EP2442649A1

EP2442649A1 - The use of metabotropic glutamate receptor potentiators for reducing nicotine dependence

Info

Publication number: EP2442649A1
Application number: EP10790110A
Authority: EP
Inventors: Joseph Frey
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2009-06-19
Filing date: 2010-06-16
Publication date: 2012-04-25
Also published as: EP2442649A4; WO2010148074A1; JP2012530710A; CN102548407A

Abstract

Methods of using potentiators of glutamate receptors for reducing nicotine usage, reducing the urge to smoke or chew tobacco or inducing the cessation of smoking are described.

Description

THE USE OF METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS FOR REDUCING NICOTINE DEPENDENCE - 772

Field of the Invention: The present invention relates to potentiators of glutamate receptors and their use in therapy. More specifically, the invention relates to the use of potentiators of glutamate receptors for reducing nicotine usage, reducing the urge to smoke or chew tobacco and inducing the cessation of smoking.

Background:

Glutamate is the primary excitatory neurotransmitter in the central nervous system and acts on two main classes of receptors, the ionotropic and metabotropic receptors. Metabotropic glutamate receptors are G-protein- coupled receptors that modulate postsynaptic responses to glutamate and presynaptic release of glutamate, GABA and 5-HT. Eight subtypes of metabotropic glutamate receptors have been identified and classified into group I (mGluRI and mGluRδ), group Il (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7 and mG!uR8) receptors.

Group Il mGluR (mGluR2 and mGluR3) are coupled via Gi/o to inhibition of adenylate cyclase and are involved primarily in the presynaptic inhibition of glutamate and GABA release. mGlur2 receptors are expressed in discrete regions of the cerebral cortex, including the anterior cingulate and prefrontal orbital area; the limbic forebrain, including the amygdala and hippocampus; and to a lesser extent, the ventral tegmental area (VTA) and nucleus accumbens (NAc). Expression of mGlurR3 is generally more diverse, and mGluR3 is also expressed in glia where it is thought play a role in modulating glutamate release as well as on GABAergic neurons. mGlur2 receptors are positioned at extrasynaptic sites on neuronal terminals where they act as autoreceptors to suppress glutamate release under hyper- glutamatergic conditions.

Glutamate is thought to play a major role in mediating nicotine reward and relapse to smoking. Nicotine increases glutamate-mediated transmission throughout brain reward circuits. For example, nicotine activates excitatory nACh receptors on terminals of glutamatergic neurons projecting from brainstem (LDT/PPT) onto mesolimbic dopamine (DA) neurons in the VTA. DA neurons in turn project to the shell of the NAc. In rats, nicotine self- administration increases DA release in the shell of the NAc and nonselective mGlur2/3 receptor agonists have been shown to preferentially reduce DA release in the shell of the NAc, whereas mGlur2/3 blockade increased DA in the NAc shell. Nonselective mGlur2/3 agonists also decrease nicotine self- administration, nicotine reward, and cue-induced reinstatement of nicotine seeking behavior (relapse) in rats without significant aggravation of the brain reward deficits associated with nicotine withdrawal.

Description of the Invention:

Positive allosteric modulators of mGlur2 (mGluR2 PAMs) act at a site remote from the glutamate-binding site on mGlur2 receptors and potentiate the activation of the glutamate-binding site. Such agents thus reduce the glutamate effect only under conditions of elevated extrasynaptic glutamate levels. Thus, we contemplate that a mGlur2 PAM, as described herein, will act in concert with endogenous glutamate to reduce dopamine release in the shell of the NAc and decrease nicotine self-administration, without significant aggravation of the brain reward deficits associated with nicotine withdrawal. It is further contemplated that in humans, mGlur2 PAMs will act to dampen glutamate responses to nicotine, to reduce tobacco use, to reduce nicotine reward and cigarette consumption, and to lessen glutamate responses to smoking cues and smoking lapses without interfering with normal glutamatergic transmission or exacerbating nicotine withdrawal symptoms.

Thus, a method of reducing nicotine use or reducing nicotine withdrawal symptoms is contemplated comprising: administering a therapeutically effective amount of a mGluR2 PAM to a subject in need thereof. More particularly a method is contemplated wherein the mGluR2 PAM is a compound selected from: 7-methyl-5-(3-piperazin-1-ylmethyl- [1 ,2,4]oxadiazol-5-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one; 2-(4-chloro-benzyl)-5-[3-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-

[1 ,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[3-(3-methyl-piperazin-1-ylmethyl)-

[1 ,2,4]oxadiazol-5-yl]-2,3-dihydro-isoindol-1-one; 2-(4-chloro-benzyl)-7-methyl-5-(3-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-5-yl)-

2,3-dihydro-isoindol-1 -one;

2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazin-1-ylmethyl)-

[1 ,2,4]oxadiazol-5-yl]-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-5-yl]-2,3-dihydro-isoindol-1-one;

7-chloro-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

7-chloro-2-(4-chlorobenzyl)-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-

2,3-dihydroisoindol-1 -one; 7-methyl-5-(5-piperazin-1 -ylmethyl-[1 ,2,4]oxadiazol-3-yl)-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

2-(4-chlorobenzyl)-7-methyl-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-

2,3-dihydroisoindoI-1 -one;

5-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-[1 ,2,4]oxadiazol-3-yl]-7-methyl- 2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

2-[(S)-1 -(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazin-1-ylmethyl-

[1 ,2,4]oxadiazol-3-yl)-2,3-dihydro-isoindol-1-one;

2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-

2-yl)methyl]-[1 ,2,4]oxadiazol-3-yl}-7-methyl-2,3-dihydro-isoindol-1-one; 2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)-

[1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1 -one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)-

[1 ,2,4]oxadiazol-3-yi]-2,3-dihydroisoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;

7-chloro-5-[5-(3,3-dimethyl-piperazin-1-ylmethyl)-[1 ,2,4]oxadiazol-3-yI]-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one; 7-methyl-5-[5-(1 -piperazin-1 -yl-ethyl)-[1 ,2,4]oxadiazol-3-yl]-2-(4- trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(1 -piperazin-1 -yl-ethyl)-[1 , 2, 4]oxadiazol-3- yl]-2,3-dihydro-isoindol-1-one, or 2-[(S)-1 -(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1 -piperazin-1 -yl-ethyl)-

[1 ,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt, active metabolite, intermediate or derivative, hydrate or solvate of any foregoing compound.

Still more particularly methods are contemplated using the compound described herein for reducing the smoking of tobacco, for reducing the chewing of tobacco and generally for reducing nicotine withdrawal symptoms experiences by subjects when attempting to reduce their dependence on tobacco.

Pharmaceutical compositions are contemplated comprising a compound described herein and at least one pharmaceutically acceptable carrier or excipient for use in the methods described herein.

It is also contemplated that compounds described herein or a pharmaceutically acceptable salts, active metabolites, intermediates or derivatives, hydrates or solvates of such compounds may be used as a medicament.

The use of compounds described herein or a pharmaceutically acceptable salts, active metabolites, intermediates or derivatives, hydrates or solvates of such compounds may be used in the manufacture of a medicament for the reduction of nicotine withdrawal symptoms, or the reduction of tobacco use.

Examples: mGluR2 PAMs: mGlur2 PAMs and active metabolites, intermediates or derivatives thereof are contemplated to be useful for to dampen glutamate responses to nicotine, to reduce nicotine reward and cigarette consumption are described in Published International Patent applications WO2006020879, WO2007021309, WO2007095024, WO2007115077, WO2008100715 and WO2008130853, or United States Published Patent Applications US20070021606A1 , US20090069340A1 , US20070032469A1 , US20080227794A1 , US20070275966A1 , US20080125431 A1 , US20080306088A1 and US20080306077A1 , the entire contents of which are incorporated herein by reference.

While it is contemplated that any mGlur2 PAM described in any of the aforementioned patent applications will lessen glutamate responses to smoking cues and smoking lapses without interfering with normal glutamatergic transmission or exacerbating nicotine withdrawal symptoms, and will facilitate cessation of smoking, it is particularly contemplated that a compound selected from:

7-methyl-5-(3-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-5-yl)-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

2-(4-chloro-benzyl)-5-[3-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)- [1 ,2,4]oxadiazol-5-yl]-7-methyl-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[3-(3-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-5-yl]-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-(3-piperazin-1-ylmethyl- [1 ,2,4]oxadiazol-5-yl)-2,3-dihydro-isoindol-1-one; 2-(4-chloro-benzyl)-7-methyl-5-[3-(2-methyl-piperazin-1-ylmethyl)-

[1 ,2,4]oxadiazol-5-yl]-2,3-dihydro-isoindol-1-one,

7-chloro-2-(4-chlorobenzyl)-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol- 3-yl)-2,3-dihydroisoindol-1-one;

7-methyl-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one; 2-(4-chlorobenzyl)-7-methyl-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-

3-yl)-2,3-dihydroisoindol-1-one;

5-[5-(2,5-diaza-bicyclo[2.2.1 ]hept-2-ylmethyl)-[1 ,2,4]oxadiazol-3-yl]-7- methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1 -one; 2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazin-1-ylmethyl- [1 ,2,4]oxadiazol-3-yl)-2,3-dihydro-isoindol-1 -one;

2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S,4S)-1-(2,5-diaza- bicyclo^^.iJhept^-yOmethyll-ti ^^Joxadiazol-S-ylJ-y-methyl^.S-dihydro- isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindoI-1 -one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindoI-1 -one; 2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazin-1 -ylmethyl)-

[1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1 -one;

7-chloro-5-[5-(3,3-dimethyl-piperazin-1-ylmethyl)-[1 ,2,4]oxadiazol-3-yl]- 2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

7-methyl-5-[5-(1 -piperazin-1 -yl-ethyl)-[1 ,2,4]oxadiazol-3-yl]-2-(4- trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(1 -piperazin-1 -yl-ethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one, or

2-[(S)"1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1 -piperazin-1 -yl-ethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt, active metabolite, intermediate, derivative, hydrate or solvate of any foregoing compound as described in US20080306088A1 or US20080306077A1 will have particular utility for this purpose. Efficacy: Efficacy of mGlur2 PAMs may be assessed by, for example, by a randomized, double-blind, double-dummy, placebo-controlled and active- controlled, parallel-group, human laboratory study conducted in healthy, treatment-seeking, male and female adult smokers. Other methods of assessing efficacy will be known to those of skill in the art. Efficacy may be shown by, for example, by abstinence from smoking, by an extended period before smoking recurrence or by subjective lessening of withdrawal symptoms and cravings (for example as assessed by the Minnesota Nicotine Withdrawal Scale - Revised and the QSU-Brief Questionnaire on smoking urges).

Other effects may be used to assess efficacy, for example, positive and negative affect as measured using the Positive and Negative Affect Schedule; Depressive symptoms as assessed using the Center for Epidemiologic

Studies - Depression scale; Anxiety levels as assessed using the Speilberger State-Trait Anxiety Inventory, or Cue reactivity utilizing: 1 ) A Visual Probe Task which assesses attentional bias toward salient cues, and; 2) a Cue Reactivity Task which measures subjective craving in response to in vivo smoking versus neutral stimuli. Effective doses:

While it is contemplated that a therapeutically effective dose will depend on the subject being treated and that such a dose may in practice be determined by one skilled in the art, in general a dose from about 1 microgram to about 40 milligrams of a mGluR2 PAM as described herein is though to comprise a therapeutically effective dose.

More particularly, a dose of from about 1 milligram to about 20 milligram of a mGluR2 PAM as described herein is though to comprise a therapeutically effective dose. In general, an appropriate dose regimen, the amount of each dose of a mGluR2 PAM administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of nicotine usage or condition being treated. More particularly it is contemplated that a dose of a mGluR2 PAM as described herein will be administered once per day. Doses of mGluR2 PAMs will in general be administered in the form of compositions containing at least one pharmaceutically acceptable carrier or excipient. Compositions:

Compositions are intended to include the formulation of the mGluR2 PAM or a pharmaceutically acceptable salt with a pharmaceuticaliy acceptable carrier, and optionally other ingredients. For preparing pharmaceutical compositions, inert, pharmaceutically acceptable carriers can be either solid or liquid. For example, compositions can be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.

Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Solid form compositions include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.

In powders, the carrier can be a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the mGluR2 PAM active ingredient with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is, thus, in association with it. Similarly, cachets are included.

The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. Methods of preparing dosage forms are disclosed in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition, 1975.

Compositions may be formulated for any suitable route and means of administration. Pharmaceutically acceptable carriers or diluents include those used in formulations suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, epidural, intraperitoneally, intrathoracically, intracerebroventricularly, and by injection into the joints) administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy.

Claims

Claims:

1. A method of reducing nicotine use or reducing nicotine withdrawal symptoms comprising: administering a therapeutically effective amount of a mGluR2 PAM to a subject in need thereof.

2. A method according to claim 1 wherein said mGluR2 PAM is a compound selected from:

7~methyl-5-(3-piperazin-1 -ylmethyl-[1 ,2,4]oxadiazol-5-yl)-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-(3-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-5-yl)- 2,3-dihydro-isoindol-1 -one;

7-chloro-2-(4-chlorobenzyl)-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)- 2,3-dihydroisoindol-1 -one;

7-methyl-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

2-(4-chlorobenzyl)-7-methyl-5-(5-piperazin-1-ylmethyl-[1 ,2,4]oxadiazol-3-yl)- 2,3-dihydroisoindol-1 -one; δ-tS^.δ-diaza-bicyclo^^.ilhept^-ylmethyO-ti ^^joxadiazol-S-yO^-methyl- 2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazin-1-ylmethyl- [1 ,2,4]oxadiazol-3-yl)-2,3-dihydro-isoindol-1 -one; 2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1 S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept- 2-yl)methyl]-[1 ,2,4]oxadiazol-3-yl}-7-methyl-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1 -one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;

7-chloro-5-[5-(3,3-dimethyl-piperazin-1-ylmethyl)-[1 ,2,4]oxadiazol-3-yl]-2-(4- trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;

7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1 ,2,4]oxadiazol-3-yl]-2-(4- trifiuoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one;

2-(4-chloro-benzyl)-7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1 ,2,4]oxadiazol-3- yl]-2,3-dihydro-isoindol-1 -one, or

2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1-piperazin-1-yl-ethyl)- [1 ,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one, or a pharmaceutically acceptable salt, hydrate or solvate of any foregoing compound.

3. A method according to claim 1 or 2, for reducing the smoking of tobacco.

4. A method according to claim 1 or 2, for reducing the chewing of tobacco.

5. A method for reducing nicotine withdrawal symptoms according to claim 1 or 2.

6. A pharmaceutical composition comprising a compound according to claim 2 and at least one pharmaceutically acceptable carrier or excipient.

7. A compound according to claim 2 for use as a medicament.

8. The use of a compound according to claim 2 in the manufacture of a medicament for the reduction of nicotine withdrawal symptoms, or the reduction of tobacco use.