DE1692035C3 - Medicines with a bronchodilator effect - Google Patents

Description

CH = CHCF {(OH) (CH ₂ ) ₄ CH,

HO

CH ₂ CH = CHi | CH ₂ ), COOR

CH = CHCH (OH) (CH ₂ I ₄ CH,

wherein R denotes hydrogen, C ₁ -C ₆ -Alk ^ l, alkali metal or a pharmaceutically acceptable cation derived from ammonia or a basic amine, and customary additives for administration by inhalation, preferably as an aerosol, in which case an inert propellant may then be included .

2. Medicament according to claim I, characterized in that that the compound 7- [3-hydroxy-2 - (3 - hydroxy - 1 - oclenyl) - 5 - oxocyclopentyl] -5-heptenoic acid or the 7- [3-hydroxy-2- (3-hydroxy -1-octenyl) -5-oxocyclopentyl] -5-heptenoic acid methyl ester is.

Bronchodilator medicines relax the bronchial smooth muscles. They are therefore suitable Counteract spasms and breathing in bronchial asthma, bronchitis, and bronchietasis To ease emphysema. The bronchodilator agents include one or more of the three basic types of connections; (a) sympathomimetic (andrinergic) agents, (b) xanthine derivatives, and (c) corticosteroids. Together with cough suppressants, for example, the medicaments can promote expectoration and mucilaginous agents can be used.

Epinephrine, isoproterenol, phenylephrine and ephedrine are often used as sympathomimetic agents used. These agents are particularly useful for relieving severe asthmatic spasms (status asthmatictis). However, they have unfavorable side effects, especially stimulation of the cardiovascular and central nervous system, hyperglycemia and tachphylaxis. Theophylline and aminophylline are mostly used as xanthine derivatives. Here there are some problems associated with therapy, such as variable oral absorption, cardiovascular Effects and the inability to obtain adequate amounts without gastric irritation. In the end Long-term treatment of asthma with corticasteroids involves the risk of sodium retention, Hypertension, ulcer, calcium loss from bone tissue and other known side effects.

wherein R is hydrogen. C ₁ -C ₆ -Alk) '!, alkali metal or a pharmaceutically acceptable cation derived from ammonia or a basic amine and contains conventional additives for administration by inhalation. The additives are preferably provided for administration of the preparation as an aerosol, in which case an inert propellant may then be included. According to a particularly preferred embodiment, the active ingredient is 7 - [3 - hydroxy - 2 - (3 - hydroxy - 1 - octenyl) - 5 - oxocyclopentyl] -5 - heplenic acid (R = hydrogen) and 7 - [3 - hydroxy - 2 - (3 - hydroxy - 1 - octenyl) - 5 - oxocyclopentyl] -5-heptenoic acid methyl ester (R = methyl). In addition to the content of a certain active ingredient, the medicaments according to the invention are distinguished by the fact that they are used as a spray or as an aerosol for inhalation therapy, ie contain the components necessary for this form of administration.

It is already known from in vitro tests that compounds of the aforementioned type are predominantly have a tone-increasing effect on the smooth muscles. Although the tracheal muscle was isolated the cat has an artificially produced tone decreased; however, the test compounds became in vivo in cats administered, there was a considerable increase in inhalation resistance (Acta Chem. Scand., 1962, 501; Arkiv for Kemi, 1962, 563; Acta Physiol. Scand., 1963, 493; Brit. J. Pharmacol. 1963, 182, and 1964, 511).

After that, these compounds must appear to be unsuitable for combating asthma, surprisingly however, the agents used according to the invention have proven to be highly effective for combating Showing breathing difficulties of the type in question when administered as inhalation preparations will. This is all the more surprising since well-known agents such as aminophylline or ephedrine are involved very effective when administered orally, but ineffective as an aerosol. The inventively used Compounds are especially effective as an aerosol. On top of that, this means as an aerosol show no side effects, even with amounts that are 100 times greater than what is required Quantities are.

Cj-C ₆ -AllCyI contains straight and branched hydrocarbon radicals, such as methyl, ethyl, n-propyl, i-propyl, η-butyl, t-butyl, n-pentyl, n-hexyl, 3-methyl pentyl and 2,3 -Demethylbutyl.

Alkali metals include, for example, sodium. Understanding potassium and lithium. Too pharmaceutical acceptable cations derived from ammonia or a basic amine are said to be positive charged ammonium ion and cationic compounds of the formula

R ¹

HNR ²
R ³

•

wherein the radicals R ¹ , R ² and R ³ independently of one another are hydrogen, alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, monocarbocyclic aryl with 6 carbon atoms, monocarbocyclic alkylaryl with 7 to 11 carbon atoms , Hydroxyalkyl with 1 to 3 carbon atoms or monocarbocyclic hydroxyalkylaryl with 7 to 15 carbon atoms or two of the radicals R ¹ . R ² and R ³ together with the nitrogen atom to which they are attached form part of a 5- or o-membered heterocyclic ring which contains carbon, hydrogen, oxygen or nitrogen. The heterocyclic rings and the respective monocarbocyclic aryl groups are unsubstituted or mono- or dialkyl-substituted by alkyl groups having 1 to 6 carbon atoms.

Examples of the radical R when it is an amine are ammonium, mono-, di- and trimethylammonium. Mono-, di- and triethylammonium, mono-. Di- and tripropylammonium (iso and normal), Ethyldimethylammonium, Benzyldimethylammonium, Cyclohexylammonium, Benzylammonium. Dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butylpiperidinium, 2-methylpiperidinium, l-ethyl-2-methylpiperidinium, Mono-, di- and triethanolammonium. Ethyl diethanolammonium, η - Butylmonoäthanoiammonium, tris- (hydroxymethyl) -methylammonium and Phenylmonoethanolammonium.

The free carboxylic acid of the formula I can be isolated from natural products, such as genital materials, for example prostate glands or sperm are produced.

However, a biosynthetic process is more suitable and preferred because it results in a product which is essentially free of tissue fragments, cell debris and foreign proteins. z. B. Incubation of arachidonic acid in the presence of sheep seminal vesicle enzyme. The esters of formula I (in which R is alkyl) are prepared by standard procedures, for example by treating a solution the free acid with diazomethane or other suitable diazo hydrocarbons, such as diazoethane, l-diazo-2-ethylpentane produced. The alkali metal salts can be prepared by mixing stoichiometrically equivalent amounts of the free acid of formula I, preferably in aqueous solution, with solutions of alkali metal bases, such as sodium, potassium and lithium hydroxides or carbonates and freeze drying the mixture. The amine salts are prepared by mixing the free acid, preferably in solution, with a solution of the appropriate one Amine in water or isopropanol and freeze-drying the mixture.

The dosage depends mainly on the severity of the symptoms and the size of the patient. at about 70 kg live weight is given by oral inhalation, for example with a hand sprayer or a pressurized aerosol drug dispenser, the usual effective dose in the range from 100 to 300 micrograms every 4 hours approximately as necessary.

For the intended administration via the oral inhalation route with conventional nebulization devices or by oxygen aerosol formation, it is advantageous to use the drug in dilute aqueous Solution, preferably in concentrations of about 1 part drug to use from 100 to 200 parts by weight of total solution. Conventional Additives can be used to stabilize these solutions or to form isotonic media for example sodium chloride, sodium citrate, citric acid and sodium bisulfite.

For arrangement as a self-spraying dosage unit, an inert propellant (e.g. a mixture dichlorodifluoromethane and dichlorotetrafluoroethane) along with a co-solvent such as ethanol. Flavorings and stabilizers be included. A dispersant such as oleyl alcohol can also be used in place of the co-solvent be used. The agents suitable for use in the aerosol inhalation therapy technique are described in detail in U.S. Patents 2,868,691 and 3,095,355, for example.

In an experiment, the bronchodilator effectiveness of the drug was determined by that one guinea pigs an aerosol of the drug at various concentrations and in exposed to different time intervals. The animals were then challenged with histamine aerosol, and protection against breathing difficulties was measured.

In carrying out the experiment, a group of test animals were exposed to the drug aerosol in a first chamber for 2 minutes; the animals were then left exposed to the aerosol for a further 1 minute after the end of the spraying (3 minutes total exposure time to the drug). The animals were then immediately placed in a second chamber into which histamine had previously been sprayed for 1 minute. The time it took for difficulty breathing (T) to begin was now recorded. In a control experiment, the guinea pigs had previously been exposed to a histamine spray in an unprotected state to determine their mean convulsion times (C), and the time it took for the convulsions to begin was measured. An animal which in the experiment shows respiratory disabilities only after a time three times longer than the convulsion time after application of the drug is considered to be completely protected. Individual controls (C) and convulsion times (T) after drug treatment were recorded and an activity value was calculated according to the formula (T / C). A mean (T / C) value greater than 1.2 indicates effectiveness. This experiment corresponds to that of S iegmu η d and co-workers, J. Pharmacol. 90, 254 (1947), and 97, 14 (1949), and its clinical correlation in humans is known to be excellent.

The results of the investigations are recorded in Table 1.

Table I.

Effects of 7- (3-hydroxy-2- (3-hydroxy-1 -octenylJ-S-oxocyclopentylj-S-heptenoic acid on bronchi (bror choconstriction) in anesthetized guinea pigs

% Spray
concentration number of
sea
piggy Number of full
constantly ge
protected sea
piggy Centered
T / C value 0-0.06-M
PO ₄ buffer,
Control ..
0.0001
0.0005
0.001
0.005
0.01
0.05
0.1
0.2 6th
10
10
10
10
10
10
15th
10 0/6
1/10
2/10
8/10
4/10
5/10
9/10
12/15
9/10 0.92
1.59
2.19
2.78
2.40
2.34
2.89
2.79
2.99

"5

3 °

As a T / C value of 1.5 or greater indicates efficacy and an animal that is three times the control pre-convulsion time can resist, considered to be fully protected, is the bronchodilator Effectiveness of the compounds easily seen.

Table II shows the lack of toxicity observed with concentrated aerosols of the drug became.

Guinea pigs were thoroughly sprayed with the drug for 2 minutes and then in the chamber leave an additional 3 minutes to expose them to the drug for a longer period of time than this was necessary for a histamine test.

45

Table Il

Effect of the drug used as an aerosol on guinea pigs

% Spray Number of sea Effects concentration piggy no changes 0.05 5 established no changes 0.1 6th established Vs the guinea pig 0.2 5 hold slow Breathing and put the Head to one side

50

55 The following examples explain the invention.

example 1

Two preparations were made using them

1 part 7 - (3 - hydroxy - 2 - (3 - hydroxy - 1 - octenyl) -5 - oxocyclopentyl) - 5 - heptenoic acid and 100 resp. 200 parts by weight of 0.06 M aqueous phosphate buffer contained. When used to alleviate Bronchial spasms from oral inhalation with a hand sprayer can occur in animals weighing 30 to 70 kg Live weight 3 to 7 inhalations of the 1: 100 solution or 5 to 15 inhalations of the 1: 200 solution all 4 hours, if necessary, are administered, with up to 0.3 ml of the 1: 100 solution and up to to be used at 0.5 ml of the 1: 200 solution per treatment.

Example 2

It became the US patent procedure

2 868 691 for the manufacture of preparations in self-spraying Dosage units prepared as follows:

An appropriate measured amount of the drug was obtained by mixing in a measured amount Co-solvent dissolved. A stabilizer can be added. A measured amount of yourself resulting solution is then introduced into an open container. The open container and its contents the same were then cooled, preferably to a temperature below the boiling point of the propellant, that should be used.

A temperature of -25 ° F (-32 ° C) was common satisfactory. A measured amount of the liquefied propellant, which is also under his Boiling point was cooled, was then introduced into the container and with the pre-existing one Mixed solution. The amount of the ingredients introduced into the container was calculated so that the desired concentration was present in each of the final formulations. Without that one Allowed the temperature of the container and its contents to rise above the boiling point of the propellant the container is closed with a closure equipped with a suitable distribution nozzle arrangement is. After warming to room temperature, the contents of the container were removed by shaking the Container mixed to ensure complete solution of the drug. The sealed container was then ready to spray the preparation and to aerosolize the medicine form.

Nebulizers, each containing 15 ml, were used according to the procedure given above filled with the following components:

The results of these investigations show that the agents according to the invention are strong, rapidly acting bronchodilatory effect on the smooth muscles of guinea pigs.

Preparation 1

60 7- (3-Hydroxy-2- (3-hydroxy-1-octenyl) -5-oxocyclopentyl) -5-heptenoic acid ...

Ethanol

Dichlorodifluoromethane

percent

0.25
34.75
65
100

7- (3-Hydroxy-2- (3-hydroxy) -1-oclenyl) -5-oxocyclopcntyl) -5-haptenoic acid

Ethanol

Dichlorotetrafluoroethane

Dichlorodifluoromethane

preparation

2 I 3

percent

0.25 34.75 40 25 KX)

0.25 34.75 45.5 19.5 TÖÖ

These packs were set to release 300 single oral inhalations, with each individual dose contains 125 micrograms. A single inhalation was used to control acute bronchial spasms applied. If necessary, a second inhalation can be given after one minute administered.

Example 3

The procedure of Examples 1 and 2 was used to prepare bronchodilators Agents of 7- (3-hydroxy-2- (3-hydroxy-l-octenyl) -S-oxocyclopentyO-S-heptenoic acid methyl ester.

$ 09625/278

Claims (1)

The object of the invention is to create a bronchodilator Medicinal product that is highly effective and free from the disadvantages of known means 5 The task at hand is given by a remedy halt "dissolved on a compound of the general formula I, which as active ingredient is a compound of the general Formula I. Patent claims:
1. Medicines with a bronchodilator effect HO CH ₂ CH = CH (CH ₂ I ₁ COOR