Antidepressant oxime ethers of dibenzocycloheptaziridones

Polycyclic aziridines, such as 0-[2-(dimethylamino)ethyl]oxime of 1a,10b-dihydrodibenzo-[3,4,6,7]cyclohept[1,2-b]-N-methylazirin-6(1H)-one, useful for alleviating depression in mammals.

BACKGROUND OF THE INVENTION 
This invention relates to antidepressant polycyclic aziridines. 
Mental illnesses include psychoses and neuroses. The symptoms requiring 
treatment include depression, anxiety, agitation and hallucinations. Drugs 
used particularly for treatment of both reactive and endogenous 
depressions include monoamine oxidase (MAO) inhibitors such as 
iproniazide, tranylcypramine, nialamide, phenelzine and pargyline and the 
non-MAO inhibiting tricyclic aromatic dibenzazepines such as imipramine 
and dibenzocycloheptadienes such as amitriptyline. 
All of these drugs have side effects that limit their usefulness. The MAO 
inhibitors may cause tremors, insomnia, hyperhydrosis, agitation, 
hypermanic behavior, confusion, hallucinations, convulsions, orthostatic 
hypertension and death. They frequently cause dizziness, vertigo, 
headache, inhibition of ejaculation, difficulty in urination, weakness, 
fatigue, dry mouth, constipation and blurred vision. Imipramine may cause 
blurred vision, dryness of mouth, constipation, urinary retention, 
orthostatic hypotension, respiration depression, myocardial infarction and 
congestive heart failure. Similar difficulties are experienced with 
amitriptyline. 
The present invention results from efforts to develop new psychotherapeutic 
agents which are effective and have fewer side effects than the drugs used 
today. 
SUMMARY OF THE INVENTION 
This invention relates to antidepressant compounds of formula I 
##STR1## 
where A is hydrogen, F, Cl, Br, NO.sub.2, CF.sub.3, C.sub.1-4 alkyl or 
C.sub.1-4 alkoxy; 
R.sup.1 is hydrogen, C.sub.1-4 alkyl, C.sub.4 -C.sub.6 cycloalkylmethyl, 
C.sub.1-4 acyl or benzoyl; and 
R.sup.2 is 
##STR2## 
or --(CH.sub.2).sub.n NXY; where 
n is 2 or 3; and 
X and Y independently are hydrogen or C.sub.1-4 alkyl, or together are 
linked to form --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 -- or --CH.sub.2 
CH.sub.2 OCH.sub.2 CH.sub.2 --; and 
pharmaceutically suitable acid addition salts thereof. 
Additionally this invention relates to compounds of the above scope of 
Formula I except R.sup.1 and R.sup.2 are hydrogen. These compounds are 
intermediates in preparation of the antidepressant compounds of formula I. 
The invention also includes a process for making the same. 
DETAILED DESCRIPTION OF THE INVENTION 
Preferred Compounds 
Preferred antidepressant compounds are where, independently: 
A is hydrogen; or 
R.sup.1 is hydrogen; or 
R.sup.2 is --(CH.sub.2).sub.n NXY wherein n is 2 and 
X and Y independently are hydrogen or methyl. 
More preferred antidepressant compounds are where 
A is hydrogen and R.sup.1 is hydrogen; or 
A is hydrogen and R.sup.2 is --(CH.sub.2).sub.n NXY where 
n is 2 and 
X and Y independently are hydrogen or methyl. 
Most preferred antidepressant compounds are where 
A is hydrogen, 
R.sup.1 is hydrogen, and 
R.sup.2 is --(CH.sub.2).sub.n NXY wherein 
n is 2 and 
X and Y independently are hydrogen or methyl. 
A preferred intermediate compound is where R.sup.1, R.sup.2 and A are 
hydrogen. 
PHARMACEUTICAL SALTS 
Pharmaceutically suitable acid addition salts of the compounds of formula I 
include those made with physiologically acceptable acids that are known in 
the art; such salts include hydrochloride, sulfate, nitrate, phosphate, 
citrate, tartrate, maleate and the like. 
SYNTHESIS 
Preparation of compounds of formula I and intermediate compounds is 
described in conjunction with the following schematic. A, R.sup.1 and 
R.sup.2 are as previously defined. 
##STR3## 
The preparation of the starting nitro-olefin II is described in U.S. Pat. 
No. 3,883,593. The nitro-olefin is treated with stannous chloride or 
stannous chloride dihydrate in a mixture of concentrated HCl and 
tetrahydrofuran (THF) at 0.degree. to 25.degree. C. for 1-24 hrs. 
resulting in a mixture of keto-oxime III and diketone IV. The mixture is 
refluxed with hydroxylamine hydrochloride in pyridine to give dioxime V 
which is refluxed with lithium aluminum hydride in tetrahydrofuran to give 
an aziridinyl oxime VI. The aziridinyl oxime is treated with base, 
preferably sodium hydride, in dry N,N-dimethylacetamide for 10-30 min., 
followed by an appropriate alkylating agent R.sup.2 X.sup.1 (X.sup.1 
=Cl,Br,I, tosylate), such as 2-dimethylaminoethyl chloride hydrochloride, 
which has been neutralized with an equivalent amount of sodium hydride in 
N,N-dimethylacetamide (DMAC), to give the antidepressant oxime ether Ia. 
Treatment of the oxime ether with hydrochloric acid in ethanol or tartaric 
acid in 2-propanol affords the acid salt Ib. The oxime ether Ia can be 
treated with base, preferably n-butyllithium, in diethyl ether at 
-78.degree., followed by addition of an appropriate alkylating agent 
R.sup.1a X.sup.2 (R.sup.1a =R.sup.1 except for excluding H;X.sup.2 
=Cl,Br,I, tosylate) such as methyl iodide or acetyl chloride, to give the 
aziridine substituted oxime ether Ic. The acid salt Id of the aziridine 
substituted compounds is prepared as described above in preparation of Ib.