Bromide l-(-)-enantiomer(endo,syn)-(-)-3-(3-hydroxy-1-oxo-2 - phenylpropoxy)-8-methyl - 8-(1-methylethyl)-8-asone - bicyclo[3.2.1]octane with a purity of 90-100% of an inhaled drug for the inhibition of the bronchoconstriction induced by acetylcholine

 

(57) Abstract:

Describes a new connection - bromide L-(-)-enantiomer (endo,SYN)-(-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane with a purity of 90-100%, preferably 95-100%. This connection can be an active substance inhaled drug for the inhibition caused by acetylcholine bronchospasm, which may contain conventional excipients and/or carriers and/or other medicinal substances. 2 S. p. f-crystals, 1 Il.

The invention relates to means with bronchospasmolytic activity, in particular bromide L-(-)-enantiomer (endo,SYN)-(-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1 - methylethyl)-8-azoniabicyclo[3.2.1] octane with a purity of 90-100%, and inhalation drug for the inhibition of the bronchoconstriction induced by acetylcholine.

Known application (endo,SYN)-(-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-(1 - methylethyl)-8-azoniabicyclo[3.2.1] octane and its salts, in particular its bromide (known as ipratropium) as the active substances in drugs with anticholinergic activity (see application DE N 4140861, class C 07 D 451/10, published. 17.06.1993 year).

Object of the invention is Raym bromide L-(-)-enantiomer (endo, Shin)-(-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8 - methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane with a purity of 90-100%, preferably 95-100%.

The task is also solved inhaled drug for the inhibition of the bronchoconstriction induced by acetylcholine containing bromide L-(-)-enantiomer of the above octane and optionally conventional auxiliary substances and/or carriers and/or other medicinal substances.

Obtaining bromide L-(-)-enantiomer of the above compounds, ipratropium, is illustrated by the following example.

Example 1. 18 g of the bromide ipratropium separated liquid chromatography under pressure on a column of type Chiracel OD (250 x 20 mm) mobile phase containing hexane, methanol, ethanol and a saturated solution of sodium bromide in an environment of alcohol in a ratio of 600:250:150:1 (feed rate 6 ml/min, wavelength 254 nm, the absorption sensitivity of 0.5 units (A. U. F. S. = Absorbance Units Full Scale), the original solution: 1 g of bromide ipratropium in the environment 5 ml ethanol + 5 ml of mobile phase + 2.5 ml of concentrated acetic acid).

By re-chromatography and recrystallization from ethanol L-(-)-enantiomer, white crystals, etc., 239-240oC (decomp.), specific rotation []2D

Elemental analysis and spectrum confirm the presence of the specified enantiomer.

The proposed active substance can be converted to inhalation drugs, examples of which are given.

Examples of drugs (data on the content of the ingredients are given in weight percent).

Example 2.

Aerosols

The proposed active substance - 0,005

Sarbatorile - 0,1

Monitorability and fluorocarbons in the ratio 2:3 To 100

Obtained by mixing the ingredients of the suspension is placed in a conventional cylinder valve device and a spray head. Each press is allocated, for example, 50 μl of the suspension. The active substance may be contained, if necessary, and in higher doses (for example, 0.02 wt.%).

Instead of chlorinated propellants can also use alternative propellants, as 1,1,1,2-Tetrafluoroethane and/or 1,1,1,2,3,3,3-Heptafluoropropane.

Example 3.

Inhalation powder

Micronized powders with a particle size of 0.5 to 7 microns is mixed with micronized lactose and serves optionally together with other additives in hard gelatin capsules. Each capsule serves, for example, Example 4.

Inhalation solution

You can also use liquid solutions of the active substances, and to obtain aerosol can be used, for example, the device described in international published application WO 91/14468. Each press is allocated, for example, 0.005 mg of active substance.

The best biological activity of the proposed L-(-)-enantiomer compared to the racemate is confirmed by the results of experiments on anesthetized dogs, which are represented in the drawing.

The drawing shows the percentage inhibition caused by acetylcholine bronchospasm depending on time. Thus the dotted line shows the inhibition when using bromide L-(-)-enantiomer (endo,SYN)-(-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane, and the solid line is the inhibition using the corresponding racemate. Give 5 mg of pure L-(-)-enantiomer and 10 mg of racemate. Pure L-(-)-enantiomer give 5 experimental animals, and the racemate - 7 experimental animals.

The drawing shows that the inhibition caused by acetylcholine bronchoconstriction in dogs reaches its maximum (about 55%) after 10 min th min already achieved initial level. When using the same number of L-(-)-enantiomer contained in the study racemate, after 10 min achieved a 60% inhibition, but only after 180 min was achieved initial level.

According to the measured half-life duration of activity of the proposed L-(-)-enantiomer is approximately 4 times longer than the duration of activity of the racemate.

The proposed active substance can also be used in combination with other drug substances such as2- mimetic means, and compared with separate application of the used dose 2-mimetic means is 50-100%.

As an example we can mention bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, geksoprenalin, ibuterol, pirbuterol, procaterol, reproterol, salbutamol, salmeterol, sulfonterol, terbutaline, tulobuterol, 1-(2-fluoro-4 oksifenil)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol, Erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminoethyl)-2H-1,4-benzoxazin-3-(4H) -, 1-(4-amino-3-chloro-5-triptoreline)-2-tert-butylamino)-ethanol, 1-(4-ethoxycarbonyl-3-cyan-5-forfinal)-2-(tert-butylamino)-ethanol.

Possible combinations with incontaminate, flunisolide, as well as anti-allergic agents like dinitrocresolates, nedocromil, epinasty. These substances can also be used in equal or smaller doses than their separate application.

1. Bromide-L-(-)-enantiomer(endo,SYN)-(-)-3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1] octane with a purity of 90 to 100%, preferably 95 to 100%.

2. Inhalation drug for the inhibition of the bronchoconstriction induced by acetylcholine, characterized in that it contains a connection on p. 1 and, if necessary, conventional excipients and/or carriers and/or other medicinal substances.

 

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