DE1518633A1 - Process for the preparation of pharmaceutically active derivatives of 2-aminoindane - Google Patents

Description

Chemical works Albert ,, Wiesbaden-Biebrioh, Albertstr. 10-14

P ate η ta η me I'd u ng

"Process for the preparation of pharmaceutically active Deri v capacitances of the 2-Amlnoindans" -

Addition to patent .. *, * ... (application C 33 848 IVb / 12 o)

Subject of the patent ...... (Application C 33 848 IVb / 12 o) is a process for the preparation of pharmaceutically active derivatives of 2-aminoindane. The connections are made by making certain 2-aminoindanes reacted with certain diarylalkyl halides or with Oxo-diarylalkyl compounds condensed and then be hydrogenated. The compounds can also be obtained by condensing 2-indanones with certain diarylalkylamines and subsequent hydrogenation, or else by reducing M-indanyl- (2) -diarylalkylcarboxamides.

It has now been found that the previously unknown Halogen-substituted N-diarylalkyl derivatives of 2-aminoindane the general structure

N-CH-A-CH

in which R _{1 to R 3 are} hydrogen, alkyl or alkoxy radicals and can be identical or different and in each case can also appear several times in the aryl radical with the same or different meanings, R ₄ and R _{6 are} hydrogen or one

9 098 U / Π 7Ϊ

-2-. Ί 518633

Denote alkyl radical and can be identical or different, R ₈ denotes hydrogen or methyl, R "and Rg denote hydrogen or a halogen and can appear several times with the same or different meanings, but at least one of the radicals R ₇ and Rg is a halogen atom and A 0 to J5 means methylene groups, especially in the form of their pharmacologically acceptable acid addition compounds, having a very good coronary effectiveness with a comparatively low peripheral vascular effect. In the radicals R _{1 to R 1,} the alkyl or alkoxy radicals should not have more than ^, preferably not more than 2, carbon atoms. In addition, the residues attached to a benzene nucleus should not contain more than h C atoms in total. Rather, a benzene nucleus should contain at most 2 identical or different halogen atoms.

Compounds of structure (i) can be used according to the invention manufacture in the following way:

1) They are halogenated according to the process of the main patent compounds prepared, preferably by the action of elemental halogen, especially chlorine or bromine. (Example l)

2) Amines of the general formula are condensed:

-NR / rH

6 ^H (ID

wherein R ₃ , R ^ and Rg have the meaning given above, optionally at elevated temperature, with oxo compounds of the general formula:

7 ·

OC-A-CH (III)

9 0 98U / 1173

in which R ₁ , R ₂ , R ^ »R ₇ * Rn and A have the meaning given above, and hydrogenated the reaction products, possibly after isolation of the same, with a suitable, not too strong hydrogenating agent, for example with an alkali borohydride. (Example 2)

The halogenation is carried out in a manner known per se at a relatively low temperature, generally between 0 and 25 ° C., preferably in the liquid phase and / or in the presence of halogen carriers such as iodine or FeCl ₃ . If appropriate, one can work in solvents and / or in the absence of halogen carriers. The condensation of the amine with the oxo compound is carried out at a temperature between the usual temperature and the boiling point of the solvent, usually at 70-150 ° C. Since the hydrogenation should take place under mild conditions to prevent halogenation, it is generally used at Temperatures below 50 * C made.

Suitable solvents for the halogenation are e.g. aliphatic carboxylic acids such as acetic acid and propionic acid and halogenated hydrocarbons such as chloroform and carbon tetrachloride; for the condensation z. B. aliphatic, cycloaliphatic or preferably aromatic hydrocarbons, such as benzene, toluene or the various xylenes, Ethers, especially of an aliphatic nature such as diethyl ether, diisopropyl ether, Tetrahydrofuran or dioxane, the various alcohols such as methanol, ethanol and especially the various Propanols and butanols, and halogenated hydrocarbons such as chloroform, carbon tetrachloride, trichlorethylene or Trichloroethane. In the hydrogenation, it is advantageous to use hydrocarbons, Ethers or alcohols, e.g. those mentioned, are used. '

Generally one works with the ordinary, but sometimes even with increased pressure. The yields are good. The raw yield is often 80-90 # of theory. The final yield

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BAD ORJGlNAL

depends of course on the placed on the product Purity requirements.

The acid addition compounds can be selected from a wide variety of acids, e.g. hydrochloric acid, hydrobromic acid, tartaric acid, Citric acid, malic acid, gluconic acid, adipic acid and lactic acid can be obtained.

Have the compounds prepared according to the invention have a very low toxicity and are excellent cardiovascular and cardiovascular effects. The very good one is particularly noticeable and specific coronary potency at relatively low peripheral effect.

Example 1 ·

2 g 2- L ^ -phenyl ~ 1- (4'-methoxyphenyl) -propylamine J-indane hydrochloride are dissolved in 50 ml of glacial acetic acid. For this purpose, a solution of 0.9 g is slowly added with vigorous stirring Bromine added dropwise to 5 ml of glacial acetic acid; then will still Stirred for a further 2 hours. Then the glacial acetic acid is under nitrogen distilled off as a protective gas in vacuo until the residue becomes cloudy. The remaining product is in Pour 10 ml of 30 # sodium hydroxide solution and the reaction product extracted with ether. The ether solution is made with potash dried and the hydrochloride of 2 [r-phenyl - ^ - O'-bromo-4 · -methoxyphenyl) -propyl-aminoJ-indane precipitated with essential hydrochloric acid. The salt is filtered off with suction and recrystallized from isopropanol. The product is thin-layer chromatography uniformly. It has a melting point of 165-169 * C.

Example 2 .

In this example, the previously unknown fl- (4 »-chlorophenyl) -hydrozlmtaldehyd used as starting material. He

.9098 U / 1 173

BAD ORIGINAL COPY

1578633

is not claimed here by condensation of p-Chlorbeiizhydrylchlorid with chloromercury acetaldehyde in dried benzene using anhydrous Tin tetrachloride produced as a condensing agent. It is an almost colorless one. Liquid with a boiling point of 158 - 168 * C at 0.2 mm pressure.

1 * 5 g of 2-aminoindane and 2.6 g of β- (4'-chlorophenyl) -hydrocinnamaldehyde are mixed; after a very short period of time warming occurs and, with separation of water, clouding occurs. The mixture is mixed with 25 ml of n-butanol and refluxed for 30 minutes. Then about 10 ml of n-butanol and the resulting water are distilled off. After cooling, 0.5 g of sodium borohydride is added to the mixture to reduce the Schiff's base formed and the mixture is left to stand overnight. The mixture is then treated with ethereal hydrochloric acid and the 2- [i-phenyl-Jf- (4'-chlorophenyl) -propylaminoj-indan 'by adding more ether is made to separate out as the hydrochloride. The compound can be recrystallized from isopropanol or from a lot of water. The product is uniform according to thin-layer chromatography. It melts at 199 - 200 * C.

The effect and toxicity of the according to Examples 1 and 2 Connections made are shown in the following table compared to that of a known preparation / the same amounts were always used.

substance LDc _n intravenous
pO
at the mouse Effect on the Langendorff
Hearts. Increase against
above the starting position 2- [I-phenyl- U (3 »-bromo-
h -me thoxyphe ny1) -propy1-
aminoJ-indan
(Example 1) 25-50 mg / kg 100 % 2- [l -phenyl- Ϊ- (4 '-ohlor-
phenyl) -pr.opylamino] -indan
(Example 2) 25-50 mg / kg 159 %

COPY BAD ORIGINAL

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N- [l »-Phenyl-iso-propyl] 1,1-diphenyl-propy1- (3) ami η

There were no differences in the measurement of the increase in flow in the isolated rabbit ear according to the Krawkow-Pissemski method. The nutrient fluid was used to tone the vessels
1- (m-Hydroxyphenyl) -2-amino-ethanol hydrochloride (θ, 5f / ml) was added.

It can be seen from the values that the compounds prepared according to the invention are only about half the toxicity with a considerably better or at least the same effect
like the comparator preparation. The therapeutic
The width is thus significantly increased.

BATH ORIGINAL 9098 U / 11 73 M.

Claims (1)

Sponsorship claims 1. Further training of the process for manufacturing pharmaceutical effective derivatives of 2-aminoindane according to patent ....... (application C 25 848 IVb / 12 o), thereby identified draws that compounds of the formula - N - CH- -A-CH (ι) where R to R, denote hydrogen, alkyl or alkoxy radicals and can be identical or different and in each case can also appear several times in the aryl radical with identical or different meanings, R ^ and R, - denote hydrogen or an alkyl radical and can be identical or different , Rg is hydrogen or methyl, R ₇ and Rg are hydrogen or a halogen and can occur several times with the same or different meanings, but at least one of the radicals R ₇ and Rg is a halogen atom and there are no more than 2 halogen atoms on a benzene nucleus , and A denotes 0 to 3 methylene groups, where in the radicals R ₁ to Re the alkyl or alkoxy radicals contain no more than 5 and the radicals attached to a benzene nucleus contain no more than U carbon atoms in total, by 1 «The compounds of the formula (I) given, in which R ₇ and Rg are hydrogen, obtained by the process of the main patent are halogenated in a manner known per se, vorzu possibly by the action of elemental halogen, or 2. Amines of the general formula -NR ₆ H BAD ORfGiNAi. 9 O 9 8 U / 1 1 7 3 in a manner known per se with oxo compounds of general formula OC - A - CH (in) R ₂ condensed and the reaction products hydrogenated, where in the formulas (II) and (III) the radicals R ₁ 'to Rg and A have the meaning given above. . 2. Compounds of the general formula (I) given in claim 1, wherein R-, to Ro and A are the given ' Have meaning. Dr.Klr / tk February 15, 1965 909814/117