Schizophrenia affects about 1% of the population worldwide. 1 The onset of symptoms is generally in the late teens to early twenties. There is no cure for the disease, and current therapies have numerous, debilitating side effects. The combination of early onset of chronic disease and problematic therapies results in high costs for the patient, his or her family, and society at large. 2 While the etiology of schizophrenia remains unknown, several lines of research point to the dopaminergic system, 3 and, in particular, the dopamine D 4 receptor, as important in schizophrenia and psychotictype diseases in general. 4 Classical antipsychotics such as haloperidol, though effective in treating certain schizophrenic states, cause extrapyramidal side effects and tardive dyskinesias. These side effects have been linked to the blockade of dopamine receptors in the striatum. 5 Clozapine (1), an "atypical" antipsychotic, is relatively free of extrapyramidal side effects, but causes tachycardia (25%), sialorrhea (30%), dizziness (20%), drowsiness and sedation (40%), and agranulocytosis (1-3%). Many of these side effects can be attributed to clozapine's high affinity for a number of central nervous system (CNS) receptors. 6 At the same time, clozapine's affinity for the D 4 receptor may play a part in its atypical nature.

A series of 1-[1-(3,4-dimethoxy-1H-2-benzopyran-1-yl)alkyl]-4-arylpiperazines that shows hypotensive activity in the conscious rat has been investigated. Structure-activity relationships are described. A typical example that was investigated in greater detail is 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-(4-fluorophenyl)piperazine. This compound decreases sympathetic nerve activity recorded from the external carotid and splanchnic nerves of baroreceptor-denervated cats and, therefore, has a central component to its mechanism of action. It also blocks pressor effects of norepinephrine and phenylephrine and is thus an alpha-adrenergic antagonist. Binding data characterize this as alpha 1-adrenergic receptor blockade.

While the previously used displacement reaction of sodim 1-adamantyl oxide on 4-fluoronitrobenzene was applicable to the preparation of 4-(1-adamantyloxy)aniline and several related compounds, certain derivatives were not easily accessible by this route. Thus the recently reported ortho alkylation of anilines and the dicyclohexylcarbodiimide-promoted coupling of 1-adamantanol with phenols were useful in the preparation of aromatic-substituted derivatives. Furthermore, addition of phenylmagnesium bromide to 1-cyanoadamantane provided entry to the 4-(1-adamantylmethyl)aniline series. 4-(1-Adamantyloxy)aniline (3) is herein reported to be a more potent hypobetalipoproteinemic agent than the previously reported bicyclooctyloxy analogue. Replacement of the oxygen atom of 3 with sulfur (74) or methylene (62), but not nitrogen (71), results in active compounds. In the oxygen series derived from 3, the widest scope of substitution on nitrogen resulting in activity is found. The N-ethoxycarbonyl (5), acetyl (6), methyl (12), ethyl (13), N-methyl-N-(2-hydroxyethyl) (19), N-methyl-N-formyl (22), N,N-dimethyl (26), pyrrolidine (14), and piperidine (15) derivatives are active. Aromatic ring substitution also provided the active 3-chloro (44b), 2-fluoro (41b, 42, and 43), and 2-methylthiomethyl (48) compounds. Thus these active compounds are identified for further development as hypobetalipoproteinemic agents.

A new assay for agents which normalize beta-lipoproteins in cholesterol-cholic acid fed rats is described. Both lowering of serum cholesterol and of serum heparin precipitable lipoproteins (HPL) were measured at the end of the treatment period. Compounds which shifted the ratio of the decrease in favor of HPL are considered hypo-beta-lipoproteinemic. p-(1-Bicyclo[2.2.2]octyloxy)aniline and several of its derivatives proved active in this assay. The synthesis of these compounds is described.