Synthesis of new piperidine and cyclohexylamino-spiro derivatives as potential anticalcium agents

Summary: The synthesis of new 1,3-benzodioxolo and 1,4- benzodioxan spiro derivatives containing a piperidine (4-6) or cyclohexylamino (7-8) group have been described. These compounds exhibit in vitro a moderate anticalcium activity.

1. S a n c h e z et al.:

Figure 1
The spiropiperidine nucleus has been investigated in several occasions. By contrast, compounds with the spirocyclohexylamine nucleus have received relatively little attention.
In a recent report from this laboratory, the preparation of a series of spiro compounds as adrenergic agents was described [4]. In this regard, several azadioxigenated-spiro compounds (type A) were prepared for comparison with them ( Fig. 2). It is interesting to note that compounds 7 and 8 (type B) have the aminocyclohexyl group instead of the piperidine ring (Fig. 2) and the general synthetic method used for obtaining the related compounds 4, 5 and 6 are now not applicable.

Figure 2
As a part of our continued program [5] [6] [7] to find new calcium antagonists with non classical structures, we have undertaken the study of compounds 4-8.
The synthesis of the alkylated amines (4-6) is presented in Scheme 1. The appropriate secondary amines, which proved to be useful intermediates, were conveniently prepared from the N-acetyl-4-piperidone. The synthesis of the corresponding alkyl halydes 9 and 10 ( Fig. 3) was developed by Riom-CERM laboratories following their own methode [5] and the amine 11 was commercially available from Aldrich.

Conclusion
On the basis of the structure, we can conclude that the substructure of spiro 1,3benzodioxole or 1,3-benzodioxan has very few influence on the calcium antagonist activity.
Synthesis of new piperidine and cyclohexylamino-spiro derivatives as potential . . . 183 The bromine introduction (compound 5) induced a decreasing of the anticalcium activity.
Compounds with the exocyclic amino group are less active than their piperidine analogues respect to the anticalcium activity in the K+ test. However, in the caffeine test, that is indicative of the intracellular activity, compounds 7 and 8 showed an agonist effect.

'-Aminospiro[l,3-benzodioxolo-2,1 '-cyclohexane] 20
A mixture of the ketone 19 (1.7 g; 7.37 mmol), benzylamine ( General procedure of alkylation Triethylamine freshly distilled (3 mmol) was added to a solution of the appropriate amine (1 mmol) and the corresponding alkylating reagent (2 mmol) in dry DMF. The reaction mixture was stirred under an argon atmosphere at 60-80 for 48 h. After the solvent was removed, the residue was diluted with water and extracted with CH2CI2. The organic layers were dried, filtered and concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography, using CH2C12 or hexane as eluent, allowed us to obtain the corresponding alkylated compound.