An aryl ether derivative of the formula ##STR1## in which A is an oxygen atom or an >N--R.sub.1 grouping, PA1 R.sub.1 is a hydrogen atom or a lower alkyl radical, PA1 B is an alkylene radical containing 2 to 4 carbon atoms, PA1 R.sub.2 and R.sub.3 each independently is a hydrogen or halogen atom, hydroxyl group or lower alkyl, lower alkoxy or lower alkanoyl radical, PA1 R.sub.4 is a hydrogen atom or an acyl radical, and PA1 n is an integer from 1 to 5, or a pharmacologically acceptable salt thereof, which possesses anti-allergic activity.

The present invention is concerned with new aryl ether derivatives and with 
a process for the preparation thereof, as well as with pharmaceutical 
compositions containing them and with the use thereof for combating 
allergic diseases. 
The aryl ether derivatives according to the present invention are compounds 
of the general formula: 
##STR2## 
in which A is an oxygen atom or an &gt;N--R.sub.1 grouping, 
R.sub.1 being a hydrogen atom or a lower alkyl radical, 
B is an alkylene radical containing 2 to 4 carbon atoms, 
R.sub.2 and R.sub.3, which can be the same or different, are hydrogen or 
halogen atoms, hydroxyl groups or lower alkyl, lower alkoxy or lower 
alkanoyl radicals, 
R.sub.4 is a hydrogen atom or an acyl radical and n is a whole number from 
1 to 5; and the pharmacologically acceptable salts thereof. 
Compounds of similar constitution are disclosed in Application Ser. No. 
104,205, filed Dec. 17, 1979, now U.S. Pat. No. 4,330,549. In further 
development of the invention of this previous German Patent Specification, 
we have now found that the new aryl ether derivatives of general formula 
(I), which have a tricyclic ring system instead of a bicyclic ring system, 
also display an outstanding anti-allergic action, which can be 
demonstrated in the pharmacological test of passive cutaneous anaphylaxis 
(PCA test) in vivo in rats. Furthermore, they display a strong 
antihistamine effect, as well as an anti-oedematous and antiphlogistic 
effectiveness. Therefore, the compounds of general formula (I) according 
to the present invention can be used especially advantageously for 
combating allergic diseases, for example asthma, hay fever and urticaria. 
The lower alkyl radicals of the substituents R.sub.1, R.sub.2 and R.sub.3 
can be straight-chained or branched and contain up to 6 and preferably up 
to 4 carbon atoms. 
The alkylene radical B can be straight-chained or branched, the 
trimethylene radical being preferred. 
The lower alkoxy radicals and lower alkanoyl radicals of the substituents 
R.sub.2 and R.sub.3 preferably contain up to 4 carbon atoms. 
The halogen atoms R.sub.2 and R.sub.3 are to be understood to be fluorine, 
chlorine or bromine atoms. 
The preferred value for n is 2, 3 or 4. 
The acyl radicals of the substituent R.sub.4 can be lower alkanoyl 
radicals, which are optionally substituted by halogen atoms or aryl 
radicals, or lower alkenoyl radicals, which are substituted by aryl 
radicals optionally having one or more substituents, or carbocyclic or 
heterocyclic aroyl radicals, which are optionally substituted one or more 
times by halogen, hydroxyl, lower alkyl, lower alkoxy, lower 
alkoxycarbonyl, lower alkanoyloxy, carboxyl, nitro, amino, lower 
alkanoylamino, nitrile, trifluoromethyl, carbamoyl, lower alkylthio, lower 
alkylsulphinyl, lower alkylsulphonyl, lower alkanoyl, aroyl, hydroxy lower 
alkyl or lower alkoxy lower alkyl. The lower alkyl moieties in the 
mentioned radicals contain up to 6 and preferably up to 4 carbon atoms, 
the radicals being straight-chained or branched. The heterocyclic aroyl 
radical may be, for example, a furancarbonyl, thiophenecarbonyl or 
pyridinecarbonyl radical and the aroyl radical may be, for example, a 
benzoyl radical. 
Furthermore, the substituent R.sub.4 may be the acid residue of a 
cycloalkylcarboxylic acid, cycloalkyl thereby preferably being understood 
to be a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl 
radical, as well as a carbamoyl radical optionally substituted by lower 
alkyl or aryl. Furthermore, R.sub.4 can also stand for the acid residue of 
a sulphonic acid, for example of a C.sub.1-4 -alkanesulphonic acid such as 
methanesulphonic acid or of benzenesulphonic acid. 
The term "aryl" in the definition of the substituent R.sub.4 preferably 
means a phenyl or naphthyl radical. Substituents which may optionally be 
present in the aryl radicals include hydroxyl, halogen, lower alkyl and 
lower alkoxy, the latter containing up to 6 carbon atoms. 
Apart from the compounds mentioned in the examples, the present invention 
also includes all compounds which display every possible combination of 
the substituents mentioned in the examples. 
According to the process of the present invention for preparing compounds 
of general formula (I), a compound of the general formula: 
##STR3## 
in which A, R.sub.2, R.sub.3 and n have the same meanings as above, is 
reacted in per se known manner with a compound of the general formula: 
EQU X--B--Y (III), 
in which X and Y are reactive residues and B has the same meaning as above, 
and with a compound of the general formula: 
##STR4## 
in which R.sub.4 has the same meaning as above, whereafter, if desired, 
the R.sub.4 substituent is converted into a different substituent R.sub.4 
having the above-given meaning, when R.sub.1 is a hydrogen atom the 
product obtained is, if desired, subsequently N-alkylated and the product 
obtained is, if desired, converted into a pharmacologically acceptable 
salt. 
The reactive residues in the compounds of general formula (III) are 
preferably chlorine or bromine atoms or mesyloxy or tosyloxy radicals. 
The process according to the present invention can be carried out, for 
example, by first condensing a compound of general formula (III) with a 
compound of general formula (IV) and the reaction product obtained is 
isolated. This intermediate is then reacted with a compound of general 
formula (II). The reaction is preferably carried out in an alkaline 
medium, for example in a lower alkanol, such as isopropanol, in the 
presence of sodium isopropanolate, or in dimethylformamide in the presence 
of potassium carbonate. 
According to another variant of the process, a compound of general formula 
(II) is first reacted with a compound of general formula (III), the 
reaction mixture obtained being subsequently reacted with a compound of 
general formula (IV) to give the desired end product of general formula 
(I). 
A subsequent conversion of the substituent R.sub.4 in a compound of general 
formula (I) into a different substituent R.sub.4 can take place, for 
example, by acylating a compound of general formula (I), in which R.sub.4 
is a hydrogen atom, with a compound of the general formula R.sub.4 -Z, in 
which Z is a reactive residue and R.sub.4 is an acyl radical. Thus, 
compounds of general formula (I), in which R.sub.4 is a hydrogen atom, are 
valuable intermediates for the preparation of other compounds of general 
formula (I), in which R.sub.4 is an acyl radical. 
The reactive residues Z can be any residues which are used in peptide 
chemistry for activating carboxylic acids, for example halogen atoms, 
azide groups and alkoxy, aryloxy and acyloxy radicals. 
Starting materials of general formulae (II), (III) and (IV) are known from 
the literature and can be prepared analogously to processes known from the 
literature. 
The pharmacologically acceptable salts of compounds of general formula (I) 
can be obtained in the usual way, for example by neutralizing compounds of 
general formula (I) with non-toxic inorganic or organic acids, such as 
hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, 
acetic acid, lactic acid, citric acid, malic acid, salicyclic acid, 
malonic acid, maleic acid or succinic acid. 
For the preparation of pharmaceutical compositions, the compounds of 
general formula (I) can be mixed in the usual manner with appropriate 
pharmaceutical carrier substances, aroma, flavoring and coloring materials 
and formed, for example into tablets or dragees or, with the addition of 
appropriate adjuvants, suspended or dissolved in water or in an oil, for 
example olive oil. 
The compounds of general formula (I) can be administered orally or 
parenterally in liquid or solid form. As injection medium, it is 
preferable to use water which contains the stabilizing agents, 
solubilizing agents and/or buffers conventional in the case of injection 
solutions. Additives of this kind include, for example, tartrate and 
borate buffers, ethanol, dimethyl sulphoxide, complex formers (such as 
ethylene-diamine-tetraacetic acid), high molecular weight polymers (such 
as liquid polyethylene oxide) for viscosity regulation and polyethylene 
derivatives of sorbitan anhydrides. 
Solid carrier materials include, for example, starch, lactose, mannitol, 
methyl cellulose, talc, highly dispersed silicic acid and high molecular 
weight polymers (such as polyethylene glycols). Compositions suitable for 
oral administration can, if desired, contain flavoring and/or sweetening 
agents. 
For external use, the compounds according to the present invention can also 
be employed in the form of powders or salves. For this purpose, they are 
mixed, for example, with powdered, physiologically acceptable diluents or 
with conventional salve bases.