Amino derivatives of 4-hydroxy-1,2-benzisothiazole

New aminopropanol derivatives of 4-hydroxy-1,2-benzisothiazole and their addition salts with acids, their preparation, and pharmaceutical formulations which contain the said compounds and may be used for the treatment and prophylaxis of cardiac and circulatory disorders.

The present invention relates to new aminopropanol derivatives of 
4-hydroxy-1,2-benzisothiazole and their addition salts with acids, their 
preparation, and pharmaceutical formulations which contain the said 
compounds and may be used for the treatment and prophylaxis of cardiac and 
circulators disorders. 
We have found that compounds of the general formula (I) 
##STR1## 
where R is hydrogen or alkyl of 1 to 8 carbon atoms which may be 
unsubstituted or substituted by hydroxyl, alkoxy of 1 to 3 carbon atoms, 
alkylthio of 1 to 3 carbon atoms, dialkylamino (where alkyl is of 1 to 5 
carbon atoms), cycloalkylamino of 3 to 7 carbon atoms in the ring, cyclic 
amine of 5 to 7 ring members or cycloalkyl of 3 to 8 carbon atoms in the 
ring, or is alkenyl or alkynyl of 2 to 8 carbon atoms, or is cycloalkyl or 
cycloalkenyl of 3 to 8 carbon atoms in the ring or bicycloalkyl of 5 to 8 
carbon atoms, the cycloalkyl rings being unsubstituted or monosubstituted 
or disubstituted by lower alkyl of 1 to 3 carbon atoms, and their addition 
salts with acids, exhibit valuable pharmacological properties. 
Examples of straight-chain or branched alkyl of 1 to 8 carbon atoms are 
methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec.-butyl, 
tert.-butyl, pentyl-2, 2-methyl-butyl-2, 3-methyl-butyl-2, 
3-methyl-pentyl-3, 2,3-dimethyl-butyl-2, 3-ethyl-pentyl-3, 
2,4-dimethyl-pentyl-3 and 2,4,4-trimethylpentyl, and examples of 
substituted alkyl are 1-methylthio-2-methyl-propyl-2, 1-methoxy-propyl-2, 
2-hydroxy-ethyl-1, 1-hydroxy-butyl-2, 3-hydroxy-3-methyl-butyl-1, 
3-piperidinopropyl-2 and 1-cyclopropyl-ethyl-1. 
Amongst the alkyl radicals, those of 3 to 6 carbon atoms which are branched 
at the carbon in the .alpha.-position to the amino nitrogen are preferred. 
Thus, preferred alkyl radicals are isopropyl, tert.-butyl, 
2-methyl-butyl-2, sec.-butyl, 3-methylpentyl-3 and pentyl-2. Suitable 
substituents of the preferred alkyl radicals are, in particular, alkoxy of 
1 to 3 carbon atoms and especially methoxy, so that an example of a 
preferred substituted alkyl is 1-methoxy-propyl-2. 
Examples of alkenyl or alkynyl of 2 to 8 carbon atoms are prop-1-enyl-3, 
but-3-ynyl-2, 2-methyl-but-3-ynyl-2 and 3-ethylpent-1-ynyl-3. Amongst 
these, alkynyl radicals of 3 to 6 carbon atoms, e.g. but-3-ynyl-2 and 
2-methyl-but-3-ynyl-2, are preferred. 
Examples of cycloalkyl, cycloalkenyl and bicycloalkyl are cyclopropyl, 
cyclobutyl, cyclopentyl, cycloheptyl, bicyclo[3.3.0]-octyl, 
3-exo-norbornanyl, cyclooctenyl-5 and dimethylcyclohexyl, a suitable alkyl 
substituent of the said cyclic radicals being, in particular, methyl. 
Accordingly, examples of compounds according to the invention, of the 
formula I, are: 
4-(2-hydroxy-3-tert.-butylamino-propoxy)-1,2-benzisothiazole, 
4-[2-hydroxy-3-(3-methylbutyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-(2-hydroxy-3-amino-propoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-methylaminopropoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-n-butylaminopropoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-isobutylaminopropoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-sec.-butylaminopropoxy)-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2-methyl-butyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(3-methyl-pentyl-3-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2,3-dimethyl-butyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(3-ethyl-pentyl-3-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2,4-dimethyl-pentyl-3-amino)-propoxy]-1,2-benzisothiazole, 
4-(2-hydroxy-3-cyclopropylamino-propoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-cyclopentylamino-propoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-cycloheptylamino-propoxy)-1,2-benzisothiazole, 
4-[2-hydroxy-3-(bicyclo[3.3.0]-octyl-1-amino)-propoxy]- 
1,2-benzisothiazole, 
4-[2-hydroxy-3-(2-exo-norbornanylamino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2,4,4-trimethyl-pentyl-2-amino)-propoxy]-1,2-benzisothiazo 
le, 
4-[2-hydroxy-3-(1-thiomethyl-2-methyl-propyl-2-amino)-propoxy]-1,2-benziso 
thiazole, 
4-[2-hydroxy-3-(2-methyl-but-3-ynyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(but-3-ynyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(1-methoxy-propyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(cyclooctenyl-5-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2,6-dimethyl-cyclohexyl-1-amino)-propoxy]-1,2-benzisothiaz 
ole, 
4[-2-hydroxy-3-(3-ethylpent-1-ynyl-3-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(prop-1-enyl-3-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(pentyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(1-cyclopropyl-ethyl-1-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2-hydroxy-ethylamino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(1-hydroxy-butyl-2-amino)-propoxy]-1,2-benzisothiazole and 
4-[2-hydroxy-3-(3-cyclohexyl-amino-propyl-2-amino)-propoxy]-1,2-benzisothi 
azole. 
Further examples are 
4-[2-hydroxy-3-(2-cyclobutyl-ethyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(1-cyclopropyl-propyl-1-amino)-propoxy]-1,2-benzisothiazole 
, 4-(2-hydroxy-3-cyclobutylamino-propoxy)-1,2-benzisothiazole and 
4-[2-hydroxy-3-(prop-2-ynyl-1-amino)-propoxy]-1,2-benzisothiazole. 
The compounds according to the invention can be manufactured by reacting a 
1,2-benzisothiazole of the general formula II 
##STR2## 
where A is 
##STR3## 
B being a nucleofugic leaving group, with an amine of the general formula 
EQU H.sub.2 N-R 
where R has the above meanings, advantageously in a solvent, and in the 
presence or absence of an acid-binding agent, in the conventional manner, 
with or without conversion of the resulting compound into the addition 
salt with a physiologically safe acid. 
The leaving group B is preferably a halogen, especially chlorine, bromine 
or iodine. Examples of other nucleofugic leaving groups are aromatic or 
aliphatic sulfonic acid radicals, e.g. the p-toluenesulfonic acid radical, 
the p-bromosulfonic acid radical or the methanesulfonic acid radical. 
The reactions are carried out at from 10.degree. to 120.degree. C., i.e. at 
room temperature or elevated temperatures, advantageously at from 
50.degree. to 120.degree. C. They may be carried out under atmospheric 
pressure or in a closed vessel under superatmospheric pressure, with or 
without heating to a temperature within the stated range. In the case of 
volatile amines H.sub.2 N-R, in particular, it may be advantageous to 
carry out the reaction in a closed system, i.e. in an autoclave. 
The starting compounds may be reacted with one another directly, i.e. 
without adding a diluent or solvent. However, the reactions are 
advantageously carried out in the presence of an inert diluent or solvent, 
for example a lower alcohol of 1 to 4 carbon atoms, e.g. methanol, 
ethanol, n- or isopropanol, preferably isopropanol or ethanol, a lower 
saturated dialkyl ether, dialkyl glycol ether or cyclic ether, e.g. 
diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, benzene or 
an alkylbenzene, e.g. toluene or xylene, an aliphatic hydrocarbon, e.g. 
hexane, heptane or octane, a lower aliphatic ketone, e.g. acetone, methyl 
ethyl ketone or methyl isobutyl ketone, a dialkylformamide or diethyl 
formamide, or dimethylsulfoxide, or in the presence of water, or in 
mixtures of the above solvents. 
The amine of the formula H.sub.2 N-R used in excess may also serve as a 
diluent or solvent. 
The preferred solvent for the reaction of 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxypropane with an amine R-NH.sub.2 
is a lower alcohol, especially ethanol or isopropanol, the reaction 
preferably being carried out at from 50.degree. C. to 120.degree. C. and 
under atmospheric pressure. 
In the case of the nucleophilic replacement of a radical B, the preferred 
solvent is a lower aliphatic ketone, e.g. acetone, methyl ethyl ketone or 
methyl isobutyl ketone, a cyclic ether, especially tetrahydrofuran or 
dioxane, or a dialkylformamide, e.g. dimethylformamide, and the preferred 
temperature is from 90.degree. to 120.degree. C. 
The reaction may or may not be carried out in the presence of a catalytic 
amount of sodium iodide or potassium iodide. 
It should be mentioned that a mixture of the epoxide with a halohydrin may 
also be used as the starting compound of the formula II, since the 
industrial manufacture of the starting compounds of the formula II at 
times results in such mixtures. 
In an advantageous embodiment of the nucleophilic replacement of the 
radical B by the amine used, the reaction is carried out in the presence 
of a base as an acid-binding agent. Preferred bases are alkali metal 
hydroxides, carbonates, bicarbonates and alcoholates, and tertiary organic 
amines, e.g. pyridine or a trialkylamine, e.g. trimethylamine or 
triethylamine. Amongst the alkali metal compounds, those of sodium and 
potassium are particularly suitable. The base is used in the 
stoichiometric amount or in slight excess. It may also be advantageous to 
use an excess of the amine H.sub.2 N-R employed for the reaction to serve, 
at the same time, as the acid-binding agent. 
The time required for complete reaction depends on the reaction temperature 
and is in general from 2 to 15 hours. The product can be isolated in the 
conventional manner, for example by filtration, or by distilling the 
diluent or solvent from the reaction mixture. The compound obtained is 
purified in the conventional manner, for example by recrystallization from 
a solvent, by conversion to an adduct with an acid, or by column 
chromatography. 
The starting compounds of the formula (II) can be obtained by alkylating 
4-hydroxy-1,2-benzisothiazole, which may be obtained from the known 
compound 4-methoxy-1,2-benzisothiazole by an ether cleavage reaction, with 
an epihalohydrin or an .alpha.,.omega.-dihalo-2-propanol. 
Suitable epihalohydrins are epichlorohydrin, epibromohydrin and 
epiiodohydrin, and suitable .alpha.,.omega.-dihalo-2-propanols are, in 
particular, 1,3-dichloro-2-propanol and 1,3-dibromo-2-propanol. 
The reaction of 4-hydroxy-1,2-benzisothiazole in order to prepare the 
starting compounds of the formula II is advantageously carried out at from 
50.degree. to 120.degree. C. under atmospheric pressure or in a closed 
vessel under superatmospheric pressure. Advantageously, the reaction is 
carried out in an inert diluent or solvent, for example a lower aliphatic 
ketone, e.g. acetone, methyl ethyl ketone or methyl isobutyl ketone, a 
lower alcohol of 1 to 4 carbon atoms, e.g. methanol, ethanol, propanol or 
butanol, a lower alkyl acetate, e.g. methyl acetate, ethyl acetate or 
propyl acetate, a dialkylformamide, e.g. dimethylformamide or 
diethylformamide, or dimethylsulfoxide, or with an excess of the 
alkylating agent as the diluent or solvent. 
The reactions are preferably carried out in the presence of a base as the 
acid-binding agent. Suitable bases are alkali metal carbonates, 
bicarbonates, hydroxides and alcoholates, especially of sodium and 
potassium, basic oxides, e.g. aluminum oxide or calcium oxide, and organic 
tertiary bases, e.g. pyridine, piperidine or lower trialkylamines, e.g. 
trimethylamine or triethylamine. In relation to the alkylating agent 
employed, the bases may be used in catalytic amount or stoichiometric 
amount or in slight excess. 
Preferably, 4-hydroxy-1,2-benzisothiazole is reacted with epibromohydrin or 
with 1,2-dibromo-2-propanol in a lower aliphatic ketone, especially 
acetone or methyl isobutyl ketone, in the presence of at least one mole 
equivalent, based on the alkylating agent, of a base, especially potassium 
carbonate, at from 50.degree. to 80.degree. C. 
Similarly to the process for reacting phenol with 1,3-dichloro-2-propanol, 
described in Liebigs Annalen der Chemie 1976, 221-224, 
4-hydroxy-1,2-benzisothiazole may be reacted with the equivalent amount of 
1,3-dichloro-2-propanol in aqueous sodium hydroxide solution at about 
50.degree. C. 
It should also be mentioned that the starting compounds of the formula II 
may be interconverted by a simple acid-base reaction. For example, 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxypropane may be converted to 
1-(1,2-benzisothiazol-4-yloxy)-3-halo-propan-2-ol, by means of the 
appropriate hydrohalic acid, the diluent or solvent used being a 
conventional solvent for such a reaction or, preferably, an aliphatic or 
cyclic ether, e.g. diethyl ether, tetrahydrofuran or dioxane, or a lower 
alcohol, e.g. methanol, ethanol or propanol. Conversely, the 
1-(1,2-benzisothiazol-4-yloxy)-3-halo-propan-2-ol compounds, especially 
1-(1,2-benzisothiazol-4-yloxy)-3-chloropropan-2-ol and 
1-(1,2-benzisothiazol-4-yloxy)-3-bromo-propan-2-ol may be converted by 
means of a base, e.g. an alkali metal hydroxide, carbonate, bicarbonate, 
alcoholate or hydride, or an organic amine, e.g. pyridine, piperidine or a 
tertiary aliphatic amine, e.g. trimethylamine or triethylamine, into 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxypropane. These reactions may be 
carried out at room temperature or be accelerated or completed by heating, 
for example at from 60.degree. to 120.degree. C. The reaction may be 
carried out under atmospheric pressure or in a closed vessel under 
superatmospheric pressure, with or without heating. The starting compounds 
for this reaction may be isolated beforehand or be produced in situ and be 
directly converted further, without isolation and purification. 
According to an alternative process of manufacture, the compounds of the 
general formula (I) are obtained by alkylating 
4-hydroxy-1,2-benzisothiazole with a compound of the general formula III 
or IV 
##STR4## 
where B and R have the above meanings and preferred meanings, 
advantageously in a solvent, and in the presence or absence of an 
acid-binding agent, at from 40.degree. to 120.degree. C., in the 
conventional manner, and the resulting compound may or may not be 
converted to its addition salt with a physiologically safe acid. 
This reaction may for example be carried out under conditions similar to 
those described in Swiss Patent 451,115 or in German Laid-Open Application 
DOS 2,007,751. 
The alkylation of 4-hydroxy-1,2-benzisothiazole with a compound of the 
formula III is preferably carried out in the presence of an acid-binding 
agent, e.g. an alkali metal hydroxide, carbonate, bicarbonate or 
alcoholate, or of a tertiary organic amine, preferably pyridine or a 
tertiary aliphatic amine, e.g. trimethylamine or triethylamine. Amongst 
the alkali metal compounds, those of sodium and potassium are particularly 
suitable. The base is advantageously used in the stoichiometric amount or 
in a slight excess. Equally, the hydroxy-benzisothiazole may, for example, 
be employed in the form of an alkali metal salt, e.g. the sodium salt or 
potassium salt. 
The alkylation reactions are advantageously carried out in an inert diluent 
or solvent, for example a lower aliphatic alcohol of 1 to 4 carbon atoms, 
e.g. methanol, ethanol, propanol, isopropanol or a butanol, or a lower 
aliphatic ketone, e.g. acetone, methyl ethyl ketone or methyl isobutyl 
ketone, a cyclic ether, e.g. tetrahydrofuran or dioxane, or a 
dialkylformamide, e.g. dimethylformamide or diethylformamide. The reaction 
is advantageously accelerated or completed by heating, for example at from 
40.degree. to 120.degree. C., preferably from 80.degree. to 100.degree. C. 
Amongst the solvents, the lower aliphatic ketones, cyclic ethers, 
dialkylformamides and dimethylsulfoxide are preferred. Mixtures of the 
said solvents, including mixtures with water, e.g. a dioxane/water 
mixture, may also be used. 
The compounds of the formula III and IV are known or can be prepared by, 
for example, processes disclosed in the literature, e.g. in Tetrahedron 
1967, pages 2,123-2,136, or British Pat. No. 1,269,776. The starting 
compounds of the formula III may be used in the form of a salt, especially 
the hydrochloride. 
According to a further method of manufacture, the compounds according to 
the invention, of the general formula (I) are obtained by hydrogenolysis 
of a compound of the general formula V 
##STR5## 
where R has the above meanings and R' is a group removable by 
hydrogenolysis, or of an addition compound of V with an acid. In the said 
compounds, R' is advantageously an .alpha.-arylalkyl radical, benzyl being 
especially preferred. 
The hydrogenolysis may be carried out as a catalytic hydrogenation, for 
example in the presence of a transition metal catalyst, preferably a 
palladium-on-charcoal catalyst, in an inert diluent or solvent, e.g. 
ethanol or aqueous ethanol, at room temperature or at up to 100.degree. 
C., but preferably at room temperature, under atmospheric pressure or 
pressures of up to 200 bars, but preferably under atmospheric pressure. If 
an amine of the formula V rather than its salt is used, the hydrogenolysis 
can be accelerated by the presence of an acid, e.g. hydrogen chloride, 
oxalic acid or maleic acid, as a catalyst. 
The starting compounds for the hydrogenolysis process are obtained by the 
processes described above, using, as the amine component, an amine of the 
formula HNRR', where R has the above meanings and the particularly 
preferred meaning of R' is benzyl. 
According to yet a further process of manufacture, the compounds of the 
general formula (I) are obtained by reacting, under reductive amine 
alkylation conditions, 4-(2-hydroxy-3-amino-propoxy)-1,2-benzisothiazole 
of the formula VII 
##STR6## 
or an addition salt thereof with an acid, and a carbonyl compound of the 
general formula VIII 
##STR7## 
where X and Y are hydrogen, alkyl of 1 to 7 carbon atoms, the sum of the 
carbon atoms of (X+Y) being at most 7 and the alkyl radicals being 
unsubstituted or substituted as described for R above, or cycloalkyl of 3 
to 8 carbon atoms in the ring, or X and Y together with the carbon atom by 
which they are linked form a bicycloalkyl radical of 5 to 8 carbon atoms, 
in which the cycloalkyl rings are unsubstituted or substituted by lower 
alkyl of 1 to 3 carbon atoms. 
The reductive amine alkylation is carried out with hydrogen under the 
conventional reaction conditions for catalytic hydrogenations. Suitable 
hydrogenation catalysts are transition metals, e.g. palladium, platinum or 
nickel, preferably palladium on a charcoal carrier, the reaction being 
carried out in an inert diluent or solvent, e.g. water and/or a lower 
alcohol of 1 to 4 carbon atoms, e.g. methanol, ethanol or propanol and/or 
an excess of the carbonyl compound employed as the alkylating agent. The 
reaction may be carried out under atmospheric pressure or at up to 150 
bars, preferably at from 50 to 100 bars, and at room temperature or with 
heating, for example at from 40.degree. to 120.degree. C. 
It should be mentioned that the Schiff's base first formed from the amine 
of the formula VII and the carbonyl compound can also be reduced by means 
of an alkali metal borohydride, especially sodium borohydride. 
In the course of the reductive amine alkylation, the carbonyl compound of 
the formula VIII is converted to the radical R, and compounds of the 
formula I in which the carbon in the .alpha.-position to the nitrogen 
carries at least one hydrogen are obtained. Examples of ketones 
preferentially used for the reductive amine alkylation are acetone, 
methoxy acetone, methyl ethyl ketone and methyl propyl ketone. 
4-(2-Hydroxy-3-amino-propoxy)-1,2-benzisothiazole of the formula VII is 
advantageously obtained in accordance with the above processes by reacting 
a compound of the formula II with ammonia. The reaction of 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxypropane with aqueous ammonia 
solution, or the reaction of the same compound, in a solution in an 
alcohol, preferably ethanol or isopropanol, with gaseous ammonia, are 
preferred. 
The compounds according to the invention, of the formula I, possess a 
chirality center on carbon atom 2 of the aliphatic side chain and are 
obtained as racemates, which can be resolved into the optically active 
antipodes by conventional methods, for example by forming diastereomeric 
salts with optically active acids, e.g. dibenzoyltartaric acid, 
camphor-10-sulfonic acid, ditoluyltartaric acid or 
3-bromo-camphor-8-sulfonic acid. 
The resulting compounds according to the invention may or may not be 
converted into addition salts with a physiologically safe acid. Examples 
of suitable conventional physiologically safe organic or inorganic acids 
are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric 
acid, amongst inorganic acids, and oxalic acid, maleic acid, fumaric acid, 
lactic acid, tartaric acid, malic acid, citric acid, salicyclic acid, 
adipic acid and benzoic acid, amongst organic acids; other physiologically 
safe acids are disclosed in Fortschritte der Arzneimittelforschung, 10 
(1966), 224-225, Birkhauser Verlag, Basel and Stuttgart. 
The addition salts with acids are as a rule obtained in the conventional 
manner by mixing the free base or a solution thereof, with the appropriate 
acid or a solution thereof, in an organic solvent, for example a lower 
alcohol, e.g. methanol, ethanol or propanol, or a lower ketone, e.g. 
acetone, methyl ethyl ketone or methyl isobutyl ketone, or an ether, e.g. 
diethyl ether, tetrahydrofuran or dioxane. Mixtures of the said solvents 
may also be used to improve the deposition of crystals. Furthermore, 
aqueous solutions, suitable for pharmaceutical use, of acid adducts of the 
aminopropanol derivatives of the general formula (I) may be prepared by 
dissolving the free base of the general formula (I) in an aqueous solution 
of an acid. 
The compounds according to the invention, and their physiologically safe 
addition salts with acids exhibit valuable pharmacological properties and 
may therefore be used for the treatment and prophylaxis of cardiac and 
circulatory disorders. 
Because of their .beta.-symphatholytic action, the compounds are 
particularly suitable for the treatment of coronary cardiac disorders, 
cardiac arrythmias, and hypertonia. 
As shown in the Table which follows, the .beta.-sympatholytic action was 
tested on rats, in comparison with the conventional .beta.-sympatholytic 
agent Propranolol. 
The following methods were used for this purpose: 
1. .beta..sub.1 -sympatholytic action: 
Isoproterenol (0.1 .mu.g/kg, given intravenously) in pithed rats 
(Sprague-Dawley, Mus rattus; weight 230-280 g) causes increases in pulse 
rate of, on average, 45%. .beta.-Sympatholytic agents inhibit such 
tachycardia. Isoproterenol was administered before, and 5 minutes after, 
the intravenous administration of the test substances. Linear 
relationships are found between the logarithms of the administered doses 
(mg/kg) of the test substances and the inhibition (in %) of Isoproterenol 
tachycardia. From these relationships, the ED 50 values, i.e. the doses 
which inhibit the Isoproterenol tachycardia by 50%, are determined. 
2. .beta..sub.2 -sympatholytic action: 
The inhibition, by .beta.-sympatholytic agents, of the reduction in blood 
pressure induced by Isoproterenol was tested on rats, weighing 230-280 g, 
under urethane narcosis (1.78 g of urethane/kg being administered 
intraperitoneally). Isoproterenol (0.215 .mu.g/kg given intravenously) 
reduces the mean pressure of the carotid artery by an average of 30%. 
.beta.-Sympatholytic agents inhibit this action. 
Linear relationships exist between the logarithms of the doses used and the 
inhibition of the Isoproterenol blood pressure reduction, from which the 
ED 50 values, i.e. the doses which inhibit the Isoproterenol blood 
pressure reduction by 50%, were determined. 
3. Acute toxicity: 
The acute toxicity was determined on groups of 10 or 20 female Swiss mice 
weighing 20-26 g, the compounds being administered intraperitoneally. The 
LD 50 was taken to be the calculated dose (Probit analysis) after which 
50% of the animals died within 24 hours. 
Table 1 shows that the pharmacotherapeutically important .beta.-.sub.1 
-sympatholytic activity of the compounds of the invention is from 2.5 
times (Example 29) to 8 times (Example 14) greater than that of the 
comparative substance Propranolol. In addition, the substances exhibit a 
greater cardioselectivity than Propranolol, i.e. the 
pharmacotherapeutically desirable effect on cardiac .beta..sub.1 
-receptors manifests itself at lower doses than the effect of the 
.beta..sub.2 -receptors on the blood vessels. In the case of Propranolol, 
about equal doses are required for both these inhibiting effects. The test 
substances block cardiac .beta..sub.1 -receptors at doses which are from 2 
times (Example 1) to 11 times (Example 35) lower than those required to 
block .beta..sub.2 -receptors. 
The therapeutic range, expressed as the quotient of the 50% lethal dose (LD 
50) and the 50% .beta..sub.1 -blocking dose (ED 50) is from 3 times 
(Example 35) to 11 times (Example 2) greater than for Propranolol. 
TABLE 1 
__________________________________________________________________________ 
.beta.-Sympatholytic action and acute toxicity 
.beta..sub.1 -Sympatholytic 
.beta..sub.2 -Sympatholytic 
Acute 
Thera- 
action 1 action 4 toxicity 
peutic 
range 8 
Example No. 
ED 50 2 
R.A. 3 
ED 50 5 
R.A. 3 
Q 6 LD 50 7 
absolute 
relative 9 
__________________________________________________________________________ 
1 0.00190 
6.47 0.00420 
2.71 2.21 
62.1 32,700 
3.72 
2 0.00163 
7.55 0.00402 
2.84 2.47 
154 94,500 
10.76 
14 0.00153 
8.04 0.0106 
1.08 6.93 
96.4 63,000 
7.18 
15 0.00184 
6.68 0.00824 
1.38 4.48 
144 78,300 
8.92 
16 0.00328 
3.75 0.0121 
0.94 3.69 
128 39,000 
4.44 
27 0.00230 
5.35 0.00575 
1.98 2.50 
184 80,000 
9.11 
29 0.00495 
2.48 0.0440 
0.26 8.90 
135 27,300 
3.11 
35 0.00252 
4.88 0.0270 
0.42 10.70 
60.3 23,900 
2.72 
Propranolol 
0.0123 
1.00 0.0114 
1.00 0.93 
108 8,780 
1.00 
__________________________________________________________________________ 
1 Inhibition of Isoproterenol tachycardia (IT).Pithed rats. Intravenous 
administration 
2 Dose (mg/kg) which inhibits the IT by 50% 
3 Relative activity. Propranolol = 1.00 
4 Inhibition of Isoproterenol blood pressure reduction (IBP). Rats under 
urethane narcosis. Intravenous administration. 
5 Dose (mg/kg) which inhibits the IBP by 50% 
##STR8## 
7 Mice, intraperitoneal administration 
##STR9## 
? 
9 Propranolol = 1.00 
Accordingly, the present invention also relates to therapeutic agents or 
formulations which contain a compound of the formula I as the active 
ingredient, together with conventional excipients and diluents, and to the 
use of the new compounds for therapeutic purposes. 
The agents or formulations are prepared in the conventional manner by 
compounding an appropriate dose with the conventional excipients or 
diluents and the conventional pharmaceutical auxiliaries, in accordance 
with the desired route of administration. 
The preferred formulations are those suitable for oral administration. 
Examples of these are tablets, film tablets, dragees, capsules, pills, 
powders, solutions or suspensions, or forms which exert a depot effect. 
Of course, formulations for parenteral administration, e.g. injection 
solutions, are also suitable. Suppositories are a further example of 
suitable formulations. 
Appropriate tablets can be obtained, for example, by mixing the active 
ingredient with conventional auxiliaries, for example inert excipients, 
e.g. dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, calcium 
carbonate, calcium phosphate or lactose, disintegrating agents, e.g. corn 
starch, or alginic acid, binders, e.g. starch or gelatin, lubricants, e.g. 
magnesium stearate or talc, and/or agents added in order to achieve a 
depot effect, e.g. carboxypolymethylene, carboxymethylcellulose, cellulose 
acetate-phthalate or polyvinyl acetate. The tablets may also consist of a 
plurality of layers. 
Dragees may be produced by coating cores, prepared similarly to the 
tablets, with agents conventionally used in dragee coatings, for example 
polyvinylpyrrolidone, or shellac, gum arabic, talc, titanium dioxide or 
sugar. The dragee coating may also consist of a plurality of layers, and 
the auxiliaries referred to above in connection with tablets may be 
employed. 
Solutions or suspensions containing the active ingredients according to the 
invention may in addition contain agents for improving the taste, e.g. 
saccharin, cyclamate or sugar, as well as, for example, flavorings, e.g. 
vanillin or orange extract. Furthermore, they may contain dispersants, 
e.g. sodium carboxymethylcellulose, or preservatives, e.g. 
p-hydroxybenzoates. Capsules containing the active ingredient may be 
produced, for example, by mixing the active ingredient with an inert 
carrier, e.g. lactose or sorbitol, and encapsulating the mixture in 
gelatin capsules. 
Suitable suppositories may be produced, for example, by mixing the active 
ingredient with an appropriate carrier for suppositories, e.g. a neutral 
fat or polyethylene glycol or a derivative thereof. 
For man, a suitable single dose of the compounds according to the invention 
is from 1 to 100 mg, preferably from 3 to 50 mg. 
The following compounds are singled out because of their activity: 
4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole, 
4-(2-hydroxy-3-tert.-butylamino-propoxy)-1,2-benzisothiazole, 
4-[2-hydroxy-3-(3-methyl-pentyl-3-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2-methyl-butyl-2-amino)-propoxy]-1,2-benzisothiazole, 
4-[2-hydroxy-3-(2-methyl-but-3-ynyl-2-amino)-propoxy]-1,2-benzisothiazole 
and 4-(2-hydroxy-3-sec.-butylamino-propoxy)-1,2-benzisothiazole, 
4-[2-hydroxy-3-(1-methoxy-propyl-2-amino)-propoxy]-1,2-benzisothiazole and 
4-[2-hydroxy-3-(pentyl-2-amino)-propoxy]-1,2-benzisothiazole. 
The Examples which follow illustrate the invention. 
Preparation of starting compounds

EXAMPLE I 
50 g of 4-methoxy-1,2-benzisothiazole are suspended in 700 ml of acetic 
acid containing 10% by weight of hydrogen bromide and 5 g of red 
phosphorus, and the suspension is heated for 30 hours at 100.degree. C. in 
a tantalum autoclave. After cooling, the material discharged from the 
autoclave is concentrated under reduced pressure and the residue is 
partitioned between methylene chloride and 2 N sodium hydroxide solution. 
The water phase is filtered to remove insoluble matter, washed with 
methylene chloride, acidified with hydrochloric acid and then repeatedly 
extracted with methylene chloride. The combined extracts are dried over 
magnesium sulfate and then concentrated under reduced pressure. 32 g (65% 
of theory) of 4-hydroxy-1,2-benzisothiazole of melting point 
133.degree.-134.degree. C. are obtained. C.sub.7 H.sub.5 ONS (151) 
______________________________________ 
calculated: 
55.6 C 3.3 H 10.6 O 9.3 N 21.2 S 
found: 56.1 C 3.4 H 10.5 O 9.1 N 20.8 S 
______________________________________ 
If the methylene chloride phases which have been washed with 2-normal 
sodium hydroxide solution are worked up in the conventional manner, 20-25% 
of the 4-methoxy-1,2-benzisothiazole employed can be recovered and 
recycled to a subsequent ether cleavage. 
EXAMPLE II 
1-(1,2-Benzisothiazol-4-yloxy)-2,3-epoxy-propane 
29 g of 4-hydroxy-1,2-benzisothiazole, 36 g of epibromohydrin and 93 g of 
dry potassium carbonate in 300 ml of acetone are refluxed for 11 hours. 
When it has cooled, the entire reaction mixture is poured into 1 liter of 
ice water and extracted with four times 150 ml of diethyl ether, and the 
combined extracts are washed with water and dried over sodium sulfate. 
After distilling off the solvent, 30 g (75% of theory) of 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane of melting point 
85.degree.-87.degree. C. remain and can be used further without 
purification. 
Analytically pure 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane of 
melting point 90.degree.-91.degree. C. is obtained by sublimation at 
110.degree.-130.degree. C. under 0.2 mm Hg. C.sub.10 H.sub.9 O.sub.2 NS 
(207) 
______________________________________ 
calculated 
58.0 C 4.4 H 15.4 O 6.8 N 15.5 S 
found 57.7 C 4.6 H 15.4 O 6.8 N 15.1 S 
______________________________________ 
EXAMPLE III 
4-(2-Hydroxy-3-aminopropoxy)-1,2-benzisothiazole 
4.0 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane in 100 ml of 
aqueous ammonia and 300 ml of ethanol are left to stand for 3 hours at 
35.degree. C. The mixture is concentrated, the semi-crystalline residue is 
dissolved in ethanol and a solution of hydrogen chloride in ether is added 
dropwise. The hydrochloride which precipitates is filtered off, washed 
with dry ether and dried. 
Yield: 3.1 g (60% of theory), melting point 240.degree.-243.degree. C. 
C.sub.10 H.sub.13 O.sub.2 N.sub.2 SCl (261) 
______________________________________ 
calculated 
46.1 C 5.0 H 12.3 O 
10.7 N 
12.3 S 
13.6 Cl 
found 45.3 C 5.0 H 12.9 O 
10.3 N 
11.7 S 
13.9 Cl 
______________________________________ 
EXAMPLE IV 
4-[2-Hydroxy-3-(N-benzyl-isopropylamino)-propoxy]-1,2-benzisothiazole 
2.0 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane and 1.5 g of 
N-benzylisopropylamine in 50 ml of ethanol are refluxed for 2 hours. The 
4-[2-hydroxy-3-(N-benzylisopropylamino)-propoxy]-1,2-benzisothiazole which 
is left after distilling off the solvent may be used directly, in the form 
obtained, for debenzylation. To characterize the compound, it is dissolved 
in a little methanol and a solution of oxalic acid in ether is added 
dropwise. The 
4-[2-hydroxy-3-(N-benzylisopropylamino)-propoxy]-1,2-benzisothiazole 
hydrogen oxalate which precipitates is filtered off, washed with dry ether 
and dried. Melting point 176.degree.-178.degree. C. C.sub.22 H.sub.26 
N.sub.2 O.sub.6 S (446) 
______________________________________ 
calculated 
59.2 C 5.8 H 6.3 N 21.5 O 7.2 S 
found 58.9 C 5.7 H 6.2 N 21.3 O 7.3 S 
______________________________________ 
EXAMPLE V 
1-(1,2-Benzisothiazol-4-yloxy)-3-chloro-propan-2-ol 
(a) 2.0 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxypropane are suspended 
in a mixture of 30 ml of ethanol and 30 ml of diethyl ether and 100 ml of 
a solution of hydrogen chloride in ether are added whilst stirring. After 
standing for three days the precipitate formed is filtered off and washed 
neutral with ether. 
Yield: 2.2 g (91% of theory) of melting point 90.degree.-92.degree. C. 
1-(1,2-Benzisothiazol-4-yloxy)-3-chloro-propan-2-ol which is pure according 
to NMR spectroscopy and has a melting point of 104.degree.-106.degree. C. 
is obtained by recrystallization from methanol. 
.sup.1 H-NMR spectrum (d.sub.6 -DMSO, TMS as internal standard): .tau.=0.82 
(s, 1H), 2.22 (d, J=4.5 Hz, 1H), 2.42 (m, 1H), 2.99 (d, J=3.0 Hz, 1H), 
3.62 (s, 0H), 5.73 (m, 3H), 6.11 (m, 2H). 
(b) 15.0 g of 4-hydroxy-1,2-benzisothiazole and 100 mg of 
2,2,6,6-tetramethylpiperidine are heated with 30 ml of epichlorohydrin for 
6 hours at 100.degree.-110.degree. C. The mixture is then freed from 
excess epichlorohydrin under reduced pressure and the residue is digested 
with three times 100 ml of methanol. The combined methanol extracts are 
evaporated to dryness under reduced pressure. 10.4 g of a semi-crystalline 
residue remain; the .sup.1 H-NMR spectrum of this material agrees with 
that of 1-(1,2-benzisothiazol-4-yloxy)-3-chloropropan-2-ol from (a). 
(c) 30.0 g of 4-hydroxy-1,2-benzisothiazole are suspended in 26.0 g of 
1,3-dichloro-propan-2-ol and a solution of 8.5 g of sodium hydroxide in 60 
ml of water is added in the course of 4 hours at 60.degree.-80.degree. C. 
After reacting for a further four hours at the same temperature, the 
organic phase is taken up in methylene chloride, dried over magnesium 
sulfate and evaporated to dryness. The residue left (35 g) is 
recrystallized from methanol. The 
1-(1,2-benzisothiazol-4-yloxy)-3-chloropropan-2-ol thus obtained is 
identical with the sample prepared as described in (a). Preparation of 
compounds according to the invention 
EXAMPLE 1 
50 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane and 25 ml of 
isopropylamine in 50 ml of ethanol are refluxed for 2 hours. The residue 
which is left after distilling off the solvent and excess amine is 
dissolved in 5 ml of ethanol and a solution of hydrogen chloride in ether 
is added dropwise. The 
4-(2-hydroxy-3-isopropylaminopropoxy)-1,2-benzisothiazole hydrochloride 
which precipitates is filtered off, washed with dry ether and dried. 
Yield: 6.0 g (83% of theory) of melting point 158.degree.-160.degree. C. 
C.sub.13 H.sub.19 O.sub.2 N.sub.2 SCl (303) 
______________________________________ 
calculated 
51.6 C 6.3 H 10.6 O 
9.3 N 10.6 S 
11.7 Cl 
found 51.4 C 6.5 H 11.4 O 
9.4 N 10.2 S 
11.5 Cl 
______________________________________ 
EXAMPLE 2 
Using the method described in Example 1, 50 g of 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane and 25 ml of 
tert.-butylamine give 6.3 g (80% of theory) of 
4-(2-hydroxy-3-tert.-butylamino-propoxy)-1,2-benzisothiazole hydrochloride 
of melting point 190.degree.-192.degree. C. C.sub.14 H.sub.21 O.sub.2 
N.sub.2 SCl (317) 
______________________________________ 
calculated 
53.1 C 6.7 H 10.1 O 
8.8 N 10.1 S 
11.2 Cl 
found 52.7 C 6.5 H 10.5 O 
8.7 N 10.0 S 
11.3 Cl 
______________________________________ 
EXAMPLE 3 
50 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane are reacted with 
tert.-butylamine as described in Example 1 and the product is then 
converted by treatment with a solution of maleic acid in ether into 
4-(2-hydroxy-3-tert.-butylaminopropoxy)-1,2-benzisothiazole hydrogen 
maleate. 
Yield: 5.4 g (55% of theory) of melting point 158.degree.-161.degree. C. 
C.sub.18 H.sub.24 O.sub.6 N.sub.2 S (396) 
______________________________________ 
calculated 
54.5 C 6.1 H 24.2 O 7.1 N 8.1 S 
found 54.0 C 6.2 H 24.6 O 6.7 N 7.9 S 
______________________________________ 
EXAMPLE 4 
Using the same method, 5.1 g (55% of theory) of 
4-(2-hydroxy-3-tert.-butylamino-propoxy)-1,2-benzisothiazole hydrogen 
oxalate, of melting point 158.degree.-160.degree. C., are obtained as 
described in Example 1. C.sub.16 H.sub.22 O.sub.6 N.sub.2 S (370) 
______________________________________ 
calculated 
51.9 C 6.0 H 25.9 O 7.6 N 8.7 S 
found 51.5 C 6.0 H 25.9 O 7.4 N 8.3 S 
______________________________________ 
EXAMPLE 5 
3.6 g of 
4-[2-hydroxy-3-(N-benzylisopropylamino)-propoxy]-1,2-benzisothiazole are 
dissolved in 100 ml of ethanol and the solution is shaken with 0.7 g of a 
5% strength palladium-on-charcoal catalyst under a hydrogen atmosphere, 
until saturation is reached. After filtering off the catalyst, the 
ethanol, and the toluene formed, are distilled off under reduced pressure, 
the residue is suspended in 100 ml of 10% strength aqueous hydrochloric 
acid and the suspension is washed three times with ether. The aqueous 
phase is rendered alkaline with 5 N sodium hydroxide solution whilst 
cooling with ice and is extracted with four times 100 ml of ether. These 
extracts are dried by means of sodium sulfate and evaporated, and the 
residue is converted, by the method described in Example 1, into 
4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole hydrochloride. 
Yield 1.8 g (60% of theory), melting point 156.degree.-160.degree. C. 
EXAMPLE 6 
2.4 g of 1-(1,2-benzisothiazol-4-yloxy)-3-chloropropan-2-ol and 10 ml of 
(1,2-dimethylpropyl)-amine in 50 ml of dioxane are heated for 10 hours in 
an autoclave at 100.degree. C. After distilling off the volatile 
constituents under reduced pressure, the highly viscous crude product is 
partitioned between ether and 4 N sulfuric acid, and the aqueous phase is 
cautiously rendered alkaline with 4 N sodium hydroxide solution and is 
finally extracted with ether. After drying the organic phase over sodium 
sulfate, the solvent is removed and the residue left is converted to 
4-[2-hydroxy-3-(3-methylbutyl-2-amine)-propoxy]-1,2-benzisothiazole 
hydrochloride by the method described in Example 1. 
Yield: 1.8 g (54% of theory), melting point 161.degree.-164.degree. C. 
C.sub.15 H.sub.20 N.sub.2 O.sub.2 SCl (331) 
______________________________________ 
calcu- 
54.5 C 7.0 H 9.7 O 8.5 N 9.7 S 10.7 
Cl 
lated 
found 54.0 C 6.8 H 10.5 O 8.2 N 9.4 S 10.7 Cl 
______________________________________ 
EXAMPLE 7 
Using isopropylamine and 
1-(1,2-benzisothiazol-4-yloxy)-3-chloro-propan-2-ol as the starting 
materials, 4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole 
hydrochloride is obtained by the method described in Example 6. The 
compound is identical with that obtained as described in Example 1. 
Using the same method, tert.-butylamine gives 
4-(2-hydroxy-3-tert.-butylamino-propoxy)-1,2-benzisothiazole 
hydrochloride, which is identical with the compound from Example 2. 
EXAMPLE 8 
3.0 g of 4-hydroxy-1,2-benzisothiazole and 5.0 g of 
1-chloro-3-isopropylaminopropan-2-ol hydrochloride in 100 ml of a 
water-dioxane mixture (20:80 by volume) are refluxed with 2 g of sodium 
hydroxide for 10 hours. When the mixture has cooled, it is extracted with 
five times 100 ml of chloroform and the combined extracts are washed with 
water, dried over sodium sulfate and evaporated to dryness. A part of the 
residue left is chromatographed on a dry silica gel column, using a 
methanol-methylene chloride mixture (60:40 by volume). The very viscous, 
pale yellow residue left on evaporating the eluate is converted to 
4-(2-hydroxy-3-isopropyl-amino-propoxy)-1,2-benzisothiazole hydrochloride 
by the method described in Example 1. The substance is identical with the 
compound obtained as described in Example 1. 
In the same way, tert.-butylamine gives 
4-(2-hydroxy-3-tert.-butylamino-propoxy)-1,2-benzisothiazole 
hydrochloride, which is identical with the compound from Example 2. 
EXAMPLE 9 
4.4 g of 4-(2-hydroxy-3-amino-propoxy)-1,2-benzisothiazole and 0.1 g of a 
10% strength palladium-on-charcoal catalyst, in a mixture of 50 ml of 
methanol and 100 ml of acetone, are left for 24 hours at 60.degree. C. 
under 100 bars hydrogen pressure. The mixture is freed from catalyst by 
filtration, and is concentrated. The residue left is converted to 
4-(2-hydroxy-3-isopropylamino-propoxy)-1,2-benzisothiazole hydrochloride 
by the method described in Example 1. The substance is identical with the 
compound obtained as described in Example 1. 
The compounds shown in the Table which follows are obtained from 
1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane and the corresponding 
amines, by the method described in Example 1. 
__________________________________________________________________________ 
##STR10## 
__________________________________________________________________________ 
Melting 
Ex. Salt with 
point 
No. 
R acid .degree.C. 
__________________________________________________________________________ 
10 
##STR11## HOOCCOOH 95-97 
4-[2-Hydroxy-3-(3-piperidino-propyl-2-amino) 
- propoxy]-1,2-benzisothiazole 
11 CH.sub.3 HCl 186-190 
4-(2-Hydroxy-3-methylamino-propoxy)-1,2-benz 
isothiazole 
12 
nC.sub.4 H.sub.9 
HCl 163-165 4-(2-Hydroxy-3-butylamino-propoxy)-benzisothiazol 
e 
13 
##STR12## -- 94-97 
4-(2-Hydroxy-3-isobutylamino-propoxy)-1,2-be 
nzisothiazole 
14 
##STR13## 
##STR14## 
146-148 
4-(2-Hydroxy-3-sec.-butylamino-propoxy)-1,2- 
benzisothiazole 
15 
##STR15## HCl 182-184 
4-[2-Hydroxy-3-(2-methyl-butyl-2-amino)-prop 
oxy]-1,2- benzisothiazole 
16 
##STR16## HCl 180-182 
4-[2-Hydroxy-3-(3-methyl-pentyl-3-amino)-pro 
poxy]-1,2- benzisothiazole 
17 
##STR17## HCl 214-216 
4-[2-Hydroxy-3-(2,3-dimethyl-butyl-2-amino)- 
propoxy]- 1,2-benzisothiazole 
18 C(C.sub.2 H.sub.5).sub.3 
-- 125 4-[2-Hydroxy-3-(3-ethyl-pentyl-3-amino)-prop 
oxy]-1,2- 
benzisothiazole 
19 
##STR18## HCl 175-178 
4-[2-Hydroxy-3-(2,4-dimethyl-pentyl-3-amino) 
-propoxy]- 1,2-benzisothiazole 
20 
##STR19## HCl 186-190 
4-(2-Hydroxy-3-cyclopropylamino-propoxy)-1,2 
-benzisothiazole 
21 
##STR20## 
##STR21## 
168-170 
4-(2-Hydroxy-3-cyclopentylamino-propoxy)-1,2 
-benzisothiazole 
22 
##STR22## HCl 160-162 
4-(2-Hydroxy-3-cycloheptylamino-propoxy)-1,2 
-benzisothiazole 
23 
##STR23## HCl 201-203 
4-[2-Hydroxy-3-(bicyclo[3.3.0]octyl-1-amino) 
-propoxy]- 1,2-benzisothiazole 
24 
##STR24## 
##STR25## 
202-203 
4-[2-Hydroxy-3-(2-exo-norbornanylamino)-prop 
oxy]-1,2- benzisothiazole 
25 
##STR26## 
##STR27## 
161-163 
4-[2-Hydroxy-3-(2,4,4-trimethyl-pentyl-2-ami 
no)-propoxy]- 1,2-benzisothiazole 
26 
##STR28## 
##STR29## 
154-156 
4-[2-Hydroxy-3-(1-thiomethyl-2-methyl-propyl 
-2-amino)- propoxy]-1,2-benzisothiazole 
27 
##STR30## HCl 151-153 
4-[2-Hydroxy-3-(2-methyl-but-3-ynyl-2-amino) 
-propoxy]- 1,2-benzisothiazole 
28 
##STR31## HCl 178-181 
4-[2-Hydroxy-3-(but-3-ynyl-2-amino)-propoxy] 
-1,2-benz- isothiazole 
29 
##STR32## 
##STR33## 
152-156 
4-[2-Hydroxy-3-(1-methoxy-propyl-2-amino)-pr 
opoxy]-1,2- benzisothiazole 
30 
##STR34## 
##STR35## 
159-161 
4-[2-Hydroxy-3-isopropylamino-propoxy)-1,2-b 
enziso- thiazole 
31 
##STR36## 
##STR37## 
179-183 
4-[2-Hydroxy-3-(cyclooctenyl-4-amino)-propox 
y]-1,2-benz- isothiazole 
32 
##STR38## HCl 193-197 
4-[2-Hydroxy-3-(2,6-dimethyl-cyclohexyl-1-am 
ino)-propoxy]- 1,2-benzisothiazole 
33 
##STR39## HCl 177-179 
4-[2-Hydroxy-3-(3-ethyl-pent-1-ynyl-3-amino) 
-propoxy]- 1,2-benzisothiazole 
34 CH.sub.2CHCH.sub.2 
-- 83-85 
4-[2-Hydroxy-3-(prop-1-ynyl-3-amino)-propoxy 
]-1,2-benz- 
isothiazole 
35 
##STR40## HOOCCOOH 154-156 
4-[2-Hydroxy-3-(pentyl-2-amino)-propoxy]-1,2 
-benziso- thiazole 
36 
##STR41## HOOCCOOH 162-164 
4-[2-Hydroxy-3-(1-cyclopropyl-ethyl-1-amino) 
-propoxy]- 1,2-isothiazole 
37 CH.sub.2CH.sub.2OH 
HCl 131-133 
4-[2-Hydroxy-3-(2-hydroxy-ethylamino)-propox 
y]-1,2- 
benzisothiazole 
38 
##STR42## HOOCCOOH 136-138 
4-[2-Hydroxy-3-(1-hydroxy-butyl-2-amino)-pro 
poxy]-1,2- benzisothiazole 
39 
##STR43## HOOCCOOH 182-184 
4-[2-Hydroxy-3-(3-hydroxy-3-methyl-butyl-2-a 
mino)- propoxy]-1,2-benzisothiazole 
__________________________________________________________________________ 
EXAMPLES 40 to 70 
The compounds shown in the preceding Table are obtained equally if 
1-(1,2-benzisothiazol-4-yloxy)-3-chloro-propan-2-ol is reacted with the 
corresponding amines by the method described in Example 6. 
There follow examples of formulations which are prepared in the 
conventional manner. 
______________________________________ 
1. Tablets 
______________________________________ 
(a) An active ingredient of the formula I 
5 mg 
lactose 200 mg 
methylcellulose 15 mg 
corn starch 50 mg 
talc 11 mg 
magnesium stearate 4 mg 
285 mg 
(b) An active ingredient of the formula I 
20 mg 
lactose 178 mg 
Avicel 80 mg 
Polywax 6000 20 mg 
magnesium stearate 2 mg 
300 mg 
(c) An active ingredient of the formula I 
50 mg 
polyvinylpyrrolidone (mean molecular 
weight 25,000) 170 mg 
polyethylene glycol (mean molecular 
weight 4,000) 14 mg 
hydroxypropylmethylcellulose 
40 mg 
talc 4 mg 
magnesium stearate 2 mg 
280 mg 
______________________________________ 
The active ingredient is moistened with a 10% strength aqueous solution of 
polyvinylpyrrolidone and the mixture is forced through a sieve of 1.0 mm 
mesh width and dried at 50.degree. C. These granules are mixed with the 
polyethylene glycol (of mean molecular weight 4,000), 
hydroxypropylmethylcellulose, talc and magnesium stearate, and the mixture 
is molded into tablets each weighing 280 mg. 
______________________________________ 
2. Dragees 
______________________________________ 
Compound of the formula I 
3 mg 
lactose 90 mg 
corn starch 60 mg 
polyvinylpyrrolidone 6 mg 
magnesium stearate 1 mg 
160 mg 
______________________________________ 
The mixture of the active ingredient with the lactose and corn starch is 
granulated by compounding with an 8% strength aqueous solution of the 
polyvinylpyrrolidone and forcing through a 1.5 mm sieve; the granules are 
dried at 50.degree. C. and forced through a 1.0 mm sieve. The granules 
thus obtained are mixed with the magnesium stearate and molded into dragee 
cores. The latter are provided with a coating, consisting essentially of 
sugar and talc, in the conventional manner. 
______________________________________ 
2. Capsules 
Compound of the formula I 
5.0 mg 
magnesium stearate 2.0 mg 
lactose 19.3 mg 
4. Injection solution 
Compound of the formula I 
10 mg 
sodium chloride 9 mg 
distilled water to make up to 1.0 ml 
______________________________________