Aromatic derivatives comprising an aminoalkoxy chain, the salts thereof, the process for preparing these derivatives and salts and the application thereof in therapeutics

New aromatic derivatives having an activity antagonistic to calcium and corresponding to formula: ##STR1## in which: A represents a chain having any one of the following structures: ##STR2## Ar represents a group of structure: ##STR3## n takes the value 1 or 2 when R is different from H; m takes the value 2 or 3.

The present invention relates to new aromatic derivatives comprising an 
aminoalkoxy chain, the salts thereof, the process for preparing these 
derivatives and salts and the application thereof in therapeutics. 
More precisely, the new derivatives of the invention correspond to the 
general formula: 
##STR4## 
in which: R represents a hydrogen or halogen atom, a methyl, hydroxyl or 
alkoxy group in which the alkyl residue comprises 1 to 4 carton atoms, or 
a benzyloxy group; 
n takes the value 1 or 2 when R is different from H; 
m takes the value 2 or 3; 
A represents a chain having any one of the following structures: 
##STR5## 
the aromatic group Ar being linked to position 1 of this chain, the pair 
(R.sub.1, R.sub.2) takes the value (H, C.sub.1 -C.sub.4 alkyl), (H, 
C.sub.5 -C.sub.6 cycloalkyl) or (H, cycloalkylalkyl comprising from 4 to 8 
carbon atoms), except in the case where 
##STR6## 
or else the value (C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkyl), 
R.sub.1 and R.sub.2 being also able to form in conjunction with the 
nitrogen atom to which they are linked a radical chosen from the 
following: pyrrolidino, piperidino, hexamethyleneimino, morpholino; and 
Ar represents: 
either a benzene group of structure: 
##STR7## 
in which R.sub.3 represents a halogen atom or a nitro or methyl group, 
R.sub.4 =alkoxy with 1 to 4 carbon atoms, p=0, 1 or 2; q=0, 1, 2, 3, 4; 
p+q.ltoreq.4 with the restrictions, when A=CO--CH.sub.2 --CH.sub.2 or 
##STR8## 
that p and q cannot simultaneously take the value 0 or a naphtalene or 
benzodioxannic group respectively of structure: 
##STR9## 
where R.sub.4 has the same meanings as previously. 
The salts of the derivatives of formula (I) are formed by the acid addition 
salts of said derivatives of formula (I), the acid being a mineral acid 
such as hydrochloric acid or an organic acid such as oxalic acid. 
The present invention further relates to the process for preparing these 
derivatives and salts. More precisely: 
A. The derivatives (I) for which A represents the chain of structure 
CO--CH.sub.2 --CH.sub.2 are obtained: 
either by reduction by catalytic hydrogenation more especially with Raney's 
nickel, preferably in a hydro-alcohol medium, respectively of the 
compounds of formula: 
##STR10## 
in which R, n, m, R.sub.1, R.sub.2 and Ar have the same meanings as in 
formula (I), 
or, when R represents a hydroxyl group, by simultaneous reduction and 
debenzylation, more particularly wth palladium on charcoal, preferably in 
a hydro-alcohol medium and in the presence of hydrochloric acid, 
respectively of the corresponding compounds of formula (II) and for which 
R represents a benzyloxy group. 
B. The derivatives of formula (I) for which R represents the chain of 
structure 
##STR11## 
are obtained: (a) by respective reduction of the corresponding compounds 
of forumula (I) preferably with the sodium borohydride-pyridine complex, 
more particularly in an alcohol medium and in the presence of NaOH, 
preferably concentrated, this latter being in a quantity of at least 
stoechiometric when R in formula (II) represents a hydroxyl group and in 
an amount at least twice stoechiometric when (R).sub.n represents two 
hydroxyl groups; 
(b) by reduction preferably with the sodium borohydride alone, more 
particularly in an alcohol medium, respectively of the corresponding 
compounds of formula (I) for which A represents the chain of structure 
CO--CH.sub.2 --CH.sub.2 and whose preparation is described in paragraph A. 
above; 
(c) when in formula (I) R represents a hydroxyl group, by hydrogenolysis 
more particularly with palladium on charcoal, preferably in a 
hydro-alcohol medium, possibly in the presence of hydrochloric acid, 
respectively of the corresponding compounds of formula (I) in which 
##STR12## 
and R represents the benzyloxy group; or (d) when in formula (I) R has 
the same meanings as before, except the value OH, by reduction, by means 
of an excess of sodium borohydride, of the compounds of formula (II) 
except for those in which R=OH. 
C. The compounds of formula (I) in which R represents the chain of 
structure CH.sub.2 --CH.sub.2 --CH.sub.2 are obtained by reduction 
preferably with triethylsilane in the presence of trifluoroacetic acid 
respectively of the corresponding compounds of formula (I) for which 
A=CO--CH.sub.2 --CH.sub.2 and whose preparation is described in paragraph 
A. above. 
D. The compounds of formula (I) for which A represents the chain of 
structure 
##STR13## 
and R has the same meanings as in formula (I) without however being able 
to represent a hydroxyl group, are obtained by condensation, preferably in 
a tetrahydrofurannic medium, in the presence of sodium hydride, of the 
compounds of formula: 
##STR14## 
in which Ar and m have the same meanings as in formula (I) and the pair 
(R'.sub.1, R'.sub.2)=(C.sub.1 -C.sub.4 alkyl; C.sub.1 -C.sub.4 alkyl) or 
R'.sub.1 and R'.sub.2 form in conjunction with the nitrogen atom to which 
they are linked, a pyrrolidino, piperidino, hexamethyleneimino or 
morpholino radical, respectively with the compounds of formula: 
##STR15## 
in which X represents a good leaving group such as a halogen atom or a 
mesyloxy or tosyloxy group and R' has the same meanings as R in formula 
(I) without however being able to represent a hydroxyl group. 
E. The compounds of formula (I) for which R represents the chain of 
structure 
##STR16## 
and R represents the hydroxyl radical are obtained by catalytic 
debenzylation (or hydrogenolysis), more particularly in the presence of 
palladium on charcoal and in an alcohol medium, possibly in the presence 
of hydrochloric acid, respectively of the corresponding compounds of 
formula (I) for which 
##STR17## 
and R represents the benzyloxy group prepared according to paragraphe D. 
above. 
F. The compounds of formula (I) for which A represents the chain of 
structure 
##STR18## 
are obtained by reduction, more particularly by means of sodium 
borohydride preferably in an alcohol medium, respectively of the 
corresponding compounds of formula (I) for which 
##STR19## 
and prepared according to paragraphes D. and E. above. 
The compounds of formula (II) are obtained by condensation of the compounds 
of formula: 
##STR20## 
in which m, --NR.sub.1 R.sub.2 and Ar have the same meanings as in formula 
(II), respectively with the aromatic aldehydes of formula 
##STR21## 
where R and n have the same meanings as in formula (II). 
The condensation may be carried out in ethanol, in the presence of sodium 
ethylate or in methanol in the presence of sodium methylate, or in alcohol 
in the presence of aqueous NaOH when R in formula (VI) represents a 
hydroxyl group. 
The compounds of formula (II) for which R represents a hydroxyl group may 
also be obtained by acid hydrolysis, preferably with dilute hydrochloric 
acid, of the compounds of formula: 
##STR22## 
in which Ar, m, n and NR.sub.1 R.sub.2 have the same meanings as in 
formula (II). 
The compounds of formula (IIa) are prepared according to the method 
described for preparing the compounds of formula (II) from the compounds 
of formula (V) but by condensing these latter respectively with the 
aromatic aldehydes of formula: 
##STR23## 
in which n takes the value 1 or 2. 
The compounds of formula (III) and those of formula (V) are obtained either 
by condensation of the derivatives of formula: 
##STR24## 
in which m and NR.sub.1 R.sub.2 have the same meanings as in formula (I), 
with the appropriate compounds of formula: 
##STR25## 
in which Ar has the same meanings as in formula (I) and R.sub.5 represents 
the methyl or isopropyl group. The condensation is carried out preferably 
in an aprotic organic solvent such as acetone, acetonitrile, DMF or THF, 
in the presence of potassium carbonate or by condensation of the amines of 
formula: 
##STR26## 
in which NR.sub.1 R.sub.2 has the same meanings as in formula (I) with the 
appropriate compounds of formula: 
##STR27## 
in which R.sub.5 has the same meanings as in formula (VIII) and m takes 
the value 2 or 3. The condensation is carried out in an aprotic solvent 
(toluene, THF, CH.sub.3 CN) in the presence either of an excess of amine 
of formula (IX) or of an organic base such as triethylamine for example, 
or of a mineral base such as potassium carbonate in the presence of sodium 
iodide. 
The compounds of formula (VIII) are already known or obtained by catalytic 
debenzylation of the compounds of formula: 
##STR28## 
in which Ar and R.sub.5 have the same meanings as in formula (VIII) in the 
presence of palladium on charcoal in an alcohol medium. 
The compounds of formula (VIII) having the particular structure: 
##STR29## 
in which R.sub.4 has the same meanings as in formula (I), R.sub.5 has the 
same meanings as in formula (XI) and X' represents the chlorine or bromine 
atom, may further be obtained by action of N-chlorosuccinimide or 
N-bromosuccinimide, in solution in carbon tetrachloride, in the presence 
of iron and azobisisobutyronitrile (AIBN), on the compounds of formula: 
##STR30## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIa). 
The compounds of formula (VIII) having the particular structure: 
##STR31## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIb) 
may be obtained by action of nitric acid in an acetic acid medium, on the 
compounds of formula (VIIIb). 
The compounds of formula (X) and those of formula (XI) are already known or 
obtained in the cases where they have the particular structures: 
##STR32## 
in which R.sub.3 and R.sub.4 have the same meanings as in formula (I), 
R.sub.5 has the same meanings as in formula (XI) and OR.sub.6 represents 
the benzyloxy group or the chain --O--(CH.sub.2).sub.m Cl where m=2 or 3, 
by a three-step synthesis which consists (a) in treating the compounds of 
formula: 
##STR33## 
in which R.sub.3 and R.sub.5 have the same meanings as in formulae (XII) 
and (XIIa), in solution in acetonitrile, and possibly in ethyl acetate or 
a chlorated solvent such as methylene chloride, in the presence of 
calcium, sodium, potassium or magnesium sulfate and either of benzylic 
alcohol (in the cases where in formulae (XII) and (XIIa), OR.sub.6 
=OCH.sub.2 .phi.), or of an alcohol or formula 
EQU HO--(CH.sub.2).sub.m Cl (XIV) 
in which m=2 or 3 (in the cases where in formulae (XII) and (XIIa), 
OR.sub.6 =O--(CH.sub.2).sub.m --Cl), by means of cuprous chloride in an 
oxygen atmosphere or a mixture of oxygen and an inert gas (nitrogen, 
argon) atmosphere, then (b) in treating the raw products obtained with 
sodium hydrosulfite (or dithionite), in the presence of sodium 
bicarbonate, in an aqueous medium, and finally (c) in treating the raw 
products thus obtained either with an alkyl halide or an alkyl sulfate [of 
formula R.sub.4 Br, R.sub.4 Cl or (R.sub.4).sub.2 SO.sub.4 where R.sub.4 
has the same meanings as in formulae (XII) and (XIIa)], in solution in an 
aprotic solvent in the presence of sodium carbonate. 
The compounds of formula (XIII) are obtained by the transposition reaction 
of FRIES on the compounds of formula: 
##STR34## 
in which R.sub.3 has the same meanings as in formula (XII) and R.sub.5 
=CH.sub.3 or isopropyl. 
The compounds of formula (VIII) having the particular structure: 
##STR35## 
in which R.sub.5 has the same meanings as in formula (VIII) and R.sub.4 
has the same meanings as in formula (I) are obtained by so-called FRIES 
transposition on the compounds of formula: 
##STR36## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIId). 
The compounds of formula (XVI) are obtained by oxidization with 36% 
hydrogen peroxid in the presence of formic acid, of the compounds of 
formula: 
##STR37## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (XVI). 
The compounds of formula (XVII) are prepared by a five-step synthesis from 
the compounds of formula: 
##STR38## 
in which R.sub.5 has the same meanings as in formula (XVII) and which 
consists (a) in treating said compounds of formula (XVIII) with 36% 
hydrogen peroxid in the presence of formic acid (so-called BAYER-WILLIGER 
reaction), then (b) in treating the compounds obtained with aluminium 
chloride in the presence of an acid chloride of formula R.sub.5 COCl where 
R.sub.5 has the same meanings as in formula (XVII), in solution in 
methylene chloride (so-called FRIES reaction), then (c) in treating the 
compounds obtained with an alkyl halide or an alkyl sulfate of formula 
R.sub.4 Br, R.sub.4 Cl or (R.sub.4).sub.2 SO.sub.4 where R.sub.4 has the 
same meaning as in formula (XVII), in the presence of potassium carbonate, 
in an aprotic solvent (such as acetone for example), then (d) in treating 
the compounds obtained with potassium carbonate in an alcohol medium 
(preferably methanol) and finally (e) in treating the compounds obtained 
with an alkyl halide or an alkyl sulfate of formula R.sub.4 Br, R.sub.4 Cl 
or (R.sub.4).sub.2 SO.sub.4 where R.sub.4 has the same meaning as above in 
the presence of potassium carbonate, in an aprotic solvent (such as 
acetone for example). 
The compounds of formula (VIII) having the particular structure: 
##STR39## 
in which R.sub.4 has the same meanings as in formula (I) and R.sub.5 has 
the same meanings as in formula (VIII) are obtained by action of chlorine 
in a chloroform medium, at 20.degree. C., on the compounds of formula: 
##STR40## 
where R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIe), 
the compounds of formula (VIIIn) being obtained by catalytic debenzylation 
(H.sub.2, Pd/C, EtOH) of the corresponding compounds of formula (XII). 
The compounds of formula (VIII) having the particular structure: 
##STR41## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIe) 
are obtained by action of chlorine in a chloroform medium at 20.degree. C. 
on the compounds of formula (VIII) having the particular structure: 
##STR42## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIf). 
The compounds of formula (VIII) having the particular structure: 
##STR43## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIe) 
are obtained by the action of chlorine, at -20.degree. C., in a carbon 
tetrachloride medium on the compounds of formula (VIIIg). 
The compounds of formula (VIII) having the particular structure: 
##STR44## 
in which R.sub.4 has the same meanings as in formula (I) are prepared 
according to the method described in Chem. Abst. 83, 9792f. 
The compounds of formula (VIII) having the particular structure: 
##STR45## 
in which R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIe) 
are obtained by the action of sodium nitrite in a dilute sulfuric acid 
medium followed by the action of cuprous chloride and hydrochloric acid, 
on the compounds of formula: 
##STR46## 
where R.sub.4 and R.sub.5 have the same meanings as in formula (VIIIe), 
the compounds of formula (VIIIm) being obtained according to the method 
described in J.C.S., 1963, 2374. 
The compound of formula (XIIIa) for which R.sub.5 represents the isopropyl 
group is prepared like the compound of formula (XIIIa) for which R.sub.5 
=CH.sub.3 (see J.C.S. 1973, 240) but from the corresponding reagents. 
The compounds of formula (XV) are obtained by treating with acid chlorides 
or anhydrides of formula R.sub.5 COCl or (R.sub.5 CO).sub.2 O where 
R.sub.5 has the same meanings as in formula (XV) in the presence of a 
basic agent (pyridine or triethylamine for example) and in solution in an 
aprotic solvent (methylene chloride, for example), the corresponding 
hydroquinone derivatives. 
Finally, the compounds of formula (XVIII) are obtained by methylation with 
methyl sulfate in the presence of a base (NaOH or K.sub.2 CO.sub.3), of 
the corresponding hydroxylated compounds. These latter are obtained, like 
5-acetyl 8-hydroxy benzodioxanne-1,4 (FRIES reaction, see Chem. Abst. 65, 
2251 h) but from the corresponding reagents. 
The salts of the derivatives of formula (I) are obtained in a conventional 
way and, for example, by the action of a mineral or organic acid in 
solution in an appropriate solvent, on said derivatives of formula (I) 
also in solution in an appropriate solution.