Cyclobutyl benzimidazoles as PDE 10 inhibitors

#The invention relates generally to compounds which act as inhibitors of the phosphodiesterase (PDE) 10 enzyme, compositions and therapeutic uses thereof.

#Schizophrenia is debilitating disorder affecting the psychic and motor functions of the brain. It is typically diagnosed in individuals in their early to mid-twenties and symptoms include hallucinations and delusions or at the other extreme, anhedonia or social withdrawal. Across the spectrum, the symptoms are indicative of cognitive impairment and functional disabilities. Notwithstanding improvements in antipsychotic treatments, current therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, have been less than acceptable and result in an extremely high rate of noncomplicance or discontinuation of medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and unacceptable side affects. The side effects have been associated with significant metabolic, extrapyramidal, prolactic and cardiac adverse events. See, Lieberman et al., N. Engl. J. Med. (2005) 353:1209-1223.

#While multiple pathways are believed to be involved with the pathogenesis of schizophrenia leading to psychosis and cognition deficits, much attention has focused on the role of glutamate/NMDA dysfunction associated with cyclic guanosine monophosphate (cGMP) levels and the dopaminergic D2 receptor associated with cyclic adenosine monophosphate (cAMP). These ubiquitous second messengers may be responsible for altering the function of many intracellular proteins. Cyclic AMP is thought to regulate the activity of cAMP-dependent protein kinase (PKA), which in turns phosphorylates and regulates many types of proteins including ion channels, enzymes and transcription factors. Similarly, cGMP may also be responsible for downstream regulation of kinases and ion channels.

#The present invention is directed to compounds of the formula I:

#wherein: each R, and Rx independently represent H, OH, halogen, or C1-6 alkyl, Rc represents H, OH, halogen, —C(R)2OR, or C1-6 alkyl, R2 is selected from the group consisting of H, O—R, CN, O(CH2)nOR, OCHR(CH2)nOR, SR, SO2R, S(O)R, N(R)2, C(O)N(R)2, C1-3 haloalkyl, O(CH2)nC1-3 haloalkyl, O(CH2)nC3-6cycloalkyl, (CH2)nC5-10heterocycle, C1-6 alkyl, and C3-10cycloalkyl, said alkyl, cycloalkyl, and heterocycle is unsubstituted or substituted with 1 to 3 groups of Ra; Ra is selected from the group consisting of: (1) halogen, (2) hydroxyl, (3) C1-6alkyl, (4) —(CH2)nO—R, (5) (CH2)nC6-10aryl, (6) (CH2)nC5-10 heterocycle, (7) OC1-5 haloalkyl; (8) CO2R; (9) C(O)N(R)2; (10) (CH2)nC(O)R; (11) CN, (12) (CH2)nN(R)2; (13) (CH2)nC3-6cycloalkyl, (14) (CH2)nC1-3 haloalkyl; (15) —O— n represents 0-4, or a pharmaceutically acceptable salt thereof.

#An embodiment of the present invention includes compounds wherein there is no Rc.