Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 4. Central nervous system depressants.

The synthesis of 1'-[3-(4-fluorobenzyoyl)propyl]-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (2a) and eight halo and methoxy analogues is described. The compounds were generally more potent per os than chlorpromazine in the Sidman avoidance paradigm in rats and less potent than haloperido. 1'-[3-(4-Fluorobenzoyl)propyl]-3-(4-fluorophenyl)spiro[isobenzofuran-1(3H),4'-piperidine] (2e) approached the per os potency of haloperidol in this test and was shown to be active in inhibiting monkey avoidance also. Compound 2e was much less active than haloperidol in antagonizing apomorphine-induced emesis in dogs, apomorphine-induced stereotypy in rats, and amphetamine-induced circling in lesioned rats. This lack of nonselective, dopamine-receptor blocking effects makes 2e attrative as a potential neuroleptic.

Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 3. omega-(6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-yl)alkanoic acids.

Omega-(6,11-Dihydro-11-oxodibenz[b,e]oxepin-2-yl)butyric, -hexanoic, and -octanoic acids were evaluated in the carrageenan paw edema assay. The most active compound, the butyric acid analogue, was 1.80 times more potent than the hexanoic compound, 1.15 times more potent than the octanoic analogue, and 0.43 times as potent as indomethacin.

Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 2. Dihydro-10-oxofuro-and -thieno[3,2-c][1]benzoxepin-8-acetic acids.

4,10-Dihydro-10-oxofuro[3,2-c][1]benzoxepin-8-acetic acid and 4,10-dihydro-10-oxothieno[3,2-c][1]benzoxepin-8-acetic acid were evaluated in the carrageenan paw edema assay with the thieno analogue being ten times more active than the furano compound and 1.3. times more active than indomethacin. The therapeutic ratio (antiinflammatory activity/gastric irritation liability) of the thieno analogue was 25 times that of indomethacin.

Dibenz[b,e]oxepinalkanoic acids as nonsteroidal antiinflammatory agents. 1. 6,11-Dihydro-11-oxodibenz]b,e]oxepin-2-acetic acids.

A series of 6,11-dihydrodibenz[b,e]oxepin-2-acetic acids has been evaluated for both antiinflammatory and analgetic activity in the carrageenan paw edema and phenylquinone writhing assays. The requirements for optimal activity in this series appear rather specific: (a) an unsubstituted 6,11-dihydrodibenz[b,e]oxepin nucleus and (b) a carbonyl group in the 11 position. One derivative, 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid (11), has been selected for further study.

Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents.

Synthesis of 1'-methyl-3-phenylspiro[isobenzofuran-1(3H),4'-piperidine] (7a, HP 365) and the demethyl analogue 9a (HP 505) was prompted by recognition of an aminoalkyl(aryl)isobenzofuran moiety common to the antidepressants talopram (Lu 3-010) and trans-10,11-dihydro-5,10-epoxy-5-[3-(methylamino)propyl]-5H-dibenzo[a,d]cyclohepten-11-ol (MK-940). Convenient laboratory synthesis of 7a was provided by lithiation of 2-bromobenzhydryl methyl ether, followed by addition of 1-methyl-4-piperidone and acid-catalyzed cyclization. N-Dealkylation by standard methods afforded 9a. Synthesis of analogues was stimulated by discovery of marked inhibition of tetrabenazine-induced ptosis for lead compounds 7a and 9a. Optimal antitetrabenazine activity is associated with the 3-phenylspiro-[isobenzofuran-1(3H),4'-piperidine] moiety where nitrogen is basic. Modification of this moiety by introduction of large nitrogen substituents or a C-3 substituent greater than H significantly reduced antitetrabenazine activity. A series of analogues with aromatic substituents was investigated; however, few of these compounds were significantly more active than 7a and 9a. Compound 9a was selected for additional studies.