DE2234713A1 - NEW PHENYL-1-PROPANE DERIVATIVES - Google Patents

Description

SYNTHELAJ3G, Paris / Prank.re3.ch

NEW PHENYL-1 - P RO PAN «DERIVATIVES

The present invention relates to (N-methyl-N-fb-eyano-athyu) ar: i.ino -? - phenyl-l-propanol-l of the formula, (l)

OH,

CH «CH - W-

- CH ₂ - CN (I)

The molecule of the compound (i) has an asymmetrical carbon dioxide and can therefore be present in the form of its racemate and in the form of one or the other of its two optical antipodes. These three forms belong to the present invention, the levorotatory antipode being the preferred connection.

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* · ■ ϊ * ί .- ■ '.

The invention also relates to all addition salts which the substance (i) with any mineral or organic pharmaceutical Compatible acids, among which certain such as hydrochloric acid, sulfuric acid, tartaric acid, and citric acid etc., have no pharmaceutical properties of their own, while others have an additional effect on top of that of the Compound (i), as is the case, for example, with theophylline or 7-ethyl-theophy11inic acid.

The invention further relates to a process for the preparation of the compound (i), which is characterized in that one N-methylamino-2-phenyl-1-propanol-1 with an excess of Acrylonitrile converts, part of the -latter serving as a solvent. The reaction is carried out at room temperature and causes at reflux temperature. Accordingly, the desired compound (I) is obtained by driving off the solvent.

The addition salts of (i) are prepared according to known methods shown. For example, the hydrochloride is prepared by dissolving the base (i) and a mixture of equal parts of alcohol and ether and introduction of a stream of hydrogen chloride and acid into the solution obtained until the end of the precipitation represents. The enantiomorphs (i) are prepared by separating the Razemates (i) using the classical method at the synthesis of N-methyl-amino-2-phenyl-1-propanol-1 as optical antipodes. - <

The invention finally encompasses the industrial uses of the compound (i), in particular its pharmaceutical use. This has pharmacological properties that

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justify their use in therapy. For example, the results of a comparative test of their levorotatory antipode (compound A) and reproduced from ephedrine (compound E).

1. Bronchodilating properties.

These are proven by the method according to Konzett and Rüssler (Arch.exp. Path. Pharmak. 194o,, 195 , 71-7 ¹ I-, modified by Halpern, Arch, int, Pharmacodyn. 1942, 68,3J59-4o8) . ■

Compounds A and E were administered intravenously or administered intraduodinally and their effect (strength and healing) on the tone of the bronchi or also by intravenous injection of acetylcholine (50 mg / kg) evoked bronchospasm examined.

a) Activity of compounds A and E, on intravenous Administered away

ev) at a dose of 1 mg / kg

After a few minutes there may be a slight decrease in bronchial tone and a partial and often total Inhibition of acetylcholine bronchospasm noted the minimum duration of which is one hour and often between 2 and 3 hours. On average the duration of the action of compound A is 1.6 times greater than that of compound E.

(i, at a dose of 2.5 mg / kg. Almost immediately after the injection, there is a sharp decrease in

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me of bronchial tone and a very strong inhibition, often total inhibition of acetylcholine bronchospasm was found. The effect both substances is very permanent and always exceeds 180 minutes. On average, the duration of action is connection A 1.5 times as long as that of connection E.

b) Activity of compounds A and E on intraduodinal Way administered at a dose of 5 mg / kg.

The two compounds are available from a dose of 5 mg / kg very effective, with a decrease in bronchial tone as well as a strong and within 20 minutes permanent inhibition of acetylcholine bronchospasm is provoked, proving that Compound A is rapidly absorbed through the alimentary canal as is Compound E. It will be here again found that the duration of action of A is greater than that of E.

2. The lack of an irritant effect of the compound according to the invention on the central nervous system.

a) lack of antagonism to hexobarbital,

evoked sleep. >

One uses a set of 10 male Swiss-;

Mice, one sentence serving as a standard (temoin). '

and the others are treated.

All animals are injected intraperitoneally 100 mg / kg hexobarbital. The animals of the standard set receive no further treatment, the animals of the

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the action set received in an intraperitoneal way 30 minutes before the Hexabarbitalinjekbioft variable Doses of Compound E or Compound A. Compare the mean sleep duration of the treatment set with-the average length of sleep of the standard rate. The results are shown below.

Doses (mg / kg)

Decrease {% ") in the duration of sleep induced by Hexpbarbital

Connection E.

43 46 52

Connection A

3 0

b) Effect on the spontaneous activity of the mouse.

3 sets of 6 Swiss mice are used in each case. 1 standard set, 2 per os treated sets, the first with compound E (40mg / kg) and the second treated with compound A (40 mg / kg). Each animal is placed in an action measuring cage with a photoelectric Cell (designer Apelab, Rue des Ecoles, Bagneux) is kept isolated and the amount of movements made is increased from hour to hour during the administration of compounds A and E (treatment sets) or distilled water (standard set) following hours registered.

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The results are as follows!

Since the beginning -
of the experiment
elapsed
Time (in h) Number of movements accumulated Sentences Sentence A 1
2
3
4th
5
6th
7th
8th Standard rate 150
400
660
900
1150
1490
l64o
1990 190
250
290
375
525
650
850
1010 345
480
570
675
750
800
820
910

Accordingly, in contrast to ephedrine, the compound according to the invention does not exert any noteworthy stimulatory effects Effect on the central nervous system.

3. Lack of the effect of the compound according to the invention on the central temperature.

Use 3 sets of 5 rats each with their rectal temperatures is measured for 6 hours. At time 0, one of the two sets (treatment sets) receives 40 mg / kg of compound A and the other 40 mg / kg of compound E.

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Time from the start of the experiment (in h)

Change in the "average temperature of the salt (in C) relative to the average Starting temperature

Standard salt

Salt E.

Salt A.

-0.15

-0.34 -0.41 -0.41 -0.24

-0.33
+0.04

+0> 15
+0.15
+0.50 (*)
+0.50 (*)

-0.15.

-0.30

-0.07

-O.13

-0.17 £ **)

-0.17

(*) This value differs significantly from the corresponding value for the Standard salt measured value.

(**) This value differs significantly from the corresponding value for the Salt E measured value.

Accordingly, the connection according to the invention changes, In contrast to ephedrine, the rectal temperature does not noticeably change.

4. Cardiovascular effects.

The comparative tests of a chlorinated dog each Compounds A and E injected intravenously show:

a) Effect on average arterial pressure.

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The maximum hypertension after injection of A is on average JX) C mmHg and for E 75 mmHg.

b) Inotropic effect.

The increase in the contraction force of the heart, measured in arbitrary units, amounts to when connected A 3 and for connection E 10.

c) Right (heart) ventricular pressure. The increase in this pressure is 12 mmHg for A and 37 mmHg for E. The connection A therefore differs from compound E in the cardiovascular effect achieved, making it a therapeutic one Advantage is given.

5. Toxicity.

a) According to Litchfield and Wilcoxon (The Journal of Pharmacology and Experimental Therapeutics, 19 ^ 9. »9.6, 2, 99-113), the DL 50 values of compounds A and E, which the isolated Swiss mouse verabr be calibrated.

Intravenous administration,

DL 50 of A 211 (19 ^ -230) mg / kg

DL 50 by E .. ^ 108 (103 -11 ² O mg / kg

oral administration

DL 50 of A 1310 (9 ^ 5-1820) mg / kg

DL 50 from E 900 (670-1200) mg / kg

b) One determines the effect of grouping the animals 209884/1410 -? -

on the toxicity of compounds A and E administered orally to the Swiss mouse grouped in sets of 10 will. Under these conditions, the DL 50 of compounds A and E, determined according to Lit-chfield and WiI-coxon, the following:

DL 50 of A 800. (610-1050) mg / kg

DL 50 from E 320 (200-510) mg / kg

The group toxicity phenomenon is much more important in E than in A- / which is additional evidence for the represents very weak activity of compound A on the central nervous system.

In summary, the compound of the invention with respect to the Ephsdrins, from which it is derived, gekennzeichne t \

Due to a significantly lower toxicity (both with intravenous and oral administration) ,

Through a longer lasting bronchodilator effect;

By the absence or the, strong · diminution of certain s disruptive secondary effects, wit, for example, the central stimulation, the general ^ terial hypertension, the hypertension of the right ventricle and the positive inotropic effect, which often occurs in patients who Treated with ephedrine were considered undesirable have been.

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The therapeutic applications of the compound of the invention mainly include their use in the treatment of various Atemschwierigkei.ten to ₇ in connexion with an increase in Bronchientonus:

Pure asthma, bronchial asthma
chronic bronchitis, etc.

For this purpose, the compound according to the invention is par ntal, administered endonasally, orally, pulmonarily and rectally.

The invention accordingly includes all pharmaceutical compositions which use the compound (i) as an active ingredient in conjunction with any solvent suitable for administration by the routes mentioned above are. These compositions can also contain other medicaments with which the compound (I) is pharmaceutical and is therapeutically acceptable.

In the case of parenteral, subcutaneous or intramuscular administration, injectable aqueous solutions are used, containing 0.001 to 0.05 g of a salt of the compound (I) as a unit dose.

In the case of endonasal administration, use is made of aqueous solutions of salts of the compound (i) or of oily solutions of the compound (i) in the base state, the 0.2 to 2 (p / V) included as an active ingredient.

All solid forms (tablets, coated tablets, capsules, etc.) or liquids are used for oral administration (Droplets, elixirs, suspensions, etc.) which contain the active ingredient (i) or its salts, the unit dose being between 0.005 and 0.05 g and the daily

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Dose can vary between 0.01 and 0.20 g.

When administered by pulmonary route, use is made of aqueous solutions of salts of the compound (i), which 0.2 to 2 to 100 (p / V) as an active ingredient. When administered by the rectal route, suppositories are used, which contain 0.01 to 0.05 g of active ingredient, which is fed 2 to J times a day.

The following examples illustrate the present invention.

Example 1; (N-methyl-N-fo-cyano-äthyl ^ -amino ^ -pheryyV l-pronanol-l turning to the left . 11 g (0.208 mol / g ) Acrylonitrile and 16.5 g (0.1 mol / g) levorotatory N-methylamino-2-phenyl-1-propanol-1 in. The mixture is kept for 4 days with stirring at room temperature, then it is brought to reflux temperature for 9 hours the excess acrylonitrile in a vacuum on a water bath and keep the viscous residue for a few days at room temperature, which gradually crystallizes, melting point 40-45 ° C. (yield 98 %).

Example 2: levorotatory (N-methyl-N-fr-.cyano-ethyl ') -amino-2-phenyl-1-propanol-1-hydrochloride.

21.4 g (0.098 mol / g) of (N-methyl-N-φ-cyano-ethyl) -amino-2-phenyl-1-propanol-1 are dissolved counterclockwise in 200 ml of a mixture of equal parts of ethyl alcohol and ether and passes a stream of hydrogen chloride into this solution until the precipitation is complete. You suck that

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Hydrochloride formed from, and washes with the mixture .aus equal parts of ethyl alcohol and ether afterwards and then with ether alone afterwards. The product obtained is on dried in the air and recrystallized from 200 ml of methyl alcohol.

17.5 g (yield 70 fo) of levorotatory (N-methyl-N- (S -cyano-ethyl) -amino-2-phenyl-1-propanol hydrochloride are thus obtained, in the form of a white crystalline water-soluble compound which at 199 to 201 ⁰ C melts.

Analysis: C ₁₅ H ₁₉ CIN ₂ O (254.5)

g C 61.3 _O H 7- ^ 7 N 11.00 Cl 13-95 0 6.29

Tr. <Fo ■ 61.24 7.53 11.10 13.83 ■ 6.47 61.46 7.70 11.27 13.91

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Claims (8)

(N-methyl-N- (i -cyano-ethyl) -amino-2-phenyl-1-prop'anol-1 of formula (I) -CH ₂ -CN (I) in the form of its racemate and its two enantiomorphs Forms, as well as the addition salts that it forms with all mineral or organic pharmaceutically acceptable acids, among which certain, for example hydrochloric acid, sulfuric acid, tartaric acid, citric acid etc. do not have their own pharmaceutical Have effects while others develop an effect additional to that of the compound (I), such as it is the case with theophylline and 7-ethyl-theophyllinic acid, for example the case is. 2. Process for the preparation of the compound of formula (I) marked by the fact that N-methylamino-2-phenyl-1-propanol-l reacted with an excess of acrylonitrile, part of the latter serving as a solvent. 3. The method according to claim 2, characterized in that that the reaction is effected at room temperature. - "14 - 2O9884 / U10 4. The method according to claim 2, characterized in that that the reaction is effected at the reflux temperature of the reaction medium. 5. Process for the preparation of the addition salts according to claim 1, characterized in that all known processes are used for the production of these salts. 6. Process for the preparation of the enantiomorphs (i) according to claim 1, characterized in that in the separation of the racemate (I) for the synthesis of the optical Antipodes of N-methylamino-2-phenyl-1-propanol-1 the classical methods are used. 7. Use of the compounds according to the invention as bronchodilators and antidyspnotic agents, particularly for treating various breathing difficulties. 8. Use of the compound (i) as an active ingredient of all pharmaceuticals Compositions that also contain all solvents that are in pharmaceutical form with regard to their Administration on parenteral, endonasal, oral, pulmonary or rectal route are suitable, wherein the compositions mentioned can also contain other drugs with which the compound (i) is pharmaceutically and therapeutically acceptable. 2098 84 / Ul ü