Alkylenedioxyphenyl ether derivatives having anti-ischaemic, memory enhancing and anti-convulsive activity

The invention relates to compounds having anti-ischaemic activity, memory enhancing activity and anti-convulsive activity of the formulae 1A and 1B ##STR1## wherein R.sub.1 +R.sub.2 together form an alkylene group having 1-3 C-atoms which may be substituted with one or more alkyl group(s) having 1-3 C-atoms and the remaining R and Z variables are defined as disclosed herein, or a pharmacologically acceptable salt thereof.

The invention relates to a group of new alkylenedioxyphenyl ether 
derivatives having interesting anti-ischaemic activity, memory enhancing 
activity and anti-convulsive activity, to a method of preparing said 
compounds, and to pharmaceutical compositions comprising at least one of 
these compounds as the active component. There is an increasing clinical 
interest in an effective pharmalogical symptomatic treatment for cerebral 
and peripheral ischaemic diseases. In patients suffering from these 
diseases the impaired blood supply causes an inadequate delivery of oxygen 
and other nutrients to the tissue as well as a diminished removal of 
metabolic waste products resulting in structural injury and functional 
deterioration. Anti-convulsive compounds can be useful in the treatment of 
epilepsy. 
The object of the present invention is to provide active compounds with 
anti-ischaemic, memory enhancing and anti-convulsive properties. 
It has been found surprisingly that compounds of formulae 1A and 1B 
##STR2## 
wherein R.sub.1 +R.sub.2 together form an alkylene group having 1-3 
C-atoms which may be substituted with one or more alkyl group(s) having 
1-3 C-atoms; 
Z is methylene optionally substituted with one alkyl group having 1-3 
C-atoms, or with one phenylalkyl group with 1-3 C-atoms in the alkyl 
group, which phenyl group may be substituted with a group (R.sub.6).sub.p 
wherein R.sub.6 is halogen, hydroxy, alkyl or hydroxyalkyl having 1-5 
C-atoms, alkoxy having 1-3 C-atoms, S-alkyl, S(O)-alkyl or S(O).sub.2 
-alkyl having 1-3 C-atoms, amino, mono- or dialkylamino having 1-3 C-atoms 
per alkyl group, trifluoromethyl, trifluoromethoxy, a sulphonylamido group 
SO.sub.2 NHR or a carbalkoxy group COOR wherein R is alkyl having 1-4 
C-atoms, the group COOH, SO.sub.3 H, CONH.sub.2, the amidino group or 
cyano group, and p has the value 0-3; 
R.sub.3 and R.sub.4 independent of each other represent hydrogen, alkyl 
having 1-10 C-atoms, alkenyl or alkynyl having 3-10 C-atoms, cycloalkyl 
having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms 
in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in 
the alkyl group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or 
heteroaryl-alkynyl group having 3-5 C-atoms in the alkenyl group or 
alkynyl group, which groups R.sub.3 and R.sub.4 may be substituted with a 
group (R.sub.6).sub.p wherein R.sub.6 and p have the above mentioned 
meanings, or wherein R.sub.3 +R.sub.4 together with the nitrogen atom form 
a saturated or unsaturated heterocyclic group of 5-7 ring atoms, which may 
contain a second hetero-atom from the group consisting of oxygen, sulphur 
and nitrogen, which ring may be substituted with a group (R.sub.6).sub.p 
wherein R.sub.6 and p have the above mentioned meanings, or with 
phenylalkyl, heteroaryl-alkyl, phenylalkenyl, heteroaryl-alkenyl, 
phenylalkynyl or heteroaryl-alkynyl having at most 3 C-atoms in the alkyl, 
alkenyl or alkynyl part, which groups may be substituted with a group 
(R.sub.6).sub.p wherein R.sub.6 and p have the above-mentioned meanings, 
or which ring may be annelated with a phenyl group; 
R.sub.5 is alkyl having 1-12 C-atoms, alkenyl or alkynyl having 3-12 
C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring 
atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl 
having 1-5 C-atoms in the alkyl sub-group, phenylalkenyl, 
heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl having 3-5 C-atoms 
in the alkenyl sub-group or alkynyl sub-group, which groups may be 
substituted with a group (R.sub.6).sub.p, wherein R.sub.6 and p have the 
above-mentioned meanings, and which alkyl sub-groups, alkenyl sub-groups 
and alkynyl sub-groups may contain a group --O--, --S-- or CO, 
prodrugs and pharmaceutically acceptable acid addition salts thereof have 
interesting and valuable anti-ischaemic, memory enhancing and 
anti-convulsive properties. 
Prodrugs are derivatives of these compounds which as such are inactive, 
from which, after splitting off an easily removable group, for example an 
ester group or an ether group, an active compound of formula 1A or 1B is 
obtained. Suitable acids with which suitable addition salts can be formed 
are, for example, hydrochloric acid, sulphuric acid, phosphoric acid, 
nitric acid, and organic acids like citric acid, fumaric acid, maleic 
acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, 
methane sulphonic acid, etc. 
One or more centers of chirality may be present in the compounds having 
formula 
1A or 1B. The invention relates both to racemates and the individual 
isomers of the compounds having formulae 1A and 1B. 
The anti-ischaemic and memory enhancing activity of the compounds has been 
determined by means of the in vivo hypobaric hypoxia test, the in vitro 
cardiomyocytes test and the in vivo memory test. These tests were used to 
characterize substances with cerebro- and/or peripheral-protective 
activity. 
The anti-convulsive activity of the compounds has been determined by means 
of chemically induced tonic convulsions in vivo. 
1) Hypobaric activity in vivo 
Cerebro-protective activity was determined by measuring the prolongation of 
the survival time of conscious mice under hypobaric conditions. 
Groups of 3 overnight fasted male NMRI mice (15-20 g) are dosed ip (30 
mg/kg), 30 minutes before being placed in a chamber at hypobaric pressure 
of 200 mBar. The prolongation of the survival time is expressed in 
percentage increase in respiration time, compared to that of the placebo 
treated control group. 
2) Cardiomyocytes in vitro 
Cyto-protective properties were determined in an in vitro model using 
isolated calcium tolerant cardiomyocytes according to L. Verdonck et al 
(Life Sciences, vol. 38, (1986) 765-772). 
Cardiomyocytes were isolated from male Wistar rat hearts. Rod shaped cells 
were incubated with the compound to be tested for 30 min. Injury was 
induced by e.g. veratrine (100 .mu.g/ml) or by hypoxia upon which the 
cells became rounded unless protected by the compound. After 20 min. the 
remaining rod-shaped cells were counted and the protecting efficacy of the 
compound was determined. 
3) Memory testing under hypoxic conditions 
Cerebroprotective activity was determined by studying the prevention of 
hypoxia induced amnesia in gerbils. 
In groups of 6-8 gerbils step through passive avoidance was measured after 
exposure to hypoxia (4% O.sub.2, 96% N.sub.2) until gasping was observed. 
Memory testing was performed 4 hrs after drug administration and exposure 
to hypoxia. 
4) Chemically induced tonic convulsions in vivo 
Protection against pentylene-tetrazole-induced convulsions (50 mg/kg i.v.) 
was demonstrated in male NMRI-mice, weighing 18-24 g. 
Tonic convulsions were measured 60 minutes after oral administration of the 
test compound. Suppression of the tonic extensor phase was considered to 
be the criterion for the anti-convulsive effect. (Purpura D. P., Penry J. 
K., Tower D. B., Woodburry D. M., Walters R. D. (eds.), Experimental 
models of epilepsy, Raven Press, New York (1972)). 
The compounds having formulae 1A and 1B, wherein the symbols have the 
above-mentioned meaning are new compounds which can be prepared according 
to methods known per se. 
For example compounds having formula 1A can be obtained by first preparing 
a compound having formula 2 
##STR3## 
wherein R.sub.1 and R.sub.2 have the above mentioned meaning and wherein 
R'.sub.5 is a so-called directed ortho-metallating group (see for example 
Acc. Chem. Res., 15, 306 (1982)), such as --CH.sub.2 OCH.sub.3 (MOM), 
--CH(CH.sub.3)OC.sub.2 H.sub.5, --CH.sub.2 O(CH.sub.2).sub.2 
Si(CH.sub.3).sub.3 (SEM) and the like, via known procedures (see for 
example, "Protective Groups in Organic Chemistry", Ed. J. F. W. McOmie, 
Plenum Press, London (1973), Chapter 4; Synthesis, 276 (1975); Synthesis 
244 (1976); J. Org. Chem., 44, 2480 (1979)), from the corresponding 
phenolic compounds 2 wherein R'.sub.5 is hydrogen. The so-obtained 
compounds of formula 2 can be converted into the corresponding compounds 
of formula 3 
##STR4## 
wherein R.sub.7 is hydrogen, alkyl having 1-3 C-atoms, phenylalkyl with 
1-3 C-atoms in the alkyl group, which phenyl group may be substituted with 
a group (R.sub.6).sub.p wherein R.sub.6 and p have the above mentioned 
meanings, via regioselective deprotonation with a strong base, for example 
n-butyllithium and the like, followed by reaction with an electrophile 
R.sub.7 --CO--X, wherein X represents a leaving group, for example halogen 
(see for analogous ortho-directed metallations for example J. Org. Chem., 
53, 3936 (1988); J. Heterocyclic Chem., 26, 1827 (1989)). 
The so-obtained compounds of formula 3 can be converted into the 
corresponding compounds of formula 4 
##STR5## 
by a reductive amination reaction with an amine of the formula R.sub.3 
R.sub.4 NH, in which formulae R.sub.1 -R.sub.4 and Z have the meanings 
given in formula 1A, and R'.sub.5 and R.sub.7 have the meanings given 
above. This reductive amination reaction can be carried out with a 
suitable reducing agent such as NaCNBH.sub.3 in an inert solvent, for 
example acetonitrile, or by other reductive amination methods (see for 
example Russ. Chem. Rev., 49, 14 (1980), or Synthesis, 135 (1975)). In 
some cases the addition of an acid catalyst may be desirable to enhance 
the reaction rate. 
The so-obtained compounds of formula 4 can be converted into the 
corresponding compounds of formula 5 
##STR6## 
in which formula R.sub.1 -R.sub.4 and Z have the meanings given in formula 
1A, by means of an acid-catalyzed removal of R'.sub.5. 
The so-obtained compounds of formula 5 can be converted into the 
corresponding compounds of formula 1A wherein R.sub.5 has the above 
mentioned meanings by means of a reaction with a compound of the formula 
R.sub.5 --X, wherein X is a so-called leaving group. This reaction is 
preferably carried out in an inert solvent such as dimethylsulphoxide 
(DMSO), N,N-dimethylformamide (DMF) and the like, in the presence of a 
suitable base such as sodium hydride or potassium tert-butoxide and the 
like. Sometimes the addition of sodium iodide is desirable. The reaction 
may be carried out at somewhat elevated temperatures. 
Compounds having general formula 1B can be obtained for example by first 
preparing a compound having formula 6 
##STR7## 
wherein R.sub.1 -R.sub.4 and Z have the above mentioned meanings, by 
reacting a compound of the formula 7 
##STR8## 
with a compound of the formula R.sub.3 R.sub.4 NH and an aldehyde of the 
formula R.sub.7 CHO, in which formulae R.sub.1 -R.sub.4 and R.sub.7 have 
the above mentioned meaning. This so-called Mannich-reaction is preferably 
carried out in an inert organic solvent, such as ethanol or acetonitrile. 
The starting compounds of formula 7 are known or can be obtained 
analogously to known compounds (see for example W. Baker and R. I. Savage, 
J. Chem. Soc., 1602 (1938)).