CH527796A - Indene deriv for treating heart diseases - Google Patents

Abstract

Cpds. are of formula:- where R is lower alkyl, and their non-toxic acid addition salts. Pref. cpd. is 7-(3-isopropylamino-2-hydroxypropoxy)indene.

Description

  

  
 



  Process for the preparation of indene derivatives
This invention relates to a process for the preparation of new indene derivatives having valuable therapeutic properties as well as their non-toxic salts.



   The therapeutically active compounds of this invention are represented by the general formula
EMI1.1
 in which R is a lower alkyl group.



   The term lower alkyl group chosen here includes both straight-chain and branched-chain saturated aliphatic hydrocarbon radicals, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl groups.



   The invention relates to a process for the preparation of indene derivatives of the general formula
EMI1.2
 in which R represents a lower alkyl group and of their non-toxic acid addition salts with inorganic or organic acids, characterized in that 7-hydroxyindene of the formula
EMI1.3
 with an alkylamine derivative of the general formula
EMI1.4
 in which R has the above meaning and X represents a halogen atom, reacted and, if desired, a base obtained is converted into an acid addition salt with a non-toxic inorganic or organic acid.



   The reaction is preferably carried out in the presence of an acid-binding agent, preferably alkali metals or their derivatives, e.g. B. hydroxide, hydride, amide, alcoholate and metal alkyl compounds performed.



   The reaction is also preferably carried out in the presence of solvents such as water, methanol, ethanol and the like at room temperature or at an elevated temperature.



   The 7-hydroxyindene (II) is isomerized in a solvent such as water or an organic diluent under certain conditions by a basic substance, whereby 4-hydroxyindene is formed.



   For this reason, in addition to the compound (I), an isomer, namely 4- (3-lower alkylamino-2-hydroxypropoxy) indene of the general formula can be used
EMI1.5
  wherein R has the same meaning already mentioned above.



   The new compounds (I) of this invention contain an asymmetric carbon atom in the 2-position in their side chain and can exist as d- or l-isomers or racemates.



   The essentially non-toxic acid addition salts can be prepared from the compounds (I) in the customary manner with pharmaceutically non-toxic inorganic or organic acids such as hydrochloric acid, sulfuric acids, nitric acid, phosphoric acid, formic acid or acetic acid.



   The compounds (I) have valuable therapeutic properties which make them useful as adrenergic, B-receptor blocking agents (see experiment 1).



   As an extremely valuable property of the compounds (I) it should be emphasized that they improve the heart function, while known adrenergic SS-receptor antagonists such as 7- (3-isopropylamino-2-hydroxypropoxy) - indan result in harmful effects (compare experiment 2) .



   Accordingly, the products (I) of this invention are useful as adrenergic B-receptor antagonists which can be administered to the patient without fear of damaging the heart.



   Another characteristic of the compounds (I) becomes apparent when they are administered orally. You can clinically orally in a daily dose of about 5 to 15 mg of the compounds, preferably in divided doses, given who the. But they can also be administered intramuscularly or intravenously in a total daily dose of about 2 to
5 mg of the compounds, preferably in divided doses.



   The invention is described in more detail below
Example described, which is only used for illustration, but is not intended to limit the scope of the invention.



   example 1
0.65 g of 1-chloro-2-hydroxy-3-isopropylaminopropane was added to a solution of 0.44 g of 7-hydroxyindene in 4 ml of 10% aqueous but potassium hydroxide solution. After stirring, the resulting mixture was left to stand at room temperature for 15 hours. The reaction mixture was extracted with ether. The ether extract was dried with anhydrous sodium carbonate and the ether was distilled off under reduced pressure. The residue was subjected to column chromatography (filling silica gel) treatment using acetone as the eluent. 0.23 g of white crystals of 7- (3-isopropylamino-2-hydroxypropoxy) indene were obtained.



   When the crystals obtained above were mixed with the 7- (3-isopropylamino-2-hydroxypropoxy) indene obtained by another method, no lowering of the melting point could be observed.



   To a solution of 0.41 g of 7- (3-isopropylamino-2-hydroxypropoxy) indene in 80 ml of absolute ether, a hydrochloric acid-ether mixture was added dropwise at 0 ° C. while stirring. The precipitates formed in this way were separated off by filtration and recrystallized from an ethanol-ether mixture. 0.44 g of 7- (3-isopropylamino-2-hydroxypropoxy) indene hydrochloride with a melting point of 147-148 ° C. was obtained.



  Elemental analysis as C1sH22NO2Cl:
Calculated: C 63.48 H 7.81 N 4.94%
Found: C 63.52 H 7.86 N 4.96%
With regard to the adrenergic ß-receptor blocking action, 7- (3-isopropylamino-2-hydroxypropoxy) indene obtained according to Example 1 and 7- (3-isopropylamino-2-hydroxypropoxy) indane according to Experiment 1 below were tested.



   Attempt 1
The striae obtained from a male Hartley Guinnea pig weighing 300-500 g were trimmed and placed in chambers, the Tyrode solution was ventilated with 95% oxygen and 5% carbon dioxide and was kept at 30 ° C as the chamber filling.



   The force of contraction was recorded with an isometric lever connected to a strain gauge and transmission system.



   Antagonistic activity of the drug to be tested by 1-isoproterenol action, increased by the auricle contraction was investigated.



   The first control reaction was made by adding 1
Isoproterenol measured in the bath liquid with a final concentration of 5 x 10-8 g / ml. Then the test object was washed and the same measurement was repeated after administration of the drug to be tested, namely 7- (3 isopropylamino-2-hydroxypropoxy) indene or 7- (3-isopropylamino-2-hydroxypropoxy) indane (final concentration of 8 x 10 -9 g / ml or 5 x 104 10 g / ml), 10 minutes beforehand. The
The results are shown in Table 1.



   Table I.
Inhibitions Tested Compound Dose (g / ml) rate (%) 7- (3-Isopropylamino-2- 8X 10-9 30.7 hydroxypropoxy) -inden 5 X 10-8 81.5 7- (3-Isopropylamino-2- 8 X 10-9 30.4 hydroxypropoxy) indan 5 X 10-8 88.4
Direct effects of the compounds on a heart without autonomic nervous control were investigated according to Experiment 2 below.

 

   Attempt 2
The studies were carried out on bearded rats weighing 250-350 g, which were anesthetized with pentobarbital (50 mg / kg, i.p.), Namely 18-24 hours after a reserpine treatment (8 mg / kg, s. C.).



  Both adrenal glands were removed and bilaterally the vagus in the neck was incised. One ml / kg of 7- (3-isopropyl amino-2-hydroxypropoxy) indene or 7- (3-isopropylamino-2-hydroxypropoxy) indan was injected intravenously over three minutes in a single dose with a range of 0.01 to 0.1 mg / kg and the heartbeat was measured with a cardiotachometer from Nihon Koden Co (RM 100). The results are shown in Table 2. In Table 2, a symbol (+) means increasing the heartbeat, a symbol (-) means decreasing the heartbeat, and a standard error range is shown in parentheses ().



  Tested Compound Number of Doses Change in heartbeat (%) of the animals (mg / kg) after 1 after 5 after 15 after 30
Minute minutes minutes minutes 7- (3-isopropylamino-2- 2 0.01 +2.4 +3.8 +3.2 +1.7 hydroxypropoxy) -inden (10.9) (10.2) (+0 , 1) (10.2)
4 0.05 +5.6 +8.4 +8.7 +5.2 (# 2.1) (# 3.4) (# 4.0) (# 3.1)
3 0.10 +1.5 +4.1 +3.5 +4.0 (# 0.4) (# 1.2) (# 1.4) (# 2.0) 7- (3-isopropylamino -2- 3 0.01-0.9 +0.3-1.9-1.7 hydroxypropoxy) -indan (+ 0.1) (# 0.8) (# 0.9) (# 0.3 )
4 0.05 -2.1 - 2.0 - 2.0 - 4.6 (+0.5) (10.5) (+0.9) (+ 1.4)
2 0.10-5.9 -8.7 -8.7 -5.4

   (# 1.4) (# 0.3) (# 0.3) (# 0.6)
When 7- (3-isopropylamino-2-hydroxypropoxy) was injected into the intravenous white mice, the LD-50 was 25 mg / kg.



  Manufacture of tablets: Formulation 7- (3-isopropylamino-2-hydroxypropoxy) indene 0.2 g microcrystalline cellulose 1.4 g starch 0.7 g talc 0.2 g
The whole thing was made into 20 tablets. The tablets were made with a 7.0 mm deep tabletting tool. They can be provided with a protective coating according to a conventional method, if desired.



  Manufacture of injection preparations:
100 mg of 7- (3-isopropylamino-2-hydroxypropoxy) indene hydrochloride was dissolved in 100 ml of saline. The solution thus formed was aseptically filled in 2 ml dimensions into 50 ampoules, each containing 2 mg of the active compound.

 

Claims (1)

PATENT CLAIM Process for the preparation of indene derivatives of the general formula EMI3.1 in which R represents a lower alkyl group and of their non-toxic acid addition salts with inorganic or organic acids, characterized in that 7-hydroxyindene of the formula EMI3.2 with an alkylamine derivative of the general formula EMI3.3 in which R has the above meaning and X is a halogen atom, reacted and a base I obtained is, if desired, converted into an acid addition salt with a non-toxic inorganic or organic acid.