DE2137275A1 - N- (2,3-DIPHENYL-PROPYL-1) -CYCLOIMINE - Google Patents

Description

The invention relates to new N- (2,3-diphenyl-propyl-1) -cycloimines with valuable pharmakologi see properties and their manufacture.

The new. Compounds correspond to formula I.

- CH - CH "- N

in which X stands for 0, NH, NCH, and m and η each 1, 2 or 3 together but at least 4, ρ mean zero or 1, m and η at ρ is 1 but both are 2, and the aryl radicals and the cycloimine can carry further substituents.

The Belgian patent 579 542 describes derivatives of 2,3-diphenylpropylamine-1, obtainable by condensation of substituted benzaldehydes with substituted phenylacetic acids. The compounds are said to have bacteriostatic, bacteriocidal, fungi statisehe and fungicidal properties. In the Belgian patent 6IO 231 and in the archive of Pharmazie 295 (1962), No. 3, pages 196-205, 2,3-Diphenylpropy1-1-amines which are monosubstituted on the nitrogen and which are produced by reacting 2,3-Di ~ phenylpropylamine can be obtained with ketones. These amines have therapeutic properties that affect blood circulation and coronary arteries in particular. French patent 1,426,908 describes N- (bis-ß-hydroxyethyl) -2,3 -dipheriylpropylamine "1 with antibacterial properties" J. Knabe, H. Roloff and UR Shuka (Archiv für Pharmazie £ 9 <3 (1965 ), No. ₀ 12, pages 879-885) describe the reaction of substituted 2 _S 3-dipnenylpropylamines with acyl halides and the conversion of the acid amides thus obtained

102/71 20 9886/127 3 bath ORIGINAL

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to tetrahydroisoquinolines, about therapeutic properties no details are given of these connections. U.S. Patent 3,527,764 discloses 2-phenyl-3- (l-aza-spiro- (4,5) -dec-l-yl) -propiophenones described with transquilizer and anti-seizure effects.

It has now been found that the cycloimines of the formula I have particularly valuable therapeutic properties. They have an antihypertensive effect, Coronary artery enlargement and also anti-inflammatory.

Substituted compounds of the formula I can be converted to P the formula II

- ck - CH

ύ ζ

II

reproduce, in the Z the Heterocycius to a pyrrolidine, Piperidine, hexamethyleneimine, octahydroindole, decahydroquinoline, 2-aza-J3,2, lj -bicyclooctane, morpholine, piperazine or N-methylpiperazine closes.

As this list shows, the cycloimine residue can also be part of a cyclic system.

The cycloimine radical can be substituted by alkyl or alkoxyalkyl, preferably with 1 to a total of 4 carbon atoms. All compounds with the pyrrolidine, piperidine,

Γ "'" 1

Hexamethyleneimine and 2-aza [3,2, II-fcicyclooctane radical and especially with asymmetrically substituted monocyclic Iminr-est-, such as 2-methyl-piperidine, 3-methyl-piperidine and 3,3-dimethyl-rolidine.

12 The phenyl radicals in formula II can have sub-substituents H and R carry, such as alkyl groups, alkoxy groups, halogen atoms, nitro,

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Hydroxyl, carboxy, carboxyalkyl groups. From the substituents lower alkyl and alkoxy radicals are preferred. Both phenyl radicals can be used. substituted in the same position with the same radicals be, but more favorable pharmacological effects are achieved, when both phenyl radicals are substituted differently.

The new compounds are generally applied as salts. Hydrohalic acids are primarily suitable for the production of salts, such as hydrogen chloride, hydrogen bromide and hydrogen iodide, also sulfuric acid and phosphoric acid, except inorganic ones Acids also include organic acids such as oxalic acid, tartaric acid, benzoic acid, and maleic acid. The connections can also be made in transfer quaternary ammonium salts.

The cycloimines mentioned cause a long-term increase in both peroral and intravenous administration Blood pressure, also have a stimulating effect on the central nervous system and are also capable of those caused by tetrabenazine To remove eyelid paralysis in mice. It should be particularly emphasized that these compounds - when administered orally and intraperitoneally are not very toxic.

The blood pressure-increasing effect was demonstrated in the usual way on the rat anesthetized with urethane. The blood pressure was measured using statham elements from the carotid artery. The test substances were injected intravenously via a cannula tied into the jugular vein. The increase in the The blood pressure after administration of the test substance was measured in mm kg measured, the duration of action is given in minutes. In general the experiments were terminated 30 minutes after administration of the test substance.

The following table shows the hypertensive effect of some substances in this class of compounds.

- OK _n - N

² "\" ₂

R-

■ - J * -

203886/1273

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R ¹ R ² Toxicity
^F - ° 'mg / kg Toxicity
^{1 # p} 'mg / kg > Maximum increase in blood pressure
in mm hg according to i..ν. In j.
mg / kg 1 0.25 Duration of action
in minutes 5 24 -Ch ₂ -CH ₂ -CH ₂ -Ch ₂ - > 200 150 12th > 30 -CK ₂ -CH ₂ -CH ₂ -Ch ₂ -Ch ₂ - > 20ü I50 18th 16 -Cn ₂ - Ch ₂ -CH ^ - Ch ₂ - Ch "-Cn" - > 200 12th > 30 30th 14th 24 12th 28 26th 12th

.he

tsi

ro

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The new compounds are expediently via the corresponding 2,3-Diphenylpropanals produced. The 2,3-diphenyl-propanale are obtained by hydroformylation of the corresponding stilbenes with the aid of rhodium catalysts. the The cycloimines are prepared in a manner known per se using the aminating hydrogenation methods. As such synthetic methods can convert the enamines and then hydrogenate them using suitable catalysts, such as Raney nickel or cobalt, palladium-silver catalysts, for example, can also be used. Also the hydrogenation of the imine-aldehyde mixture leads to the formation of the imines substituted on the nitrogen. The so-called Leuckhardt-Wallach synthesis can be used as a further synthesis method be applied. You can also use a 2,3-diphenylpropyl-1 derivative, e.g. the bromide alkylate the cycloimine. Man can also be used in a connection

- Ν

in which X 'are radicals suitable for O or NH ring closure, the Close ring (X = O or NH) or optionally X β Nil methylie-

In the following examples, parts by weight and parts by volume are in the ratio of grams to milliliters.

In a Schutteiautoklaven with a content of 220 parts by volume of 53 parts of 2,3-Diphenylpropanal, MO, parts of piperidine, 5 parts are filled Rtney nickel as a catalyst and 50 parts of methanol. The hydrogenation is carried out at 80 ° C. under a hydrogen pressure of 50 atmospheres. 50 atmospheres of hydrogen are injected in the course of 10 hours. In the fractionation of the autoclave product, ^ 5 parts of the

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Cycloimines transitioning at 185 ~ 1 ^ 8 C / 5 "Torr. By neutralizing this amine fraction with 50 parts of 20% strength Hydrochloric acid and subsequent clarification of the salt solution by boiling with animal charcoal, 18 parts of hydrochloride with a melting point of 2O3 ° C. are obtained.

Analysis: C ₂₀ H ₂₆ NCl MW = 215.5

"C h N Cl

cal. 76.2 % 8.3 % 4.4 % 11.2 %

found 75.8 % 8.3 % 4.6 % 11.4 %

Example 2

2,3-Diphenyl-1- (N-hexamethyleneimino) -propane:

53 parts of 2,3-diphen'ylpropanal, 40 parts of hexamethyleneimine and 50 parts of cyclohexane are in a 250 ml flask fitted with a Azeotropic distillation attachment (with recycling of the solvent) is equipped, 8 hours removed from the system. There are 5 parts Get water. The resulting enamine is purified by fractional distillation at a pressure of 5 Torr » 34 parts that pass between I98 - 203 C are won.

The hydrogenation of the enamine is reacted with Raney nickel in methanolic solution is performed (8O ⁰ C, at 50, 12 h). The cycloimine is purified by fractionation at 5 torr. There are 24 parts in the

* ο

Skip the boiling range I78 - I90. The transfer to the

Hydrobromide provides a salt which can be recrystallized from ethanol-water (1: 1). Mp 235 ° C

Analysis: C ₃₁ Ii ₂₈ NBr MW = 374

C L N Br

cal. 67.6 % 7.4 % 3.8 % 21.4 %

found 68.0 % 7.4 % 3.7 % 21.2 %

Example 3

2,3-Diphenyl-1- (N-3-methyl-hexamethyleneimirio) -propane:

52 parts of 2,3-Diphenylpropanal together with} ü parts of 3-methyl hexamethyleneimine! And 69 parts of formic acid (98% 'iQ) 8 slur "

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heated to reflux. The excess formic acid is then drawn off at a pressure of 20 torr. 78 parts of a dark red-brown residue remain. This is refluxed for one hour together with 12 parts of 25% sodium hydroxide solution. After cooling, the reaction mixture separates into an aqueous and an organic phase. For better separation, 50 parts of toluene are added. After the toluene has been stripped off, the organic phase is fractionated at 0.5 torr. The amine passes over at 18.5-187 ° C. The hyaroiodide melts at 176 ⁰ C.

The substituted cycloimines listed in the table below can be obtained by the synthesis methods explained above.

R ¹ R ²

■ (Ch ₂ ) ₂ -N- (CH ₃ ) - (CH ₂ ) ₂ · (CH ") - CH- (CH,) - (CH"), "

-Ch (CH ₃ ) - - (Ch ₂ ) ₂ -CH (Cli ₃ ) - (CH ₂ ).

Free base
Kp / mmHg salt
Fp ο ς 179 ° 171-177 ° / 5, E. HBr = 217 ° 198-2OO ° / 5, E. 2HBr = 210 ° 137-1M3 ° / E, 5 HBr = 175-183 ° / 5, E. 163 ° 188-191 ° / 5, o HBr = 160 ° lil4-15O ° / O, 5 HBr =

209086/1273 BATH ORIGINAL

Claims (4)

Patent claims
Process for the preparation of compounds of the formula in which X stands for O, NH, NCH, and m and η each 1, 2 or 3, but together at least 4, ρ is zero or 1, m and η when ρ is 1 but both are 2, and the aryl radicals and that Cycloimine can carry further substituents, characterized in that a 2,3-diphenylpropanal is condensed with a corresponding cycloimine and hydrogenated at the same time or subsequently, or the corresponding cycloimine with a 2,3-diphenylpropyl (I) compound is added known methods alkylated or that one in the compound —Χ » - CH ₂ '- üf , ^ ^CH 2'n X ¹ radicals suitable for inclusion in the ring, according to methods known per se, closes the ring or, if appropriate, methylates this when X = Nii. 2. N- (2,3-Diphenyl-propyl-1) -cycloimines of the formula -CK - CK ₂ - N in which X stands for 0, NH, NCH, and m and η each 1, 2 or 3, but together at least 4, ρ means zero or 1, m and η when ρ is 1, however, both are 2, and the aryl radicals and the oycloimine carry further substituents, and their pharmacologically useful salts. - 9 203886/1273 BATH ORIGINAL - 9 - O.Z. 27 6l8 3, compounds of the formula of claim 2, in which m and η together 4, 5 or 6 and ρ is zero « 4. Compounds of the formula of claim 2, in which X is NH or NCH, and ρ is 1. Badische Anilin- & Soda-Fabrik AG 20S8 8G / 1273