Nor-tropane derivatives, and their application in therapeutics

Novel 3 .beta.-aroylamino and 3 .beta.-heteroaroylamino nor-tropanes and granatanes are provided having the general formula: ##STR1## Wherein n=1 or 2, R represents a benzyl or a substituted benzyl group and A-CO represents one of a specific range of aroyl groups. The compounds of the invention are useful in the treatment of psychism or digestive troubles.

The present invention relates to new nor-tropane and granatane derivatives, 
more especially to new 3-aroylamino and 3-heteroaroylamino nor-tropanes 
and granatanes, respectively substituted in position -8 and -9, the 
process for preparing same and the application of same in therapeutics. 
These new compounds correspond more precisely to the general formula: 
##STR2## 
in which: 
n assumes the values 1 or 2; 
R represents a benzyl group; a benzyl group substituted by one or two 
halogen atoms, a methyl group or a cyano group or a (furyl-3)methyl chain; 
and --A--CO represents: 
a pyrimidinic group of structure: 
##STR3## 
in which R.sub.1 represents a methyl or ethyl group; R.sub.2 represents an 
alkyloxy group with 1 or 2 carbon atoms or an amino group; and R.sub.3 
represents a hydrogen atom, a bromine atom or a methoxy group, a nitro 
group, an acetyl group or an alkylmercapto group with 1 or 2 carbon atoms; 
the whole (R.sub.3 l, n, R) however not being able to assume the value (H, 
1, benzyl); or 
an aromatic group of structure: 
##STR4## 
in which R.sub.1 .dbd.CH.sub.3 or C.sub.2 H.sub.5 and x.dbd.Br or Cl, the 
whole (X, n, R.sub.1, R) however not being able to assume the following 
values: 
##STR5## 
The compounds preferred among those of formula (I) are the compounds for 
which the pair (n, R) assumes the value: 
(1, benzyl) and the whole (R.sub.1, R.sub.2, R.sub.3) assumes the following 
values: (CH.sub.3, NH.sub.2, Br); (C.sub.2 H.sub.5, OC.sub.2 H.sub.5, H), 
(CH.sub.3, OCH.sub.3, OCH.sub.3); (C.sub.2 H.sub.5, OCH.sub.3, H); 
(CH.sub.3, OC.sub.2 H.sub.5, H); (C.sub.2 H.sub.5, OCH.sub.3, OCH.sub.3); 
(CH.sub.3, OCH.sub.3,NO.sub.2); (CH.sub.3, OCH.sub.3, Br); (CH.sub.3, 
OCH.sub.3, SCH.sub.3); (CH.sub.3, OCH.sub.3, C.sub.2 H.sub.5 S); 
(CH.sub.3, OCH.sub.3, COCH.sub.3); 
(2, benzyl) and the whole (R.sub.1, R.sub.2, R.sub.3) assumes the values 
(C.sub.2 H.sub.5, OCH.sub.3, H), (CH.sub.3, OCH.sub.3, H); 
##STR6## 
and the whole (R.sub.1, R.sub.2, R.sub.3) assumes the value 
(CH.sub.3,OCH.sub.3, H); 
##STR7## 
and the whole (R.sub.1, R.sub.2, R.sub.3) assumes the value (C.sub.2 
H.sub.5,OCH.sub.3, H); 
##STR8## 
and the pair (R.sub.1, X).dbd.(CH.sub.3, Br); 
##STR9## 
and the pair (R.sub.1, X) assumes the value (C.sub.2 H.sub.5, Br), or 
##STR10## 
and the pair (R.sub.1, X) assumes the value (CH.sub.3, Cl). 
It should be noted that in formula (I) the A--CO--NH chain is in the 
equatorial position and the tropanes, nor-tropanes and granatanes having 
such a substituent in the equatorial position will be called .beta. in 
what follows. 
The present invention of course also relates to the salts of the compounds 
of formula (I) and more precisely the pharmaceutically mineral or organic 
acid addition salts. 
The compounds of formula (I) of the invention are obtained by condensing, 
by means of the mixed anhydride method, the acids of formula: 
EQU A--COOH (II) 
in which A--CO has the same meaning as in formula (I), with the 3 
.beta.-amino nor-tropanes and 3 .beta.-amino granatanes of formula: 
##STR11## 
in which R and n have the same meanings as in formula (I). 
The compounds of formula (I) of the invention, except those for which 
R.sub.2 represents an amino group and those for which the A--CO pattern 
has the following structure: 
##STR12## 
where R.sub.1 and X have the same meanings as above, may also be obtained 
by condensing, preferably in a tetrahydrofuranic medium and in the 
presence of triethylamine, the compounds of formula (III) previously 
defined, with the acid chlorides of the compounds of formula: 
EQU A'--COOH (II') 
where A'--CO has the same meaning as A--CO in formula (I) with however the 
above stated restrictions as regards R.sub.2 and without being able to 
have the structure: 
##STR13## 
Finally, the compounds of formula (I) of the invention, except those for 
which the A--CO pattern has the particular structure: 
##STR14## 
and those for which R represents a benzyl group, may also be prepared by 
condensation of the compounds of formula: 
##STR15## 
in which n=1 or 2 and A"--CO has the same meanings as A--CO in formula (I) 
with however the above stated restrictions, with the compounds of formula: 
EQU X'--R' (V) 
where X' is a chlorine or bromine atom or a mesyloxy or tosyloxy group, and 
R' has the same meaning as R in formula (I) without however being able to 
represent a benzyl group, this condensation reaction being carried out 
preferably at reflux in an organic solvent such as acetone, acetonitrile 
or DMF and in the presence of a base such as potassium carbonate or 
triethylamine. 
The compounds of formula (III) may be prepared in accordance with the 
processes described in French patent application No. 2 446 823 and Belgian 
Pat. No. 881 134. 
The compounds of formula (IV) are obtained by hydrogenolysis, preferably in 
an acid alcohol medium, at ambient temperature, at a pressure of 90 m bars 
and in the presence of palladium on carbon (10% of palladium) of the 
compounds of formula (I) having the particular structure: 
##STR16## 
in which n and A"--CO have the same meanings as in formula (IV), A"--CO 
not however being able to represent the pattern: 
##STR17## 
where R.sub.1 has the same meanings as in formula (I), and the compounds 
of formula (IV) having the particular structure: 
##STR18## 
in which R.sub.1 and n have the same meanings as in formula (I), are 
obtained by bromation, preferably in an acetic acid medium, of the 
compounds of formula: 
##STR19## 
in which R.sub.1 and n have the same meanings as in formula (IVa). 
The compounds of formula (VI) are themselves obtained by hydrogenolysis of 
the compounds of formula (I) having the particular structure: 
##STR20## 
in which R.sub.1 and n have the same meanings as in formula (IV). 
Some compounds of formula (II) are new. It is a question more precisely of 
those having the particular formula: 
##STR21## 
in which R.sub.3 ' represents an alkylmercapto group with 1 or 2 carbon 
atoms or an acetyl group. 
The compounds of formula (IIa) for which R.sub.3 ' represents an 
alkylmercapto group with 1 or 2 carbon atoms are obtained by a two step 
process which consists in reducing by means of tin in a hydrochoric 
medium, the compound of formula: 
##STR22## 
then in treating the intermediate compound thus obtained with the 
corresponding alkyl sulfate having 1 to 2 carbon atoms in the presence of 
aqueous sodium hydroxide. 
The compound of formula (IIb) is obtained by treating, by means of 
chlorosulfonic acid (ClSO.sub.3 H), the compound of formula: 
##STR23## 
The compound of formula (IIa) for which R.sub.3 ' represents an acetyl 
group is obtained by oxidizing, by means of the pyridinium 
chloride-chromic oxide complex, the compound of formula: 
##STR24## 
Finally, the compound of formula (IId) is obtained by a two stage process 
which consists in treating the compound of formula: 
##STR25## 
by means of a lithium containing derivative of formula CH.sub.3 -Li, then 
in reacting, on the intermediate compound thus obtained, carbon dioxide. 
The following preparations are given by way of example to illustrate the 
invention.