Azetidinecarboxamide derivatives for treating CNS disorders

Details Azetidinecarboxamide derivatives for treating CNS disorders Azetidinecarboxamide derivatives for treating CNS disorders

2001-02-12

2004-12-14

Chang, Ceila (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C548S950000, C548S952000, C548S953000, C546S208000, C546S268100, C514S210100, C514S210200

Reexamination Certificate

active

06831078

ABSTRACT:

The present invention relates to chemical compounds useful in the treatment of disorders of the central nervous system (CNS), such as anxiety and all forms of epilepsy, particularly in humans. The invention also relates to the use of such compounds, pharmaceutical preparations containing such compounds and to methods of preparing such compounds.
Anxiety disorders affect an estimated 73 million people world-wide. The benzodiazepines have provided the dominant therapy for anxiety over the past three decades and there is no doubt that they are remarkably effective anxiolytics. However, chronic administration of benzodiazepines produces severe dependence liability, withdrawal syndromes, and side effects (sedation, amnesia, muscle relaxation). The only non-benzodiazepine anxiolytic that has been launched over the past decade is the 5-HT receptor ligand buspirone (Buspar®). This drug has had a remarkable commercial success despite being regarded as a weak anxiolytic (compared with the benzodiazepines) and having a long latency to onset of therapeutic action (2-4 weeks). In addition, buspirone and all related 5-HT
1A
partial agonists suffer from a dose-limiting side-effect profile comprising nausea, vertigo and endocrine changes.
The aetiology of anxiety disorders is not fully understood, but it is now established that benzodiazepines act by potentiating GABAergic neurotransmission although there is strong evidence that other neurotransmitter systems are modulated indirectly—in particular, the serotonergic and noraenergic systems. Many pharmaceutical companies have invested considerable resource into the development of serotonergic anxiolytics. However, it is now apparent that ligands selective for 5-HT receptor subtypes, despite displaying anxiolytic-like activity in a restricted range of anxiety models, have, at best, very weak and/or non-dose-related mixiolytic effects in the clinic. The 5-HT
3
receptor antagonists are now discredited as psychotropics: they have a restricted range of activity in functional and anxiety models; they show no convincing anxiolytic effects in the clinic; and they are now accepted only as useful anti-emetics. The 5-HT
2A
antagonists similarly are regarded as ineffective in terms of psychotropic activity. The clinical utility of 5-HT
1A
receptor agonists and partial agonists is severely limited by their intrinsically weak action and by the dose-limiting side-effects (vertigo, endocrine changes, nausea) which become more intense as the agonist efficacy of these molecules is increased. The selective CCK
B
receptor antagonists have displayed an unimpressive preclinical profile similar to that of selective 5-HT ligands such as the 5-HT
3
antagonists.
Serotonergic anxiolytics include the selective serotonin reuptake inhibitors (SSRIs) which, in addition to displaying antidepressant properties, are also effective in anxiety disorders such as panic disorder and obsessive-compulsive disorder. However, as with their antidepressant action, the major drawback with these compounds is the long delay (6-8 weeks) in the onset of clinical improvement following chronic administration.
A strategy in recent years towards improving the clinical profile of classical benzodiazepines is that of developing benzodiazepine receptor partial agonists, according to the rationale that they would have a more selective anxiolytic action and be less liable to induce dependence. However, this approach appears to have failed owing to the very weak anxiolytic actions of these compounds and their poor side-effect profiles (there is either a low or non-existent ratio between anxiolytic and sedative doses).
U.S. Pat. No. 4,956,359 and EP-A-0194112 disclose 3-aryloxy and 3-arylthio azetidinecarboxamides and their anti-convulsant and anti-epileptic activity. These compounds, like the benzodiazepines, have low water solubility which leads to difficulties in formulation. The presence of an oxygen or sulphur atom, present as a linking atom between the aryl group and the azetidine ring, is a key feature of these compounds since such atoms can undergo hydrogenbonding interactions with other molecules, affect molecular conformation and increase electron density in the aryl rings.
There remains therefore a need for novel anxiolytic and anti-epileptic agents which do not suffer the above-mentioned drawbacks.
It has now been found that the oxygen and sulphur linking atoms are not necessary for pharmacological action. It is unexpected that compounds in which such atoms are absent exhibit pharmacological activity.
According to the present invention there is provided a chemical compound of formula (1)
wherein:
R
1
is aryl; and
R
2
is hydrogen or alkyl;
and pharmaceutically acceptable addition compounds thereof.
Reference in the present specification to an “alkyl” group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical. Where cyclic or acyclic the alkyl group is preferably C
1
to C
12
, more preferably C
1
to C
8
(such as methyl, ethyl, propyl, isopropyl butyl, isobutyl, tert-butyl, amyl, isoamyl, hexyl, heptyl, octyl).
Reference in the present specification to an “aryl” group means a mono or bicyclic aromatic group, such as phenyl or naphthyl.
The alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 or 2 substituents. Substituents may include:
carbon containing groups such as
alkyl
aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted berzyl);
halogen atoms and halogen containing groups such as
haloalkyl (e.g. trifluoromethyl);
oxygen containing groups such as
alcohols (e.g. hydroxy, hydroxyalkyl, (aryl)(hydroxy)alkyl),
ethers (e.g. alkoxy, alkoxyalkyl, aryloxyalkyl),
aldehydes (e.g. carboxaldehyde),
ketones (e.g. alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl),
acids (e.g. carboxy, carboxyalkyl),
acid derivatives such as esters
(e.g. alkoxycarbonyl, alkoxycatbonylalkyl, alkycarbonylyoxy, alkycarbonylyoxyalkyl) and amides
(e.g. aminocarbonyl, mono- or dialkylaminocarbonyl, arninocarbonylalkyl, mono- or dialkylaminocarbonylalkyl, arylaniinocarbonyl);
nitrogen containing groups such as
amines (e.g. amino, mono- or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl),
azides,
nitriles (e.g. cyano, cyanoalkyl),
nitro;
sulphur containing groups such as
thiols, thioethers, sulphoxides and sulphones
(e.g. alkylthio, alkylsulfinyl, alkylsufonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arysylalkyl arylsulfonylalkyl); and
heterocyclic groups containing one or more, preferably one, heteroatom,
(e.g. thienyl, fliranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrflranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl thionaphthyl, benzofirayl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl).
Preferred substituents include alkyl, aryl, halo, or an halogen-containing group such as trifluoromethyl.
As used herein, the term “alkoxy” means alkyl-O— and “alkoyl” means alkyl-CO—.
As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical.
The compounds of formula (1) may exist in a number of diastereomeric and/or enantiomeric forms. Reference in the present specification to “a compound of formula (1)” is a reference to all stereoisomeric forms of the compound and includes a reference to the unseparated stereoisomers in a mixture, racemic or non-racemic, and to each stereoisomer in its pure form.
In the compounds of formula (1), preferably R
1
is a subst

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