DE2207460A1 - NEW LUNG THERAPEUTIC - Google Patents

Description

Case 5/532
Dr. Fl / wt

DBx_KARL_THOMAE_GMBH _J. ^ _ BIBERACH_AN_DER_RISS

New lung therapy

In the German Auslegeschrift 1 593 579 Hydroxycyclohexy! Amines of the general formula I,

in the

R. denotes a hydrogen atom or the methyl group, and their Physiologically acceptable acid addition salts with inorganic or organic acids described, which are valuable pharmacological Have properties, in particular an antitussive and expectorant effect.

It has now surprisingly been found that compounds of the above general formula I have a stimulating effect the production of the surfactant or anti-electasis factor? own.

In the active metabolism of higher mammals, transportation is required large volumes of gas create a lung at the contact surface

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Gas-liquid has a very large surface. This is caused by the existence of tiny vesicles in the lungs, the so-called Alveoli, reached. The respiratory surface of these alveoli is covered by a film of substance, the so-called surfactant or anti-electasis factor coated, which counteracts an alveolar collapse. In the event of an error in this factor, the alveoli would collapse or If this factor were deficient, the small alveoli would be reduced in favor of the large ones, since not all alveoli are of the same size. This would in turn reduce the surface area of the lungs available for gas exchange. Because the constitution this factor stabilizing the respiratory surface of the alveoli is not exactly known, it was of great importance to find connections, which have a stimulating effect on the cells producing it. This increases its release into the alveolar space.

The subject of the present application is therefore a new lung therapeutic agent for the treatment of edematous-atelectatic lung changes, in particular, however, with an increasing effect on the production of the surfactant or anti-electasis factor of the alveoli.

. Compounds of the above general formula I are therefore suitable for Treatment of clinical pictures that can be traced back to a surfactant deficiency, e.g. for the treatment of the respiratory distress syndrome, the pulmonary hyaline membrane disease or postperfusional lung syndrome. The compounds of general formula I above can be used for this purpose in combination with other active ingredients such as antibiotics, bronchodilators, cough suppressants, Respiratory maleptics, antisilicosis agents, corticosteroids, or antihistamines in the usual pharmaceutical preparation forms such as Tablets, coated tablets, gelatine capsules, ampoules, solutions or suspensions be incorporated.

The single dose is 2–16 mg, but preferably 2–6 mg.

The new action of the compounds of general formula I would

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for example with N- (trans-p-hydroxycyclohexyl) - (2-amino-3,5 "dibromobenzyl) amine hydrochloride proven as follows:

The experiments were carried out on albino mice. The static volume-pressure diagram in the isolated lung was used to assess the surface-active substances in the alveoli. For this it is necessary that the animals are killed in such a way that no terminal edema can form (see Ann.Ist.C.Porlanini.
29, 221-237 (1969)).

In order to be able to assess a possible effect of the substance to be examined in the sense of an increase in the formation of surface-active substances, an artificial test was carried out on the test animals
Deficiency of these substances provoked, for this purpose the animals were exposed to hunger or cold.

Withdrawal of feed with unhindered water intake

Groups of 15 mice each received no putter for 72 hours.
The substance to be examined was given in a dose of MO mg / kg
2 times a day using a stomach tube, in 0.2 ml physiological
Saline solution, applied. Only physiological saline solution was instilled in the control animals. The applications began
5 days before the start of food deprivation and continued during the starvation period.

The statistical evaluation of the difference in the means of the
Deflation volumes at different pressures compared to controls clearly shows that the volumes in the treated animals are significantly larger:

Transpulmo mean values of the deflation volumes in % V min nal pressure normal animals treated animals control
in cm HpO (room temperature + feeding)

I ^ 315 264 123

10 272 228 107

6 196 166 83

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The histochemical investigations also clearly show that the content of surface-active substances in the treated animals in the alveoli is considerably higher than that of the control animals and almost reaches the normal value. It should also be emphasized that that the treated animals were quite vital during the starvation period and their pellet remained smooth, while the untreated Animals remained exhausted and almost motionless and their fur became shaggy; analogous findings are also found after exposure to cold. In addition, it should be noted here that the substance examined is a acute toxicity of 268 mg / kg i. p. on the mouse.

The following examples are intended to explain the invention in more detail:

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Example A N- (trans-p-Hydroxy-cyGlohexyl) - (2-3.mino - 5 _> 5-dibromo-benzyl) -amine

6.5 g of N- (trans-p-hydroxy-cyclohexyl) - (2-aminobenzyl) -amine are dissolved in 80 ecm of glacial acetic acid and 20 ecm of water, and 9.6 g of bromine are added dropwise while stirring at room temperature. The reaction mixture is then stirred for a further 2 hours and then concentrated in a water-jet vacuum. The residue is taken up in 2 η ammonia, extracted several times with chloroform, and the organic phase is dried and concentrated. The crude base is purified by column chromatography over silica gel with chloroform and ethyl acetate and the N- (trans-p-hydroxy-cyclohexyl) - (2-amino-3,5-dibromobenzyl) amine is precipitated as the hydrochloride from ethanol-ether with concentrated hydrochloric acid . Recrystallization from ethanol-ether. Melting point: 233 - 234.5 ° C (dec.)
The following connections were made in the same way:

N- (trans-p-Hydroxy-cyclohexyl) -N-methyl- (2-amino-3,5-dibromobenzyl) -

Melting point of the hydrochloride: 216.5 - 217.5 ° C (dec.)

N- (trans-m-Hydroxy-cyclohexyl) - (2-amino-3,5-dibromobenzyl) -amine Melting point of the dihydrochloride: ^{190-192 0} C (dec.)

N- (cis-m-Hydroxy-cyclohexyl) - (2-amino-3 »5-dibromo-benzyl) -amine Melting point of the hydrochloride: 200-202.5 ° C

N- (trans-m-Hydroxy-cyclohexyl) -N-methyl- (2-amino-3,5-dibromobenzyl) -amine

Melting point of the hydrochloride: 206.5 - 208.5 ° C (dec.)

N- (cis-m-Hydroxy-cyclohexyl) -N-methyl- (2-amino-3,5-dibromobenzyl) -

Melting point of the hydrochloride: 207 - 2O8 ° C (dec.)

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N- (trans- o -hydroxy-cyclohexyl) -N-methyl- (2-amino-3,5-dibromobenzyl) -amine '.,> ■ ·:

Melting point of the hydrochloride: 159-161 ° C

N- (cis -p-Hydroxyclohexyl) -N-methy 1- (2-amino-3,5-dibroyn-benzyl)>

Melting point of the hydrochloride: 208 - 210 ⁰ C (decomp.)

example 1

Capsules with 4 mg of N- (trans-p-Hydroxycyclohexyl) - (2-amino-3,5-di -bromobenzyl) -amine-hydrochloride ■ -. ^; '■ - ·,

Composition: 4.0 mg 1 capsule contains: 164.0 mg Active ingredient 2.0 mg Corn starch sep. 170.0 mg Aerosil 200 Production method:

The ingredients are mixed and passed through a 0.75 mesh sieve, then in on a capsule machine Hard gelatine capsules size 4 filled. Capsule filling weight: 170 mg ■ ·· ■,; - .. ·

Example 2

Capsules with 1 mg N- (trans-p-hydroxycyclohexyl) - (2- * amino-3,5 ~ di '^; bromobenzyl) -amine hydrochloride (active substance I) and 40 mg N- (2-benzoylamino- 6-chloro-benzyl) -N-methy1-glycine-morpholide-hydrochloride (active substance II)

Composition:

1 capsule contains:

Active ingredient I 4.0 mg

Active ingredient II 40.0 mg

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Corn starch sep. 211.0 mg

Aerosil 200 15.0 W,

270.0 mg

Production method:

The substances are mixed homogeneously, sieved through 0.75 nm a capsule filling machine filled into hard gelatine capsules size 2. Capsule filling weight: 270 mg

Example 3

Ampoules with ¹ l mg of N-Ctrans-p-HydroxycyclohexyD - ^ - amino ^^ - di -bromobenzyl) -amine-hydrochloride / 2 ml

Composition:

1 ampoule contains:

Active ingredient ¹ 1.0 mg

Tartaric acid 2.0 mg

Glucose 95> 0 mg

Distilled water to 2.0 ml

Nitrogen q.s.

Manufacturing process: (100 1)

The corresponding amount of tartaric acid and active substance are dissolved in 90 liters of water at about 80 ° C. while gassing with nitrogen and stirring. After cooling to room temperature while gassing with nitrogen, the grape sugar is then dissolved and made up to 100 l. After sterile filtration and filling into 2 ml ampoules, it is ^{sterilized at 120 °} C. for 20 minutes.

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example

Ampoules with 2 mg N-itrans-p-HydroxycyclohexyD - ^ - amino ^ jS-di bromo-benzyl) -amine-hydrochloride / 2 ml

Composition:

1 ampoule contains:

Active ingredient 2.0 mg

Tartaric acid 2.0 mg

Glucose 95.0 mg

Distilled water to 2.0 ml

Manufacturing process: (100 1)

The corresponding amount of tartaric acid and active substance are dissolved in 90 liters of water at approx. 80 ^{° C. while gassing with nitrogen and stirring.} After cooling to room temperature while gassing with nitrogen, grape sugar is then dissolved and made up to 100 l. After sterile filtration and filling into 2 ml ampoules, it is sterilized at 120 ° C. for 20 minutes.

Example 5

Tablets with Ί mg N-Ctrans-p-HydroxycyclohexyD - ^ - amino-SiS-di- bromo-benzyp-amine-hydrochloride

Composition: 4.0 mg 1 tablet contains: 50.0 mg Active ingredient 53.0 mg Lactose 2.0 mg Potato starch 1.0 mg Polyvinyl pyrrolidone Magnesium stearate

110.0 mg Manufacturing process:

Active ingredient is mixed with milk sugar and potato starch, with

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an aqueous PVP solution evenly moistened, the mass passed through a 1.5 mm sieve, the granules in the circulating air drying cabinet dried at approx. 40 C and then passed through a sieve with a mesh size of 1.0 mm happened. After the lubricant has been mixed in, the tablets are pressed. Stamp: 7 mm, biplane with facets on both sides, partial notch

one side tablet weight: 110 mg

Example 6

Dragees with 4 mg of N-Ctrans-p-HydroxycyclohexyD - ^ - amino ^^ - di bromobenzyl) amine hydrochloride

a) Dragee core: composition and production analogous to 5.)

b) Coating: A customary sugar coating suspension is coated to a final weight of approx. 160 mg.

Stamp: 7 mm, biconvex tablet weight: l60 mg

Example 7

Juice with ¹ J mg of N-Ctrans-p-HydroxycyclohexyD - ^ - amino ^ jS-di bromobenzyl ) amine hydrochloride

Composition:

Active ingredient citric acid sodium hydroxide sodium benzoate Glycerin • Sorbitol solution 70% ethanol

Naphthol Red S plum aroma

Distilled water to 100.0 ml

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0.08 G G 0.5 G 0, OiJ ε 0.2 G 20.0 G 70.0 G 5.0 G 0.0003g 0.2

Manufacturing description:

Distilled water is heated to 80 ° C. and citric acid, sodium hydroxide, active ingredient, glycerine and sorbitol solution are added one after the other while stirring and dissolved. After cooling to room temperature, the sodium benzoate and naphthol red S are added and dissolved
as well as the solution of the aroma in the specified amount of alcohol mixed in.

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Claims (3)

- ii - Claims 1. New lung therapeutic agent for the treatment of edematous-atelectatic Changes in the lungs, but in particular with an increasing effect on the production of the surfactant or Anti-electasis factor of the alveoli, containing at least one compound of the general formula I, in the R ₁ denotes a hydrogen or methyl group, or their physiologically acceptable acid addition salts with inorganic or organic acids and optionally one or more customary carriers or diluents. 2. New lung therapeutic agent according to claim 1, containing N- (transp-hydroxycyclohexyl) - (2-amino-3,5-dibromobenzyl) amine or its acid addition salts. 3. New lung therapeutic agent according to claim 1 and 2, characterized in that that this still has other active ingredients such as cough suppressants, respiratory maleptics, bronchodilators, antibiotics, antisilicosis agents, Contains corticosteroids and / or antihistamines. Ι. New lung therapeutic agent according to claims 1-3 »containing 2 - 16 mg, but preferably 2 - 6 mg, of a compound of the general formula I. 309834/1097 Process for the production of a new lung therapeutic for the treatment of edematous-atelectatic lung changes, but in particular with an increasing effect on the production of the surfactant or anti-electasis factor in the alveoli, characterized in that at least one compound of the above general formula I or its physiologically acceptable acid addition salts, if appropriate in combination with other active ingredients such as cough suppressants, respiratory maleptics, bronchodilators, antibiotics, antisilicosis agents, corticosteroids and / or antihistamines in the usual pharmaceutical preparation forms . 309834/1097