9,10-Dihydro-9,10-methanoanthracene N-oxide derivatives represented by the formula: ##STR1## wherein A represents a straight or branched C.sub.1 -C.sub.6 alkylene; R.sup.1 and R.sup.2 each represents C.sub.1 -C.sub.4 alkyl or phenyl-C.sub.1 -C.sub.4 alkyl, or ##STR2## represents the group ##STR3## and X represents methylene, hydroxymethylene, C.sub.1 -C.sub.4 ##STR4## or hydroxy-C.sub.1 -C.sub.4 ##STR5## and their pharmaceutically acceptable acid addition salts which are useful as anti-depressants, tranquilizers, or anti-epileptics.

The present invention relates to 9,10-dihydro-9,10-methanoanthracene 
N-oxide derivatives and to the production thereof. More particularly, this 
invention relates to 9,10-dihydro-9,10-methanoanthracene N-oxide 
derivatives represented by the formula: 
##STR6## 
wherein A represents a straight or branched C.sub.1 -C.sub.6 alkylene; 
R.sup.1 and R.sup.2 each represents C.sub.1 -C.sub.4 alkyl or 
phenyl-C.sub.1 -C.sub.4 alkyl, 
##STR7## 
represents the group 
##STR8## 
and X represents methylene, hydroxymethylene, C.sub.1 -C.sub.4 
##STR9## 
or hydroxy-C.sub.1 -C.sub.4 
##STR10## 
and their acid addition salts, which are useful as antidepressants, 
tranquilizers, or anti-epileptics. Furthermore, it relates to the 
production the above compounds (I). 
In the above definition, the straight or branched C.sub.1 -C.sub.6 alkylene 
involves methylene, ethylene, propylene, trimethylene, tetramethylene, 
2-methyl-tetramethylene, 2-ethyltetramethylene, pentamethylene, and 
hexamethylene. The C.sub.1 -C.sub.4 alkyl includes methyl, ethyl, propyl, 
isopropyl, butyl, isobutyl, and t-butyl. 
The preferred significance for A is C.sub.3 -C.sub.4 alkylene. The 
preferred significance for each R.sup.1 and R.sup.2 is C.sub.1 -C.sub.3 
alkyl, especially methyl. 
The compounds represented by the formula (I) may form pharmaceutically 
acceptable salts with a variety of inorganic or organic acids. Such salts 
include the hydrochloride, sulfate, nitrate, phosphate, thiocyanate, 
acetate, succinate, oxalate, maleate, malate, phthalate, methanesufonate, 
and salicylate. 
The objective compounds of this invention can be prepared by several 
methods, one of which is shown by the following scheme: 
##STR11## 
wherein B represents a reactive group (e.g. halogen, a residue of ester); 
R.sup.1' and R.sup.2' each represents C.sub.1 -C.sub.4 alkyl or 
phenyl-C.sub.1 -C.sub.4 alkyl, or 
##STR12## 
represents the group 
##STR13## 
X' represents methylene, hydroxymethylene, C.sub.1 -C.sub.4 alkyl-N.dbd. 
or hydroxy-C.sub.1 -C.sub.4 alkyl-N.dbd.; and A, R.sup.1 and R.sup.2 each 
is as defined above. 
The starting compound (IV), for example, 
9,10-dihydro-9,10-methano-9-anthrylcarbonyl chloride (IVa) is prepared by 
using benzonorbornadiene-1-carboxylic acid (VI) [Chenier et al., J. Org. 
Chem., 38, 4350 (1973)] as in the following scheme: 
##STR14## 
Other starting compounds, for example, 
9,10-dihydro-9,10-methano-9-anthrylacetyl chloride can be prepared by 
subjecting 9,10-dihydro-9,10-methano-9-anthrylcarbonyl chloride (IVa) to a 
conventional procedure for increasing the carbon chain such as the 
Arndt-Eistert reaction. 
The first step of this invention is carried out by reacting the starting 
compound (IV) with the compound (V), if necessary, in an excess amount in 
a solvent (e.g. chloroform, methylene chloride, dimethylformamide, 
dioxane) at room temperature or under cooling. Examples of the compound 
(V) are dimethylamine, diethylamine, methylethylamine, methylbenzylamine, 
piperidine, 4-hydroxypiperidine, N-methylpiperazine, and 
N-(2-hydroxyethyl)piperazine. 
The second step of the process is carried out by reducing the amide (III) 
with a metallic hydride complex such as lithium aluminum hydride or 
potassium aluminum hydride in an inert solvent (e.g. tetrahydrofuran, 
dioxane, ether) with warming. 
Thus-obtained amine derivative (II) is subjected to N-oxidation in the 
third step. The third step is carried out by treating the amine (II) with 
an N-oxidizing agent (e.g. hydrogen peroxide, perphthalic acid, peracetic 
acid) in a suitable solvent (e.g. methanol, acetic acid, acetone, 
chloroform, dimethylformamide) at room temperature or under cooling or 
heating. 
The 9,10-dihydro-9,10-methanoanthracene N-oxide derivatives may be 
converted into pharmaceutically acceptable acid addition salts as 
mentioned above. 
The 9,10-dihydro-9,10-methanoanthracene N-oxide derivatives (I) and their 
acid addition salts are useful as anti-depressants, tranquilizers, and 
anti-epileptics. The pharmacological test examined by the following 
methods shows that 
9-(3-dimethylaminopropyl)-9,10-dihdyro-9,10-methanoanthracene N-oxide is 
as potent in antagonism to reserpine ptosis as imipramine, a commercially 
available anti-depressant, but about 4 times less toxic in the acute 
toxicity than the drug. 
Test Method 
Anti-reserpine ptosis: This test was effected on a group of 10 female 
Wistar rats, their body weight ranging from 200 to 230 g. A prescribed 
amount of the test compound was orally administered, and 30 minutes later 
reserpine (5 mg/kg) was intraperitoneally administered. After the lapse of 
4 hours, the effect of the test compound on the reserpine-induced ptotic 
symptom was observed in 9 orders. [Rubin et al., J. Pharmacol. exp. 
Therap., 120, 125 (1957)]. Acute toxicity: The test compound was orally 
administered to DS male mice in different single doses. For each dose, 10 
mice were used, their body weight ranging from 20 to 23 g. The mice were 
observed for 72 hours after the administration of the compound. The 
mortality was calculated by the Bliss method [Bliss, Ann. Appl. Biol., 22, 
134-307 (1935); Quant, J. Pharmacol., 11, 192 (1938)]. 
Other compounds of this invention exhibit similar pharmacological 
activities. 
Thus, the compounds (I) and their pharmaceutically acceptable acid addition 
salts are useful in the treatment of, for example, manic-depressive 
insanity and epilepsy. 
The 9,10-dihydro-9,10-methanoanthracene N-oxide derivatives (I) or their 
pharmaceutically acceptable acid addition salts are applicable singly or 
in combination with pharmaceutically suitable carriers such as wheat 
starch, corn starch, potato starch, gelatin, and the like. The choice of 
carriers is determined by the preferred route of administration, the 
solubility of the substance and the standard pharmaceutical practice. 
Examples of pharmaceutical preparations are tablets, capsules, pills, 
suspensions, syrups, powders, and solutions. These compositions can be 
prepared in a conventional manner. A suitable dosage of the 9,10 
-dihyro-9,10-methanoanthracene N-oxide derivatives (I) or their 
pharmaceutically acceptable acid addition salts for human adults is in the 
order of about 10 to 200 mg per day.