NO125590B - - Google Patents

Description

Procedure for manufacturing new ones

levorotatory indole derivs.

The present invention relates to a process for the production of previously not isolated levorotatory indole derivatives of formula 1>

wherein R 1 and R 2 are each hydrogen or methyl, and their salts with inorganic or organic acids. A possible methyl group on the indole skeleton can be in the 2- or 3-position. The peculiarity of the method according to the invention is that hydroxy-indoles of formula II in which R.j has the above-mentioned meaning, in an alkaline environment and under the exclusion of oxygen, are reacted with left-rotating epichlorohydrin or epibromohydrin, the reaction products are heated with amines of formula III

in which R2 has the above meaning and R^ stands for hydrogen or benzyl, a possible occurring benzyl group is cleaved,

the obtained mixture of the levorotatory compounds of formula I and the racemic compounds of formula I are separated by fractional crystallization, whereby the poorly soluble in organic solvents racemic compounds of formula I precipitate out first, and the obtained levorotatory compounds with formula I is optionally transferred in its acid addition salts.

The preparation of the racemic compounds of formula I is known from Norwegian patent document no. 120.07<1>*.

As it would be of interest to produce (3-blockers such as

in their effect are superior to the known P-blockers and which have a better specific effect, an attempt was made to separate the racemates obtainable according to the aforementioned patent document.

Attempts in this direction to carry out separation by means of fractional crystallization of the salts failed, as the salts - as well as the bases - were so difficult to dissolve that they immediately precipitated when acids were added.

In an attempt to arrive at the levorotatory indole derivatives of formula I by reaction of an optically active halohydrin with an N-benzylamine, subsequent condensation of the thus obtained optically active reaction product with the corresponding 2f-hydroxyindole and subsequent cleavage of the benzyl group, complete racemization occurred.

It was now surprisingly established that no complete racemization occurred in the process according to the invention and that the racemate could very easily be separated from the levorotatory antipode. Here, the separation was carried out by fractional crystallization. It was found that the left-rotating antipodes in organic solvents such as cyclic or open-chain ethers (dioxane, tetrahydrofuran), lower alcohols (methanol, ethanol) and especially in aromatic hydrocarbons (benzene, toluene) are significantly more easily soluble (size factor of 10^ ) than the racemates. Yields of approximately yd% of the levorotatory compounds of formula I can thereby be easily obtained in addition to approximately 60% of the corresponding racemic compounds.

The invention is illustrated in more detail in the following:

As a hydroxyindole derivative of formula II, β-hydroxyindole, <1>+-hydroxy-2-methylindole or β-hydroxy-B-methylindole are used. The hydroxyindole of formula II is added in the form of an alkali metal or ammonium salt, preferably as a sodium salt. It is traded, e.g. in an equimolar solution of alkali hydroxide or ammonia in water, lower alkanols, dioxane/water etc., or in an organic solvent inert under the reaction conditions, such as e.g. benzene or toluene, with the equimolar amount of an alkali metal alcoholate, amide or hydride.

According to another embodiment, the alcoholic solution is evaporated

of an alkali metal salt of the hydroxyindole derivative of formula II to dryness and the residue is suspended in an organic solvent inert under the reaction conditions, e.g. dimethoxyethane.

To the solution or suspension of the hydroxyindole salt, 1-5 equivalents of left-handed epichlorohydrin or epibromohydrin are added and the mixture is stirred for a longer time, e.g. for 10-2^ hours at room temperature. The hydroxyindoles of formula II are extremely sensitive to oxidation in an alkaline environment, and therefore the previously described precautions are carried out with the exclusion of oxygen, e.g. under a nitrogen atmosphere.

The product obtained is isolated according to known methods, possibly purified and then heated for approx. 10-25 hours with an amine of formula III at 50-80°C. Addition of an acid-binding agent, e.g. an inorganic base, such as potassium carbonate, a tertiary organic base such as pyridine, triethylamine, etc., or also an excess of the amine component used, may be advantageous, but is not necessary. If a primary amine (formula III, R^=H) is used as the amine component, such as e.g. isopropylamine, then the reaction takes place - due to the low boiling point of this amine - in a higher boiling, under the reaction conditions inert organic solvent such as dioxane, benzene, toluene etc, and/or in a pressure vessel. If a secondary amine (formula III, R^=benzyl) is used as amine component, such as e.g. N-benzyl-isopropylamine, then the reaction can be carried out at normal pressure and without solvent. Preferably, however, work is also done in this case in an organic solvent that is inert under the reaction conditions, such as dioxane, benzene, toluene etc.

The subsequent cleavage of an occurring benzyl group is carried out, e.g. by hydration in the presence of a suitable catalyst, such as e.g. palladium, in methanol, ethanol, ethyl acetate or in another suitable organic solvent.

The present process does not lead exclusively to the levorotatory compounds of formula I, but also gives as by-product the corresponding racemic compounds. The latter, due to their less readability, can be separated from the left-rotating compounds - by crystallization from suitable solvents, such as benzene.

The levorotatory compounds of formula I constitute basic substances which are practically insoluble in water, but which in most organic solvents and in aqueous solutions of organic or inorganic acids are quite easily or easily soluble. With Keller's reagent (glacial vinegar containing ferric chloride and concentrated sulfuric acid) and Van Urk's reagent (p-dimethylamino-benzaldehyde and dilute sulfuric acid) they generally give characteristic tints. With inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid etc. or with organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, benzoic acid, methane-, ethane- or p-toluene-sulphonic acid, N-cyclohexylsulfamic acid etc. they give stable, most often water-insoluble salts.

The racemic compounds of formula I are previously known and constitute highly effective P-receptor blocking agents, which is why they can be used as pharmaceuticals. The isolation of the levorotatory compounds of formula I, on the other hand, has not previously been described.

They are distinguished by interesting pharmacodynamic properties in animal experiments and can therefore be used as pharmaceuticals. They show on spontaneously beating isolated guinea-pig atria an antagonistic effect on the frequency-increasing and contractility-increasing effect of adrenaline and are thus characterized as (3-receptor blocking agents. In this respect, they are superior to the corresponding racemic compounds. They are also distinguished by a particularly favorable relationship between β-blocking and negativinotropic action The previously unisolated left-turning compounds are suitable for the prophylaxis and therapy of coronary diseases, especially angina pectoris for the treatment of the hyperkinetic heart syndrome,

the muscular-hypertrophic subvalvular aortic stenosis, as well as the prophylaxis and therapy of heart rhythm disorders and tachycardic conditions. The average daily dose can amount to approx. 1-40 mg.

As pharmaceuticals, the new left-rotating compounds of formula I or their water-soluble, physiologically tolerable acid addition salts can be used alone or in corresponding pharmaceutical forms, such as tablets, dragees, suppositories, injection solutions, etc., administered enterally or parenterally. In addition to the usual inorganic or organic, pharmacologically indifferent excipients, such as milk sugar, starch, talc, stearic acid, water, alcohols, natural or hardened oils and waxes and the like, the preparations can also contain suitable preservatives, stabilizers or wetting agents, release agents, sooting agents -or colourings, aroma components etc

In the following examples to illustrate the invention,

are all temperature indications in degrees Celsius without correction.

Example 1; (-) -|+-(2-hy_droksv--3-hysop^

A solution of 6.5 g of sodium hydroxide in 150 ml of water is added under a nitrogen atmosphere and, under stirring, 21.6 g of M-hydroxyindole and then 15.0 g of (-)-epichlorohydrin. The mixture is then stirred for 1^f hours at room temperature, the reaction mixture is extracted four times with methylene chloride and the combined, dried over magnesium sulphate organic layers are evaporated under reduced pressure. The oily residue is taken up in 120 mm dioxane and 60 ml isopropylamine and heated for 20 hours at 80°C. It is evaporated to dryness under reduced pressure, shaken 3 times between ethyl acetate and 1 N of an aqueous tartaric acid solution and then 5 N caustic soda is added to the combined tartaric acid phases for an alkaline reaction. It is extracted 3 times with methylene chloride and the combined organic phases dried over magnesium sulphate are evaporated under reduced pressure. The residue is taken up in benzene, undissolved is filtered off, the filtrate is evaporated and the residue is crystallized three times from benzene. The obtained (_)_<L>(._(2-hydroxy-3-isopropylaminopropoxy)indole melts at 89-91°C, (oc)p°= -lf.2° (c = 5.3 in methanol) .

In an analogous way, the following compounds can also be produced:

(_)_L|__ (2;h^drox^-3;isoDroD^laminopr ^a^D = -3.8° from ^-hydroxy-2-methylindole, (-)-epichlorohydrin and isopropylamine. The hydrogen oxalate melts at 199 -202°C (from methanol). (a){<p>= -21° (a = 0.5 in methanol). izii^lI^-hv-droksv-^-isopr^ ^a^D 20= - ^.5° from <l>+-hydroxy-3-methylindole, (-)-epichlorohydrin and isopropylamine. <20 >-•+.1° from ^-hydroxyindole, (-)-epichlorohydrin and tert.butylamine. 20 - <1>+.9° from <i>+-hydroxy-2-methylindole, (-)-epichlorotjdrine and tert. butylamine. 20 ll2z!<+>"l<2>Z^ål2^§Zl3li<ert>i<but>^<l>a<m>inop<r>oDO ^a^D = -1+.3° from ^ --hydroxy-3-methylindole, (-)-epichlorohydrin and tert-butylamine.

Example 2: lilzltzl<2->h^droks^-3-isoDrop_^lami^

Proceed analogously to the method given in example 1, using (-)-epibromohydrin and not (-)-epichlorohydrin. The compound mentioned in the title is identical to the product produced according to example 1. Melting point 89-91°C (after 3 times crystallization from benzene). (a)^= -^.2° (c=5.3 in methanol).

Example 3; lililti (2-hydroxy^-3-isoprop^laminop

Analogously to the regulation stated in example 1, h-hydroxyindole is reacted in aqueous sodium hydroxide solution under a nitrogen atmosphere with (-)-epichlorohydrin and the reaction product is heated

with N-benzylisopropylamine in dioxane for 20 hours at 80°C.

15 grams of the product obtained is dissolved in 200 ml of methanol and hydrogenated in the presence of 100 grams of a palladium catalyst (5% on aluminum oxide) at room temperature until complete hydrogen absorption. The catalyst is filtered off, the filtrate is evaporated under reduced pressure to dryness and the residue is taken up in benzene. Undissolved is filtered off, the filtrate is evaporated and the residue is crystallized 3 times from benzene. The obtained (-)-lf-(2-hydroxy-3-isopropylamine-propoxy)indole is identical to the product prepared according to examples 1 and 2. Melting point 89-91°C (after 3 times crystallization from benzene). (a)j^= -^-.2°

(c - 5j3 in methanol).

Claims (1)

Process for the preparation of previously unisolated levorotatory indole derivatives of formula I in which R and R^ each mean hydrogen or methyl, and their acid addition salts, characterized in that hydroxyindoles of formula II in which R1 has the above meaning, in an alkaline environment and under the exclusion of oxygen is reacted with left-rotating epichlorohydrin or epibromohydrin, the reaction products are heated with amines of formula III in which R 2 has the above meaning and R 1 stands for hydrogen or benzyl, a possible occurring benzyl group is cleaved off, the resulting mixture of the levorotatory compounds of formula I and the racemic compounds of formula I is separated by fractional crystallization, whereby they in organic solution -means sparingly soluble racemic compounds of formula I precipitate out first, and the obtained levorotatory compounds of formula I are optionally transferred into their acid addition salts.