

Another aspect of the invention provides a method of treating an addictive craving in an individual, comprising administering to the individual an effective amount of an imidazolylmethyl-pyridine of formula 1.

Yet another aspect of the invention provides a method of preventing a relapse in drug use in an individual that comprises administering to the individual an effective amount of an imidazolylmethyl-pyridine of formula 1.

The foregoing and other features of the invention will be apparent from the following more particular description of embodiments of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows stimulated tritium outflow from rat striatal slices at baseline; FIG. 2 shows the effect of [2-(2-methylimidazol-1-yl)methyl]pyridine on basal and stimulated tritium outflow at varying concentrations;

FIGS. 3 and 4 show the effects of [2-(2-methylimidazol-1-yl)methyl]pyridine on basal and stimulated tritium outflow in the presence of cocaine and tetrodotoxin.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "lower," in the context of alkyl and alkoxy groups, denotes a radical having up to 7 carbon atoms, preferably up to 4 carbon atoms and more preferably up to 2 carbon atoms. Consequently, lower alkyl has especially up to 7 carbon atoms, preferably up to 4 carbon atoms, and in particular up to 2 carbon atoms and is, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, or hexyl. Accordingly, lower alkoxy has up to 7 carbon atoms, preferably up to 4 carbon atoms, and in particular up to 2 carbon atoms and is, for example, methoxy, ethoxy, propoxy, butoxy, tert-butoxy or hexyloxy.

Insofar as above-defined, lower alkyl or lower alkoxy groups present in the compounds of formula (I), preferably have one or two carbon atoms and especially signify methyl or methoxy. The imidazolylmethyl radical is preferably in position 2 of the pyridine. Ri is preferably methyl or ethyl, more preferably methyl. R2 and R3 are preferably each hydrogen. R4 is preferably methyl, ethyl or hydrogen, more preferably methyl or hydrogen, and in particular hydrogen. The compound [2-(2- methylimidazol-1-yl)methyl]pyridine, exemplified in Example 1 of U.S. Patent No. 5,635,521 is preferred.

In a particular group of compounds of formula (I), Ri is lower alkyl, R2 and R3 independently of one another are hydrogen or lower alkyl, and R4 is hydrogen, lower alkyl, or halogen with an atomic number of 9 to 35.

In a further particular group of compounds of formula (I), Ri is methyl, R2 and R3 independently of one another are hydrogen or methyl, and R4 is hydrogen, methyl, or halogen with an atomic number of 9 to 35.

Halogen with an atomic number of 9 to 35 denotes in particular a fluorine and chlorine residue, more preferably a chlorine residue.

The compounds of formula (I) may be present in free base form or in the form of their acid addition salts, including, for example, hydrogen fumarate and fumarate salt forms. Acid addition salts may be produced from the free bases in known manner, and vice versa.

The compounds of formula (I) are known, e.g., from U.S. Patent Nos. 5,856,343 and 5,635,521 , which are incorporated herein by reference, or may be produced in accordance with known processes, i.e., analogously to known processes.

U.S. Patent No. 5,856,343 describes synthesis of [2-(2-methylimidazol-1- yl)methyl]pyridine as follows:

"9.7 g (75 mM) of 2-(chloromethyl)pyridine and 42 g (512 mM) of 2- methyl- imidazole are suspended in 40 ml dimethylformamide, then stirred for 3 hours at 105 0C. The dimethylformamide is distilled off and the crystalline residue is diluted with ethyl acetate and a little hexane. Following filtration, the mother solution is concentrated by evaporation and the dimethylformamide distilled off, and then shaken out several times between water and methylene chloride. 10.3 g of the oily title compound are obtained."

Preparation of the fumarate salt is described as follows: "9.3g of the obtained base in ethanol are mixed with 12.7g of fumaric acid. The resulting bis(base)-tris(hydrogen fumarate) crystallizes from ethanol/ethyl acetate and is recrystallized once from ethanol/ethyl acetate. It is uniform upon thin- layer chromatography and melts at 109°-110°. The fumarate is obtained analogously and melts at 120°-121 °."

Enhanced Dopamine Release

In a neurotransmitter release study, the fumarate salt of [2-(2-methylimidazol- 1-yl)methyl]pyridine was shown to be able to enhance dopamine release.

1. Methods

Rat striatal slices were preincubated with tritium-labeled dopamine and superfused with Krebs-Ringer bicarbonate buffer saturated with 95% O2 / 5% CO2 (1.2 mL/min). Fractions were collected at 5 minute intervals after 60 minutes superfusion. This enables the study of a drug's effect on dopamine release from striatal terminals independent from the influence of the substantia nigra. Tritium overflow from such striatal slices has been shown to reflect dopamine release.

The striatal slices were stimulated by electric pulses (2 Hz, 2 ms, 12 mA) twice for two minutes after 75 minutes (S1 ) and 130 or 150 minutes (S2) of supervision. [2-(2-methylimidazol-1-yl)methyl]pyridine was present during the entire experiment or was added 30 minutes before the second stimulation (S2).

2. Results

As can be seen in FIG. 1 , the striatal slices continually release small amounts of tritium, but that release is markedly enhanced by electrical stimulation. Average basal tritium outflow in the first fraction was approximately 1.33% of tissue tritium content every five minutes. The average outflow evoked by stimulation at S1 was approximately 2.23% of tissue tritium content.

In FIG. 2, it can be seen that [2-(2-methylimidazol-1-yl)methyl]pyridine decreased stimulated tritium outflow at a concentration of 10 μM and increased basal tritium outflow at concentrations of 100 μM and 1000 μM. At 100 μM, the basal outflow was increased 1.7 fold and at 1000 μM, it was increased 10 fold over vehicle alone (FIG. 1 ). The results shown in FIGS. 3 and 4 demonstrate that [2-(2- methylimidazol-1-yl)methyl]pyridine increases basal tritium outflow even in the presence of cocaine (10 μM) or tetrodotoxin (TTX; 0.1 μM), respectively.

3. Conclusions

These results show that [2-(2-methylimidazol-1-yl)methyl]pyridine enhances dopamine release by directly affecting presynaptic release modulating heteroreceptors rather than by uptake inhibition (stimulation-evoked tritium release was decreased), indirect mediation by endogenous factors (tritium release was enhanced in the presence of tetrodotoxin), or the displacement of dopamine from intraneuronal stores (basal dopamine release was not inhibited by cocaine). Accordingly, these results indicate that [2-(2-methylimidazol-1-yl)methyl]pyridine would be useful in treating addictive disorders and abnormal addictive behaviors that are ameliorated by enhanced dopamine activity.

In another study, [2-(2-methylimidazol-1-yl)methyl]pyridine was found to enhance dopamine release from the striatum, in vivo. [2-(2-methylimidazol-1- yl)methyl]pyridine was administered orally to three groups of rats at concentrations of 5 mg/kg, 10 mg/kg, and 20 mg/kg. The group receiving the 5 mg/kg dose exhibited a 25% increase in dopamine release over basal values after one hour. Dopamine release increased to 120% over basal values in the 20 mg/kg group.

Additional data support the use of the fumarate salt for the treatment of addictions: gene expression profiling experiments in animals exposed to the fumarate salt demonstrate an increase of gene transcripts previously shown to be decreased in nucleus accumbens of human cocaine abusers (Albertson et al. J Neurochem. 2004 Mar; 88(5):1211-9). More specifically, for a number of myelin- related genes, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin-associated oligodendrocyte basic protein (MOBP), we observed that, upon treatment with the fumarate salt, gene expression of MBP was increased in rat retina and monkey hippocampus, MOBP was increased in monkey hippocampus, and PLP was increased in rat retina.

The compounds of formula (I) and their physiologically acceptable salts exhibit positive effects on treating or preventing certain addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction and/or nicotine addiction and may be used in the treatment of such conditions. The compounds according to the invention are therefore useful to treat or prevent symptoms of withdrawal, cravings, and relapses associated with addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction and/or nicotine addiction.

As used herein the terms "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease-modifying treatment, including treatment of patients at risk of contracting the disease/disorder or suspected to have contracted the disease/disorder as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, i.e., an addictive disorder. The terms "treatment" or "treat" may also refer to the administration to an individual of an agent less harmful to the individual than a more harmful agent (e.g., alcohol, a narcotic, nicotine, etc.) currently or previously administered to or self- administered by the individual. Typically, such more harmful agents induce cravings for the agents or other addictive behavior in the individual, such that the dosage less harmful agent administered to the individual may gradually be reduced and eliminated upon the diminishment or elimination of such cravings or other addictive behavior. In other words, the compounds of the present invention may be provided as less addictive substances than the addictive substances associated with addictive disorders. In other cases, for example, when the addictive disorder is not associated with an addictive substance, the compounds of the invention may provide an alternative stimulation that reduces the compulsion to engage ion the addictive disorder.

The compounds according to the invention may be administered by any conventional route, in particular enterally, orally, or topically, for example in the form of tablets, capsules or eye drops, or parenterally, for example in the form of injectable solutions or suspensions.

An effective amount of the active agent of the invention, e.g., an imidazolylmethyl-pyridine such as the fumarate salt, may be administered to a subject animal (typically a human but other animals, e.g., farm animals, pets and racing animals, can also be treated, e.g., for behavioral disorders). An effective amount is an amount that prevents, inhibits, or terminates symptoms of withdrawal or cravings, or prevents relapses associated with addictive disorders, psychoactive substance use disorders, intoxication disorders, inhalation disorders, alcohol addiction, tobacco addiction and/or nicotine addiction.

Symptoms associated with withdrawal from an addictive substance such as alcohol, narcotics, and nicotine may include, for example, feelings of jumpiness, feelings of nervousness, feelings of shakiness, anxiety, irritability, a condition of being easily excited, emotional volatility, rapid emotional changes, depression, fatigue, difficulty thinking clearly, bad dreams, a state of confusion and visual hallucination (i.e., delirium tremens), agitation, fever, convulsions, "black outs" (when the person forgets what happened), headache - general, pulsating, sweating (especially the palms of the hands or the face), nausea, vomiting, loss of appetite, insomnia, sleeping difficulty, paleness, rapid heart rate (palpitations), pupils of different size (enlarged, dilated pupils), clammy skin, and abnormal movements (e.g., tremor of the hands, and involuntary, abnormal movements of the eyelids).

For the indications as described herein, the appropriate dosage will, of course, vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at daily dosages from about 0.05 to about 50 mg/kg animal body weight. In larger mammals, such as humans, an indicated daily dosage may typically range from about 0.1 mg to about 1600 mg, more typically about 1 mg to about 800 mg, and most typically about 10 mg to about 200 mg, conveniently administered, for example, in divided doses up to four times a day. Such dosages typically represent initial dosages. Upon the diminishment or elimination of cravings or other addictive behavior, such dosages may be reduced and/or eliminated. Such a reduction in dosage is preferably gradual over a period of weeks or months.

It will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

For therapeutic or prophylactic use, an imidazolylmethyl-pyridine will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal, intravenous, transdermal (such as via a dermal patch, gel, microneedle, iontophoresis, sonophoresis, or phonophoresis)), bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, in the form of a troche or lozenge, or in a chewable format such as a chewing gum. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and the like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to parenteral dosage forms. Particularly useful is the administration of a compound of Formula I in oral dosage formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.

In making pharmaceutical compositions containing compounds of the present invention, the active ingredient(s) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, gum, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

Some examples of suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to 800 mg of the active ingredient. The term "unit 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 association with the required pharmaceutical carrier.

The compounds of the present invention can also be used in combination with other agents, especially agents also shown to be useful in treating addictive disorders, by substitution for a more harmful substance.

Claims

CLAIMSWhat is claimed is:
1. A method of treating or preventing in an individual an addictive disorder, the method comprising: internally administering to the individual an effective amount of a compound having the formula:
Figure imgf000017_0001
wherein
Ri is hydrogen, lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl;
R2 and R3 independently of one another are hydrogen or lower alkyl;
R4 is hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen with an atomic number of 9 to 35; and the bridge between the pyridine and the imidazole, illustrated as methylene, is methylene or ethylene.
2. The method of claim 1 , wherein the addictive disorder is selected from psychoactive substance use disorders, intoxication disorders, inhalation disorders, eating disorders, alcohol addiction, tobacco addiction and/or nicotine addiction and Ri is lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl and the bridge between the pyridine and the imidazole is methylene.
3. The method of claim 2, wherein Ri is methyl.
4. The method of claim 1 , 2, or 3 wherein the compound administered is in free base, hydrogen fumarate, or fumarate salt form.
5. The method of claim 1 , wherein the compound administered is [2-(2- methylimidazol-1-yl-)methyl]pyridine, in free base or physiologically acceptable acid addition salt form.
6. The method of claim 5, wherein the compound administered is [2-(2- methylimidazol-1-yl)methyl]pyridine in free base, hydrogen fumarate, or fumarate salt form.
7. The method of claim 5, wherein the compound administered is [2-(2- methylimidazol-1 -yl)methyl]pyridine fumarate.
8. The method of claim 1 , wherein the addictive disorder is selected from a group consisting of: alcohol addiction, nicotine, addiction, tobacco addiction, drug addiction, gambling addiction, sexual addiction, and food addiction.
9. The method of any of the above claims wherein the compound administered has the formula:
Figure imgf000019_0001
wherein Ri is methyl.
10. The method of claim 9, wherein the compound administered is in free base or physiologically acceptable acid addition salt form.
11. The method of claim 9, wherein the compound administered is in free base, hydrogen fumarate, or fumarate salt form.
12. The method of any of the above claims wherein the compound is administered orally, by inhalation, topically, transmucosally, parenterally, intravenously, or intraocularly.
13. The method of any of the above claims wherein the compound is administered in at least one of an immediate release form, a controlled release form, and a sustained release form.
14. The method of any of the above claims wherein the effective amount is between about 0.1 and about 1600 mg/kg/day.
15. The method of any of the above claims wherein the effective amount is between about 1 and about 800 mg/kg/day.
16. The method of claim 15, wherein the effective amount is between about 10 and about 200 mg/kg/day.
17. A method of treating or preventing symptoms of withdrawal from an addictive substance in an individual comprising: internally administering to the mammal an effective amount of a compound having the formula:
Figure imgf000021_0001
wherein
Ri is hydrogen, lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl;
R2 and R3 independently of one another are hydrogen or lower alkyl;
R4 is hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen with an atomic number of 9 to 35; and the bridge between the pyridine and the imidazole, illustrated as methylene, is methylene or ethylene.
18. The method of claim 17, wherein Ri is lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl and the bridge between the pyridine and the imidazole is methylene.
19. The method of claim 18, wherein Ri is methyl.
20. The method of claim 17, 18, or 19 wherein the compound administered is in free base, hydrogen fumarate, or fumarate salt form.
21. The method of claim 17, wherein the compound administered is [2-(2- methylimidazol-1-yl-)methyl]pyridine, in free base or physiologically acceptable acid addition salt form.
22. The method of claim 21 , wherein the compound administered is [2-(2- methylimidazol-1-yl)methyl]pyridine in free base, hydrogen fumarate, or fumarate salt form.
23. The method of claim 21 , wherein the compound administered is [2-(2- methylimidazol-1 -yl)methyl]pyridine fumarate.
24. The method of any of the claims 17 through 23 wherein the addictive disorder is selected from a group consisting of: alcohol addiction, nicotine, addiction, tobacco addiction, drug addiction, gambling addiction, sexual addiction, or food addiction.
25. The method of any of the claims 17 through 24 wherein symptoms of withdrawal include at least one of the following: feeling of jumpiness or nervousness, feeling of shakiness, anxiety, irritability or easily excited, emotional volatility, rapid emotional changes, depression, fatigue, difficulty with thinking clearly, bad dreams, a state of confusion and hallucinations (visual) - known as delirium tremens, agitation, fever, convulsions, "black outs" (when the person forgets what happened), headache - general, pulsating, sweating, especially the palms of the hands or the face, nausea, vomiting, loss of appetite, insomnia, sleeping difficulty, paleness, rapid heart rate (palpitations), pupils different size (enlarged, dilated pupils), clammy skin, and abnormal movements (tremor of the hands, involuntary, abnormal movements of the eyelids).
26. A method of treating or preventing cravings in an individual comprising: internally administering to the individual an effective amount of a compound having the formula:
Figure imgf000024_0001
wherein
Ri is hydrogen, lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl;
R2 and R3 independently of one another are hydrogen or lower alkyl;
R4 is hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen with an atomic number of 9 to 35; and the bridge between the pyridine and the imidazole, illustrated as methylene, is methylene or ethylene.
27. The method of claim 26, wherein Ri is lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl and the bridge between the pyridine and the imidazole is methylene.
28. The method of claim 27, wherein Ri is methyl.
29. The method of claim 26, 27, or 28 wherein the compound administered is in free base, hydrogen fumarate, or fumarate salt form.
30. The method of claim 26, wherein the compound administered is [2-(2- methylimidazol-1-yl-)methyl]pyridine, in free base or physiologically acceptable acid addition salt form.
31. The method of claim 30, wherein the compound administered is [2-(2- methylimidazol-1-yl)methyl]pyridine in free base, hydrogen fumarate, or fumarate salt form.
32. The method of claim 30, wherein the compound administered is [2-(2- methylimidazol-1 -yl)methyl]pyridine fumarate.
33. A method of treating or preventing a relapse in the use of an addictive substance in an individual comprising: internally administering to the mammal an effective amount of a compound having the formula:
Figure imgf000026_0001
wherein
Ri is hydrogen, lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl;
R2 and R3 independently of one another are hydrogen or lower alkyl;
R4 is hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen with an atomic number of 9 to 35; and the bridge between the pyridine and the imidazole, illustrated as methylene, is methylene or ethylene.
34. The method of claim 33, wherein Ri is lower alkyl, halogen with an atomic number of 9 to 35 or amino optionally mono- or disubstituted by lower alkyl and the bridge between the pyridine and the imidazole is methylene.
35. The method of claim 34, wherein Ri is methyl.
36. The method of claim 33, 34, or 35 wherein the compound administered is in free base, hydrogen fumarate, or fumarate salt form.
37. The method of claim 33, wherein the compound administered is [2-(2- methylimidazol-1-yl-)methyl]pyridine, in free base or physiologically acceptable acid addition salt form.
38. The method of claim 37, wherein the compound administered is [2-(2- methylimidazol-1-yl)methyl]pyridine in free base, hydrogen fumarate, or fumarate salt form.
39. The method of claim 37, wherein the compound administered is [2-(2- methylimidazol-1 -yl)methyl]pyridine fumarate.
40. The method of any of the claims 33 through 39 wherein the addictive disorder is selected from a group consisting of: alcohol addiction, nicotine, addiction, tobacco addiction, drug addiction, gambling addiction, sexual addiction, and food addiction.
41. The method of any of the claims 33 through 40 wherein the compound is administered orally, by inhalation, topically, transmucosally, parenterally, intravenously, or intraocularly.
42. The method of any of the claims 33 through 40 wherein the compound is administered in at least one of an immediate release form, a controlled release form, and a sustained release form.
43. The method of any of the claims 33 through 42 wherein the effective amount is between about 0.1 and about 1600 mg/kg/day.
44. The method of claim 43, wherein the effective amount is between about 1 and about 800 mg/kg/day.
45. The method of claim 44, wherein the effective amount is between about 10 and about 200 mg/kg/day.
46. The method of claim 33, wherein the compound administered has the formula:
Figure imgf000028_0001
wherein Ri is methyl.
47. The method of claim 46, wherein the compound administered is in free base or physiologically acceptable acid addition salt form.
48. The method of claim 46, wherein the compound administered is in free base, hydrogen fumarate, or fumarate salt form.
49. The method of claim 46, 47, or 48 wherein the compound is administered orally, by inhalation, topically, transmucosally, parenterally, intravenously, or intraocularly.
50. The method of claim 46, 47, or 48 wherein the compound is administered in at least one of an immediate release form, a controlled release form, and a sustained release form.
51. The method of any of claims 46 through 50 wherein the effective amount is between about 0.1 and about 1600 mg/kg/day.
52. The method of claim 51 , wherein the effective amount is between about 1 and about 800 mg/kg/day.
53. The method of claim 52, wherein the effective amount is between about 10 and about 200 mg/kg/day.
54. The method of any of claims 46 through 50 wherein the addictive disorder is selected from a group consisting of: alcohol addiction, nicotine, addiction, tobacco addiction, drug addiction, gambling addiction, sexual addiction, and food addiction.
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WO2001078726A1 (en) * 2000-04-13 2001-10-25 Novartis Ag New uses of imidazolylmethyl-pyridines
WO2001081326A1 (en) * 2000-04-21 2001-11-01 Suntory Limited Substituted 1-aza-2-imino-heterocycles and their use as nicotinic acetylcholine receptors activators
EP1176141A1 (en) * 1999-03-05 2002-01-30 Suntory Limited HETEROCYCLIC COMPOUNDS HAVING EFFECT OF ACTIVATING NICOTINIC ACETYLCHOLINE $g(a)4$g(b)2 RECEPTOR
WO2004087653A2 (en) * 2003-04-03 2004-10-14 Merck & Co., Inc. 4-ring imidazole derivatives as modulators of metabotropic glutamate receptor-5
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Publication number Priority date Publication date Assignee Title
US5856343A (en) * 1991-09-23 1999-01-05 Novartis Ag Imidazolylmethyl-pyridines used for senile dementia
EP1176141A1 (en) * 1999-03-05 2002-01-30 Suntory Limited HETEROCYCLIC COMPOUNDS HAVING EFFECT OF ACTIVATING NICOTINIC ACETYLCHOLINE $g(a)4$g(b)2 RECEPTOR
US6303638B1 (en) * 1999-08-06 2001-10-16 The Regents Of The University Of California Substituted pyridines as modulators of the mammalian neuronal nicotinic acetylcholine receptor
WO2001078726A1 (en) * 2000-04-13 2001-10-25 Novartis Ag New uses of imidazolylmethyl-pyridines
WO2001081326A1 (en) * 2000-04-21 2001-11-01 Suntory Limited Substituted 1-aza-2-imino-heterocycles and their use as nicotinic acetylcholine receptors activators
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