Indazolyl-(4)-oxypropanolamine compounds and therapeutic compositions

New indazolyl-(4)-oxypropanolamine compounds of the formula ##STR1## wherein R.sub.1 is hydrogen or lower alkyl; and PA1 R.sub.2 is straight-chain or branched lower alkyl which can be substituted by lower alkylthio; And the pharmacologically compatible salts thereof; are outstandingly effective adrenergic .beta.-receptor inhibitors and useful in the treatment or prevention of a recurrence of cardiac and circulatory diseases.

The present invention is concerned with new indazolyl-(4)-oxypropanolamine 
compounds and with therapeutic compositions and methods useful in the 
treatment of cardiac and circulatory diseases, utilizing such compounds. 
The new indazolyl-(4)-oxypropanolamines according to the present invention 
are compounds of the formula: 
##STR2## 
wherein R.sub.1 is hydrogen or lower alkyl; and 
R.sub.2 is straight-chain or branched lower alkyl which can be substituted 
by lower alkylthio; and the pharmacologically compatible salts thereof. 
The new compounds (I), as well as the pharmacologically-compatible salts 
thereof, bring about an inhibition of adrenergic .beta.-receptors and can, 
therefore, be used for the treatment or prevention of a recurrence of 
cardiac and circulatory diseases. 
The new compounds (I) according to the present invention can be prepared, 
for example, by one of the following methods: 
A. REACTION OF A COMPOUND OF THE GENERAL FORMULA: 
##STR3## 
with a compound of the general formula: 
EQU Z -- R.sub.2 (III) 
wherein R.sub.1 and R.sub.2 have the same meanings as above, R' is a 
hydrogen atom or an acyl radical, one of the symbols Y and Z represents an 
amino group and the other represents a reactive residue and X is a 
.dbd.C.dbd.O or .dbd.CH--A group, A being a hydroxyl group or, together 
with Y, representing an oxygen atom; or 
B. REACTION OF A 4-HYDROXYINDAZOLE OF THE GENERAL FORMULA: 
##STR4## 
wherein R.sub.1 and R' have the same meanings as above, with a compound of 
the general formula: 
EQU Y'--CH.sub.2 --X--CH.sub.2 --NH--R.sub.2 (V) 
wherein X and R.sub.2 have the same meanings as above and Y' is a reactive 
residue; or 
c. saponification of a compound of the general formula: 
##STR5## 
wherein R', R.sub.1 and R.sub.2 have the same meanings as above and A is a 
.dbd.C.dbd.O or .dbd.CR''(R''') group, R'' and R''', which may be the same 
or different, being hydrogen atoms or lower alkyl or aryl radicals; or of 
a compound of the general formula: 
##STR6## 
wherein R', R.sub.1 and R.sub.2 have the same meanings as above; after the 
reaction a protective group R' possibly present is then split off and, 
when X is a .dbd.C.dbd.O group, this is reduced; and the compound obtained 
of general formula (I) is, if desired, converted into a pharmacologically 
compatible salt. 
The lower alkyl radical substituents R.sub.1 can contain up to 4 carbon 
atoms, the methyl radical being preferred. 
The lower alkyl radical substituents R.sub.2 can contain up to 5 carbon 
atoms, the isopropyl and tert.-butyl radicals being preferred. 
The lower alkylthio radical can contain up to 3 carbon atoms, the 
methylthio radical being preferred. 
The protective acyl radical R' is to be understood to be a radical 
containing up to 7 carbon atoms, the acetyl and benzoyl radicals being 
preferred. 
Reactive radicals Y, Y' and Z in the compounds of general formulae (II), 
(III) and (V) are preferably acid residues, for example of hydrohalic 
acids or sulphonic acids. 
Compounds of general formula (II) are also new. They can be obtained, for 
example, from 4-hydroxyindazoles by reaction with reactive compounds of 
the general formula: 
EQU Y'--CH.sub.2 --X--CH.sub.2 --Y (VIII) 
wherein Y, Y' and X have the same meanings as above. 
The processes according to the present invention are preferably carried out 
in an organic solvent which is inert under the reaction conditions, for 
example toluene, dioxan, ethylene glycol dimethyl ether, ethanol, 
n-butanol or dimethyl formamide, possibly in the presence of an 
acid-binding agent. However, the reaction can also be brought about, after 
mixing the reaction components, by leaving the reaction mixture to stand 
at ambient temperature or by heating it. 
The reaction of compounds of general formula (IV) with compounds of general 
formula (V) according to process (b) is preferably carried out with the 
exclusion of oxygen and in the presence of an acid acceptor. However, an 
alkali metal salt of the hydroxy compound of general formula (IV) can also 
be used. 
The compounds of general formulae (VI) and (VII) can be prepared in known 
manner. Thus, for example, compounds of general formula (VI) can be 
obtained by the reaction of 4-hydroxyindazoles of general formula (IV) 
with reactive esters of 5-hydroxymethyl-oxazolidines which are optionally 
substituted in the 2-position. 
For the preparation of these esters, for example derivatives of 
2,3-epoxypropanol, in which the hydroxyl group is etherified or esterified 
with a protective group, are reacted with amines of the general formula 
H.sub.2 NR.sub.2, in which R.sub.2 has the same meaning as above, the 
aminoalcohols thereby obtained are converted, by reaction with a reagent 
providing a carbonyl group, such as phosgene or carbonyl-bis-imidazole, 
into the oxazolidin-2-ones or with aldehydes or ketones into the 
oxazolidines, whereupon the protective group is split off and the 
5-hydroxymethyl-oxazolidines thereby formed are esterified with a strong 
acid. The preferred protective group is the benzyl radical and the 
preferred strong acids are methane-sulphonic acid and p-toluene-sulphonic 
acid. 
The compounds of general formula (VII) can be obtained from the allyl 
ethers of compounds of general formula (IV), via the bromine addition 
products, by reaction with appropriate primary amines. 
The saponification of the compounds of general formulae (VI) and (VII) 
generally takes place in a water-containing medium in the presence of 
acids or bases. 
If R' in general formulae (II), (IV), (VI) or (VII) represents an acyl 
radical, this can be split off under mild conditions by aminolysis or 
hydrolysis. 
If it is necessary to reduce a .dbd.C.dbd.O group, this can be carried out, 
for example, by means of sodium borohydride or by catalytic hydrogenation 
in the presence of noble metal catalysts. 
For the conversion of compounds of general formula (I) into their 
pharmacologically compatible salts, these are reacted, preferably in an 
organic solvent, with an equivalent amount of an inorganic or organic 
acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, 
sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid. 
For the preparation of pharmaceutical compositions, the compounds (I) are 
mixed in known manner with appropriate solid or liquid pharmaceutical 
diluents or carriers and optionally with 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 (I) according to the present invention and the salts thereof 
can be administered enterally or parenterally in liquid or solid form. As 
injection medium, it is preferable to use water which contains the 
additives usual in the case of injection solutions, such as stabilising 
agents, solubilising agents or buffers. Additives of this type include, 
for example, tartrate and citrate buffers, ethanol, complex-forming agents 
(such as ethylene-diamine-tetraacetic acid and the non-toxic salts 
thereof), and high molecular weight polymers (such as liquid polyethylene 
oxide) for viscosity regulation. Solid carrier materials include, for 
example, starch, lactose, mannitol, methyl cellulose, talc, 
highly-dispersed silicic acid, high molecular weight fatty acids (such as 
stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, 
animal and vegetable fats and solid high molecular weight polymers (such 
as polyethylene glycols). Compositions suitable for oral administration 
can, if desired, contain flavoring and sweetening agents.

The following Examples are given for the purpose of illustrating the 
present invention: 
EXAMPLE 1 
1-[Indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol 
12.5 g. 1-Acetyl-4-(2,3-epoxypropoxy)-indazole are heated under reflux for 
3 hours in 50 ml. isopropylamine. The reaction mixture is then evaporated 
to dryness, the residue is triturated with diethyl ether and the product 
obtained is recrystallized from ethyl acetate. There are obtained 8.0 g. 
(60% of theory) 1-[indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol in the 
form of colorless crystals; m.p. 166.degree.-167.degree. C. 
The 1-acetyl-4-(2,3-epoxypropoxy)-indazole used as starting material is 
prepared in several stages as follows: 
a. (3-Amino-2-methylphenyl)-benzyl ether 
By the reduction of (2-methyl-3-nitrophenyl)-benzyl ether with hydrazine 
hydrate and Raney nickel in methanol, there is obtained the crude product 
in the form of a green oil. 
b. (3-Acetamino-2-methylphenyl)-benzyl ether 
Acetylation of the product described in (a) with acetic anhydride in 
toluene gives the desired product in the form of colorless crystals; m.p. 
142.degree.-143.degree. C. (after recrystallization from toluene). 
c. 1-Acetyl-4-benzyloxy-indazole 
A mixture of 64 g. (3-acetamido-2-methylphenyl)-benzyl ether, 25 g. sodium 
acetate, 69 ml. acetic anhydride, 50 ml. isoamyl nitrite and 2 liters 
toluene is stirred for 15-20 hours at 80.degree.-90.degree. C. After 
cooling the reaction mixture to 10.degree. C., the salts are filtered off 
with suction and the filtrate is evaporated to dryness in a vacuum. By 
trituration of the residue with 300 ml. methanol, there are obtained 47.5 
g. 1-acetyl-4-benzyloxy-indazole in the form of almost colorless crystals; 
m.p. 97.degree. C. 
d. 1-Acetyl-4-hydroxy-indazole 
By the hydrogenolysis of the 4-benzyloxy compound obtained in (c) in the 
presence of palladium-charcoal (10%) in methanol at atmospheric pressure, 
there is obtained 1-acetyl-4-hydroxy-indazole in the form of beige 
crystals; m.p. 140.degree.-142.degree. C. (after recrystallization from 
water). 
e. 1-Acetyl-4-(2,3-epoxypropoxy)-indazole 
To 17 g. 1-acetyl-4-hydroxy-indazole, dissolved in 200 ml. anhydrous 
dimethyl sulphoxide, there are added, while stirring, 5 g. of a sodium 
hydride suspension (50-60% in paraffin) and, after termination of the 
evolution of hydrogen, 30 g. p-toluene-sulphonic acid 2,3-epoxypropyl 
ester are added thereto in 10 g. portions. The reaction mixture is then 
heated to 60.degree. C. for 2 hours, poured into 2 liters water, acidified 
with acetic acid and extracted with methylene chloride. The extract is 
washed with water, dried with anhydrous sodium sulphate, treated with 
fullers' earth and then evaporated to dryness in a vacuum. The residue is 
triturated at -40.degree. C. with 100-200 ml. methanol, filtered with 
suction and thereafter washed with methanol. There are obtained 12.5 g. 
1-acetyl-4-(2,3-epoxypropoxy)-indazole in the form of colorless crystals; 
m.p. 83.degree. C. 
EXAMPLE 2 
1-[Indazolyl-(4)-oxy]-3-tert.-butylaminopropan-2-ol 
12.4 g. 1-Acetyl-4-(2,3-epoxypropoxy)-indazole and 50 ml. tert.-butylamine 
are boiled under reflux for 15 hours. The reaction mixture is evaporated 
to dryness and the residue is triturated with diethyl ether and then 
recrystallized from ethyl acetate. There are obtained 6.0 g. (42.6% of 
theory) 1-[indazolyl-(4)-oxy]-3-tert.-butylaminopropan-2-ol in the form of 
colorless crystals; m.p. 193.degree.-194.degree. C. 
EXAMPLE 3 
1-[Indazolyl-(4)-oxy]-3-[1-methylthiopropyl-(2)-amino]-propan-2-ol 
3.5 g. 4-(2,3-Epoxypropoxy)-indazole are stirred in an atmosphere of 
nitrogen with 15 ml. methylthioisopropylamine for 7 hours at 60.degree. C. 
The reaction mixture is evaporated to dryness in a vacuum and the residue 
is recrystallized from ethyl acetate. There is obtained 0.5 g. 
1-[indazolyl-(4)-oxy]-3-[1-methylthiopropyl-(2)-amino]-propan-2-ol in the 
form of colorless crystals; m.p. 96.degree.-98.degree. C. 
The 4-(2,3-epoxypropoxy)-indazole used as starting material is prepared as 
follows: 
The 1-acetyl compound described in Example 1 is stirred in a mixture of 
methylene chloride and liquid ammonia (cooling with solid carbon dioxide) 
for 4 hours. Upon evaporating in a vacuum, there is obtained a brownish 
oil which is sufficiently pure for the reaction with amines. By stirring 
with water, there is obtained a beige product; m.p. about 60.degree. C. 
(after melting, it solidifies again and then has a second melting point at 
&gt; 260.degree. C.). 
EXAMPLE 4 
1-[6-Methyl-indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol 
5.0 g. 1-Acetyl-4-(2,3-epoxypropoxy)-6-methylindazole are heated under 
reflux for 6 hours with 25 ml. isopropylamine. The reaction mixture is 
evaporated to dryness and the residue is triturated with diethyl ether and 
then recrystallized from ethyl acetate, with the use of active charcoal 
and fullers' earth. There are obtained 2.8 g. (52.3% of theory) 
1-[6-methyl-indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol in the form of 
colorless crystals; m.p. 157.degree.-158.degree. C. 
The acetic acid salt of the compound is obtained by adding 1 ml. acetic 
acid to the filtrate obtained by the crystallization, evaporating to 
dryness, taking up the residue in a little methanol, mixing the solution 
with diethyl ether until a slight turbidity is obtained and, after 
triturating in the cold, leaving to crystallize. After recrystallization 
from ethyl acetate, the salt is obtained in the form of colorless 
crystals; m.p. 141.degree.-142.degree. C. 
The 1-acetyl-4-(2,3-epoxypropoxy)-6-methyl-indazole used as starting 
material is obtained in several stages as follows: 
a. (2,5-Dimethyl-3-nitrophenyl)-benzyl ether 
A mixture of 433 g. 2,5-dimethyl-3-nitrophenol, 360 g. potassium carbonate, 
326 ml. benzyl chloride and 2 liters dimethyl formamide is stirred 
overnight at 50.degree. C. The reaction mixture is then filtered with 
suction and the filtrate is evaporated to dryness in a vacuum. The residue 
is poured on to 4 liters ice-water and, after suction filtration and 
drying in the air, there are obtained 668 g. 
(2,5-dimethyl-3-nitrophenyl)-benzyl ether in the form of yellowish 
crystals; m.p. 66.degree.-68.degree. C. 
b. (3-Amino-2,5-dimethylphenyl)-benzyl ether 
The nitro compound obtained in (a) above is reduced with hydrazine hydrate 
and Raney nickel in methanol to give, in good yield, crude 
(3-amino-2,5-dimethylphenyl)-benzyl ether in the form of a brown oil. 
c. (3-Acetamino-2,5-dimethylphenyl)-benzyl ether 
Acetylation of the amino compound obtained in (b) above with acetic 
anhydride in toluene gives (3-acetamino-2,5-dimethylphenyl)-benzyl ether 
in the form of colorless crystals; m.p. 169.degree.-171.degree. C. (after 
recrystallization from toluene). 
d. 1-Acetyl-4-benzyloxy-6-methylindazole 
A mixture of 149 g. (3-acetamino-2,5-dimethylphenyl)-benzyl ether, 50 g. 
sodium acetate, 138 ml. acetic anhydride, 50 ml. isoamyl nitrite and 3 
liters toluene is stirred for 15-20 hours at 80.degree.-90.degree. C. 
After cooling, the reaction mixture is filtered with suction and the 
filtrate is evaporated to dryness in a vacuum. The residue is taken up in 
about 300 ml. methanol, whereupon the product crystallizes in the cold. 
There are obtained 103 g. 1-acetyl-4-benzyloxy-6-methylindazole in the 
form of yellowish crystals; m.p. 91.degree.-93.degree. C. 
e. 1-Acetyl-4-hydroxy-6-methylindazole 
The benzyl compound obtained according to (d) above is hydrogenated in the 
presence of palladium-charcoal (10%) in methanol at atmospheric pressure. 
1-Acetyl-4-hydroxy-6-methylindazole is obtained in the form of pale 
yellowish crystals; m.p. 191.degree.-192.degree. C. (after 
recrystallization from methanol). 
f. 1-Acetyl-4-(2,3-epoxypropoxy)-6-methylindazole 
19 g. of the hydroxy compound obtained according to (e) above, 16.4 g. 
epibromohydrin and 16.6 g. potassium carbonate are stirred at 60.degree. 
C. for 20 hours in 100 ml. dimethyl formamide. The reaction mixture is 
then poured on to water and extracted with methylene chloride. The extract 
is dried with anhydrous sodium sulphate, treated with fullers' earth and 
evaporated to dryness in a vacuum. After taking up the residue in 100 ml. 
methanol, the product crystallizes. There are obtained 11.0 g. 
1-acetyl-4-(2,3-epoxypropoxy)-6-methylindazole in the form of colorless 
crystals; m.p. 105.degree.-107.degree. C. 
EXAMPLE 5 
1-[6-Methyl-indazolyl-(4)-oxy]-3-tert.-butylaminopropan-2-ol 
5.0 g. 1-Acetyl-4-(2,3-epoxypropoxy)-6-methyl-indazole and 25 ml. 
tert.-butylamine are boiled under reflux for 9 hours. The reaction mixture 
is then evaporated to dryness, the residue is triturated with diethyl 
ether and the product is recrystallized from ethyl acetate. There are 
obtained 1.2 g. (21.3% of theory) 
1-[6-methylindazolyl-(4)-oxy]-3-tert.-butylaminopropan-2-ol in the form of 
colorless crystals; m.p. 174.degree.-175.degree. C. 
The acetic acid salt of the compound is prepared in a manner analogous to 
that described in Example 4 and is obtained in the form of colorless 
crystals; m.p. 156.degree.-157.degree. C. (after recrystallization from 
ethyl acetate). 
In an analogous manner, there is obtained: 
a. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-6-methyl-indazole with 
sec.-butylamine: 
1-[6-methyl-indazolyl-(4)-oxy]-3-sec.-butylamino-propan-2-ol; 
b. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-5-methyl-indazole with 
isopropylamine; m.p. 75.degree.-76.degree. C. 
1-[5-methyl-indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol; m.p. 
123.degree.-124.degree. C. 
The 1-acetyl-4-(2,3-epoxypropoxy)-5-methyl-indazole used as starting 
material is prepared by several stages analogously to the process used for 
the preparation of the corresponding 6-methyl-indazole compound (cf. the 
process stages described in Example 4(a)-(f). 
c. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-5-methyl-indazole with 
tert.-butylamine: 
1-[5-methyl-indazolyl-(4)-oxy]-3-tert.-butylamino-propan-2-ol; m.p. 
124.degree.-125.degree. C. 
d. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-7-methyl-indazole with 
isopropylamine; m.p. 108.degree.-109.degree. C. 
1-[7-methyl-indazolyl-(4)-oxy]-3-isopropylamino-propan-2-ol; m.p. 
135.degree.-136.degree. C. 
The 1-acetyl-4-(2,3-epoxypropoxy)-7-methyl-indazole used as starting 
material is prepared by several stages in a manner analogous to that used 
for the preparation of the corresponding 6-methyl-indazole compound (cf. 
the process stages described in Example 4(a)-(f). 
e. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-7-methyl-indazole with 
tert.-butylamine: 
1-[7-methyl-indazolyl-(4)-oxy]-3-tert.-butylamino-propan-2-ol; m.p. 
118,5.degree.-119,5.degree. C. 
f. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-5-ethyl-indazole with 
isopropylamine: 
1-[6-ethyl-indazolyl-(4)-oxy]-3-isopropylamino-propan-2-ol; m.p. 
77.degree.-78.degree. C. 
The 1-acetyl-4-(2,3-epoxypropoxy)-6-ethyl-indazole used as starting 
material is prepared by several stages in a manner analogous to that used 
for the preparation of the corresponding 6-methyl-indazole compound (cf. 
the process stages described in Example 4(a)-(f); 
g. by the reaction of 1-acetyl-4-(2,3-epoxypropoxy)-6-ethyl-indazole with 
tert.-butylamine: 
1-[6-ethyl-indazolyl-(4)-oxy]-3-tert.-butylamino-propan-2-ol. 
EXAMPLE 6 
1-[6-Methyl-indazolyl-(4)-oxy]-3-[1-methylthiopropyl-(2)-amino]-propan-2-ol 
3.0 g. 4-(2,3-Epoxypropoxy)-6-methyl-indazole are stirred for 8 hours at 
50.degree.-60.degree. C. in an atmosphere of nitrogen with 15 ml. 
methylthioisopropylamine. The reaction mixture is evaporated to dryness 
and about 40 ml. diethyl ether and a few drops of methanol are added to 
the residue. After trituration and complete crystallization, the product 
is filtered off with suction and then washed with diethyl ether. There are 
obtained 3.2 g. (70.4% of theory) 
1-[6-methyl-indazolyl-(4)-oxy]-3-[1-methylthiopropyl-(2)-amino]-propan-2-o 
l; m.p. 91.degree.-94.degree. C. 
From ethyl acetate, with the use of active charcoal and fullers' earth, 
there are obtained 1.7 g. of colorless crystals; m.p. 
102.degree.-104.degree. C. 
The 4-(2,3-epoxypropoxy)-6-methyl-indazole used as starting material is 
prepared as follows: 
18 g. of the acetyl compound described in Example 4 are stirred for 8 hours 
in 200 ml. methylene chloride and 100 ml. liquid ammonia. The reaction 
mixture is then evaporated to dryness and the residue is treated with 
water. There are obtained 14.5 g. 4-(2,3-epoxypropoxy)-6-methyl-indazole 
in the form of colorless crystals; m.p. 123.degree.-125.degree. C. After 
recrystallization from methylene chloride (after cooling to -80.degree. 
C.): m.p. 138.degree.-139.degree. C. but in the case of a slower heating 
rate, the substance melts at a lower temperature. 
EXAMPLE 7 
1-[6-Methyl-indazolyl-(4)-oxy]-3-(methylthio-tert.-butyl-amino)-propan-2-ol 
3.0 g. 4-(2,3-Epoxypropoxy)-6-methyl-indazole are stirred for 12 hours 
under an atmosphere of nitrogen at 50.degree.-60.degree. C. with 15 ml. 
methylthio-tert.-butylamine. After evaporating the reaction mixture to 
dryness in a vacuum, the residue is triturated with diethyl ether. There 
are obtained 3.8 g. (80.0% of theory) 
1-[6-methyl-indazolyl-(4)-oxy]-3-(methylthio-tert.-butylamino)-propan-2-ol 
; m.p. 110.degree.-112.degree. C. 
Recrystallized from ethyl acetate, with the use of active charcoal and 
fullers' earth, there are obtained therefrom 2.8 g. of colorless crystals; 
m.p. 113.degree.-115.degree. C. 
EXAMPLE 8 
1-[6-Methyl-indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol 
0.5 g. 4-(3-Chloro-2-hydroxy-propoxy)-6-methylindazole are heated in a 
glass autoclave for 9 days at 70.degree. C. in 100 ml. isopropylamine. The 
reaction mixture is evaporated to dryness and the residue is taken up in 
water, rendered alkaline and extracted with chloroform. After drying over 
anhydrous sodium sulphate, the extract is evaporated and the residue (0.55 
g) is recrystallized from ethyl acetate, with the use of fullers' earth. 
There are obtained crystals with a melting point of 
154.degree.-156.degree. C. which show no melting point depression in 
admixture with the product obtained according to Example 4 from 
1-acetyl-4-(2,3-epoxypropoxy)-6-methyl-indazole. 
The 4-(3-chloro-2-hydroxypropoxy)-6-methyl-indazole used as starting 
material is prepared as follows: 
A solution of 2.7 g. 4-(2,3-epoxypropoxy)-6-methylindazole in 10 ml. 
glacial acetic acid is introduced, while stirring, into 10 ml. of glacial 
acetic acid which have been saturated with hydrogen chloride at ambient 
temperature. After 1 hour at ambient temperature, the reaction mixture is 
poured into 300 ml. water and neutralized with sodium bicarbonate, a 
viscous oil thereby separating out which solidifies after stirring for a 
comparatively long time or upon triturating with toluene. When 
recrystallized from toluene, with the use of fullers' earth, the product 
is obtained in the form of colorless needles; m.p. 171.degree.-172.degree. 
C. 
The following tests were carried out to determine the cardiac 
.beta.-receptor blocking activity of certain test compounds by determining 
the inhibition of the heart beat frequency increase induced by intravenous 
administration of isoprenalin 
(=3,4-dihydroxy-.alpha.-[(isopropylamino)-methyl]benzylalcohol). 
The test compounds representative of the invention were the following: 
Compound I: 1-[Indazolyl-(4)-oxy]-3-isopropyl-aminopropan-2ol 
Compound II: 1-[Indazolyl-(4)-oxy]-3-tert.-butyl-aminopropan-2-ol 
Compound III: 1-[6-Methyl-indazolyl-(4)-oxy]-3-isopropylaminopropan-2-ol 
Compound IV: 1-[6-methyl-indazolyl-(4)-oxy]-3-tert.-butylaminopropan-2-ol 
Compound V: 
1-[6-methyl-indazolyl-(4)-oxy]-3-[1-methylthiopropyl-(2)-amino]propan-2-ol 
Compound VI: 
1-[6-methyl-indazolyl-(4)-oxy]-3-(methylthio-tert.-butylamino)propan-2-ol. 
As comparison compound there was included: 
Compound A: 1-Isopropylamino-3-(1-naphthoxy)-2-propanol (Propranolol) 
These compounds were tested in the following manner: 
The .beta.-receptor blocking activity of the test compounds was tested on 
wake rabbits weighing between 2 to 3.5 kg and kept in wooden cages. 
EKG-electrodes were inserted into the hind quarters of the rabbits s.c. 
(II. lead) and the heart frequency was measured using an integrator (15 
seconds) as a digital value. The test compounds were then infused through 
a small tube to the ear vein of the rabbits over a period of 15 minutes. 
30 Minutes after the infusion isoprenalin was injected intravenously at 1 
.mu.g/kg. 
The results are set forth in terms of inhibition of isoprenalin 
tachycardia, and are set forth in the table below. 
TABLE 
__________________________________________________________________________ 
Blocking of Isoprenalin Tachycardia 
in Wake Rabbits 
Heartbeat Frequency 
DE 
Test Dosage (min.) 250* 
Substance 
mg/kg i.v. 
-x .+-. s-.sub.x 
.mu.g/kg i.v. 
__________________________________________________________________________ 
Control 
without Iso- 
209 .+-. 9 
-- 
prenalin 
Control 
with Iso- 
338 .+-. 10 
-- 
prenalin 
Compound A 
0.01 342 .+-. 5 
400 
(Propranolol) 
0.1 309 .+-. 9 
0.25 259 .+-. 7 
0.5 248 .+-. 6 
1.0 210 .+-. 8 
4.0 191 .+-. 6 
Compound I 
0.001 314 .+-. 8 
30 
(Example 1) 
0.005 280 .+-. 6 
0.01 259 .+-. 7 
0.1 237 .+-. 6 
0.5 239 .+-. 4 
1.0 237 .+-. 2 
5.0 238 .+-. 8 
Compound II 
0.001 294 .+-. 7 
(Example 2) 
0.005 264 .+-. 9 
20 
0.01 253 .+-. 4 
0.1 237 .+-. 10 
0.5 242 .+-. 4 
1.0 238 .+-. 6 
Compound III 
0.001 299 .+-. 6 
(Example 4) 
0.01 236 .+-. 7 
6 
0.1 214 .+-. 6 
3.0 199 .+-. 11 
Compound IV 
0.0003 327 .+-. 7 
(Example 5) 
0.003 258 .+-. 15 
4 
0.007 235 .+-. 7 
0.03 198 .+-. 9 
Compound V 
0.01 315 .+-. 11 
(Example 6) 
0.03 258 .+-. 10 
40 
1.0 228 .+-. 11 
Compound VI 
0.01 276 .+-. 10 
(Example 7) 
0.03 229 .+-. 6 
18 
0.1 222 .+-. 8 
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*Interpolated dosage which limits the frequency increas to 250 beats/min. 
The above data show that the inventive compounds are already effective at a 
dosage much smaller than those required of the comparison substances. 
The compounds according to the present invention are thus unexpectedly 
superior in effectiveness to known compounds and thus present a valuable 
contribution to the art. 
The dosages of the novel compounds of the present invention depend on the 
age, weight, and condition of the patient being treated. Generally 
speaking, for adultoral administration, the preferred unit dosage of 
active compound with suitable pharmaceutical diluent or lubricant is 1 
mg.-40 mg. four times a day. In general the oral dosage is 20-40 mg., 
whereas the intravenous dosage is generally 1-5 mg., four times a day. 
For preparing therapeutic compositions such as tablets and other compressed 
formulations, the compounds can include any compatible and edible 
tableting material used in pharmaceutical practice as for example, corn 
starch, lactose, stearic acid, magnesium stearate, talc, methyl cellulose 
and the like. 
Similarly the compounds of the present invention can be mixed with suitable 
adjuvants for the preparation of resorbable hard gelatin or soft capsules 
utilizing conventional pharmaceutical practices. 
Further, the compounds can be employed in the form of their solutions or 
suspensions suitable for parenteral administrations. 
It will be appreciated that the instant specification and examples are set 
forth by way of illustration and not limitation, and that various 
modifications and changes may be made without departing from the spirit 
and scope of the present invention.