NO791895L - ANALOGICAL PROCEDURE FOR PREPARATION OF PHARMACOLOGICAL ACTIVE CONTENT DERIVATIVES - Google Patents

Description

"Analogous process for the production of pharmacologically active indole derivatives"

This invention relates to the preparation of one of the possible diastereomers of 2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole-1-carboxaldehyde of formula I

and both enantiomers thereof, and the physiologically compatible salts with inorganic or organic acids. In the diastereomer produced, the 2-methyl group must be in the trans position to the 3-phenyl group. The new diastereomer with melting point 71-72°C is characterized by the following "'"H-NMR data:

1H-NMR (dg-DMSO, 90 MHz, TMS as internal standard):.

a) 400 K; δ = 8.63 (1H-s, CHO); 7.0-7.7 (9H-m, arom. H); 4.65 (1H-q, 2H, J = 6 Hz); 1.76-2.5 (3H-m, protons in l1 and 2'); 2.03 (6H-s, N(CH3)2); 1.38 (3H-d, 2-CH3, J = 6 Hz); 0.66 (3H-d, CH3in the side chain, J = 6 Hz) b) 300 K: 6 = 8.48 and 8.82 (each s, together. 1H) ; 7.6-8.05 (1H-m, aromatic. H); 7.0-7.5 (8H-m, aromatic. H); 4.52 and.

4.86 (each q, together 1H, J = 6 Hz); 1.7-2.75

(9H-m) ;■ 1.37 and 1.22 (each d, together 3H, J = 6 Hz);

0.5-0.8 (3H-m, possibly double doublet)

The connections are in possession of valuable

therapeutic properties, in particular they have a strong antitussive effect.

The diastereomer resp. the enantiomers thereof are prepared

by formylation of the corresponding diastereomer of 2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole of formula II

respectively of the enantiomers thereof, and then

a) by direct treatment with formic acid,

b) by the action of the mixed anhydride of acetic acid and formic acid,

c) by reaction with formic acid esters,

d) by reaction with formic acid using carbodiimides, e) by reaction with the formic acid imidazolide obtained from formic acid and carbonyldiimidazole,

f) when converting a compound of formula III

with melting point 102°C with formic acid under hydrogenating conditions.

The reaction of the compound of formula II with formic acid is carried out with or without an additional inert solvent,

e.g. benzene, toluene or chloroform, at temperatures between 50 and 150°C, preferably at 100°C.

The formylation using the mixed anhydride of acetic acid and formic acid can be carried out with or without a solvent. Inert, anhydrous solvents such as chloroform, benzene or dioxane can be used as possible solvents. The turnover is carried out at room temperature or at temperatures

up to 50°C, preferably at 25 to 30°C.

For formylation with formic acid esters can be used

such esters where the alcohol component contains up to 7 carbon atoms. One works at temperatures between 50 and 150°C, preferably approx. 120°C, and using an autoclave. An excess of ester also serves as a preferred solvent.

For formylation of the compound of formula II with formic acid in the presence of carbodiimides, the reaction components are reacted at -30 to +50°C, preferably at room temperature, in an inert solvent such as acetone, tetrahydrofuran or methylene chloride.

The reagent required for formylation with formic acid imidazolide is prepared in situ from formic acid and carbonyl-N,N<1->diimidazole using dry, inert solvents such as methylene chloride, dioxane or dimethylformamide. The reaction is carried out at -30 to +50°C, preferably at room temperature.

The reductive formylation of the compound of formula III can be carried out in formic acid solution using noble metal catalysts, such as e.g. palladium-charcoal, at a hydrogen pressure

of 1 to 50 bar and at a temperature of 20 to 50°C, preferably at 30°C. It has proven appropriate to heat the reaction mixture to boiling in connection with the hydrogenation.

The racemate of formula I and its enantiomers can

by methods known per se are transferred to their physiologically compatible salts with inorganic or organic acids, and suitable acids are e.g. hydrochloric acid, sulfuric acid, tartaric acid and lactic acid.

The starting compound of formula II is described in

German Publication No. 1,931,477, and the compound of formula III is described in German Publication No. 1,470,370.

The starting compound of formula II can be prepared from the compound of formula III by catalytic hydrogenation in 1N hydrochloric acid solution and using palladium-on-charcoal

as a catalyst. The thus obtained compound of formula II, which is then pyrmylated, melts at 122-124°C (ether) and has the following NMR spectrum:

^"H-NMR (CDC13 after replacement with D2O, 80 MHz, TMS as internal standard, room temperature): 6 = 6.7-7.7 (9H-m, aromatic. H) ; 3.67 (1H-q, 2 -H, J = 6.5 Hz);

2.08 (6H-s, N(CH 3 ) 2 ); 1.8-2.9 (3H-m, protons in 1' and 2');

1.26 (3H-d, 2-CH3, J ='6.5Hz); 0.66 (3H-d, CH3i side chain, J = 6.5 Hz).

The compound of formula III is produced by reaction

of the phenylhydrazone of 2-dimethylamino-4-phenyl-hexanone-5 with anhydrous zinc chloride in ethanol at temperatures up to the boiling point of the reaction mixture. The compound of formula III has the following NMR spectrum:

<1>H-NMR (CDC13, 80 MHz, TMS as internal standard):

6 = 7.65 (1H-d, 7-H, J = 7 Hz); 7.0-7.5 (8 H-m, arom. H);

2.12 (3H-s, 2-CH3) ; 2.06 ('6H-s; N(CH3)2); 1.7-2.9 (3H-m,. protons in 1' and 2 V) ; 0.64 (3H-d, CH3in the side chain,

J = 6.5 Hz).

The diastereomer of formula I and its enantiomers

and their salts with physiologically compatible acids possess valuable pharmacological properties. They work in animal experiments

particularly antitussive, and the racemate and (-)-enantiomer also broncholytic.

The cough experiments were carried out on awake male white rats. Cough induction was achieved by inhaling a 7.5% citric acid spray over 2 minutes. 10 animals per dose the test compound was administered orally as a tylose suspension. The assessment was made on the basis of the average percentage reduction in the number of coughing fits 30 minutes after administration in relation to the control values. (Further descriptions of the method: Engelhorn and Puschmann, Arzneim.-Forsch. 13, 474-480 (1963)). EDdC O_ is the dose which causes the number of coughing fits to be halved on average, and the calculation is made using the method according to Litchfield and Wilcoxon. For the racemate, an ED,-0 of 3.9 mg/kg was found. p.o.

By the method according to Domenjoz (Arch. Exp. Path.

Pharmacol. 2L5, 191 (1952)) the racemate and the (+)-enantiomer were examined for antitussive action in cats and showed in the dose range 0.5 to 2 mg/kg i.v. a clear antitussive effect.

The broncholytic effect was investigated in guinea pigs

by the method of Konzett and Rossler (Arch. exp. Path. Pharmakol. 195, 71 (1940)). The reduction of the acetylcholine-induced bronchial spasms by 50% was achieved by i.v. injection of 1.5 mg/kg of the racemate, and with the (-)-enantiomer only 1 mg/kg was sufficient to have the same effect.

For the determination of the acute toxicity was used

mice of both sexes with a body weight of 20 g. 10 animals per dose the compound was administered once. Calculation of DL^q,

the dose which led to the death of 50% of the animals during the observation period after administration was determined by the method according to Litchfield and Wilcoxon after an observation period of 14 days:

Racemate DL^0p.o.: 545 mg/kg

DL.-Q i.v.: 66 mg/kg

(+)-enantiomer DL^q p.o.:^500 mg/kg

(-)-enantiomer p.o.: % 5 60 mg/kg.

The following examples shall serve to further illustrate the invention.

Example 1

Rac. 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl-1H- indole- 1- carboxaldehyde

46.0 g of trans-2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole (m.p.: 122-124°C) are dissolved in 500 ml of toluene, and with vigorous stirring, 45 ml of 99% formic acid is added. With further vigorous stirring, the mixture is heated for 3 hours under reflux. A further 20 ml of formic acid is then added and boiled again for 2 hours under reflux cooling.

The volatile components are distilled off in a water jet vacuum, the oily residue is taken up in a little water and the formate is transferred to the free base with cold, 20% potassium carbonate solution. During cooling, further solid potassium carbonate is added and the product is shaken 3 times with 200 ml of methylene chloride each time. After drying the organic phase with sodium sulphate, the solution is filtered, evaporated and the oily residue taken up in 80 ml of 60°C hot hexane. After cooling the solution, the base, which is placed in a test tube for crystallization, is seeded with some crystals.

The whole thing is left to stand for 2 hours under ice cooling, the crystals are sucked off well and washed with a little ice-cold hexane.

Yield: 94% of the theoretical, m.p. 71-72°C.

Dissolve 46.0 g of the base in 100 ml of acetic acid ethyl ester-acetone (9:1) and add a solution of 13.5 g of methanesulfonic acid in 50 ml of the same mixture. The precipitated crystal porridge is suctioned off in a cold state, then the crystallisate is boiled out with it

acetic acid ethyl ester with vigorous stirring, suction off the crystals in a hot state and dry at 100°C in a vacuum.

Melting point: 169-171°C.

Similarly, the hydrochloride is prepared, m.p. 178-180°C.

Example 2

Rac. 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl- 1 H- indole- 1- carboxaldehyde

30.0 g of acetic anhydride and 18.0 g of formic acid (99%) are stirred for 3 hours at 50°C. After cooling, you put it

mixed anhydride to 4.0 g of trans-2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole (m.p.: 122-124°C) , stirring for 4 hours at room temperature, splitting the reaction solution with ice, making the solution alkaline with potassium carbonate and decanting the base obtained with ether. The separated ether phase is dried with potassium carbonate, filtered and the volatile components evaporated on a water bath. The. oily residues are dissolved in hexane and a few drops of ether and the base is allowed to crystallize while cooling. Yield: 4.0 g, m.p.: 71-72°C.

Example 3

Rac. 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl- 1H- indol- 1- carboxaldehyde,

Dissolve 8.0 g of dicyclohexylcarbodiimide in 100 ml of dry acetone, add 2 ml of formic acid (99%) and add a solution of 3.0 g of trans-2,3-dihydro-2-methyl-3-[2-(dimethylamino )-propyl]-3-phenyl-1H-indole (m.p. 122-124°C) in 20 ml of dry acetone. The well-stirred solution is allowed to stand for 4 hours at room temperature. Dicyclohexylurea formed is filtered off and the acetone filtrate is evaporated. The residue is distributed between cold, 20% potassium carbonate solution and ether, the separated ether layer is filtered after drying with anhydrous sodium sulfate and evaporated. The oily residue is dissolved

in 5 ml of hexane and add a few drops of ether. The precipitate obtained after ice-cooling is suctioned off and washed with cold hexane. Yield: 2.1 g, m.p. 71-72°C.

Example 4

Rac. 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl-1H- indole- 1- carboxaldehyde

Dissolve 5.0 g of 2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole (m.p.: 122-124°C) in 100 ml ethyl formic acid ester and heated in a pressure vessel for 12 hours to 120°C. After cooling, the reaction mixture is transferred to a distillation flask and the volatile components are distilled off in a water jet vacuum. The remaining oil is distributed between cold, saturated potassium carbonate solution and ether. The ether layer is separated, dried with sodium sulphate, filtered and the ether evaporated. The residue is taken up in 10 ml of hexane to which 5 drops of ether have been added.

After ice cooling, the base is precipitated. Yield: 4.5 g, m.p. 71-72°C. The resulting methanesulfonate has a melting point of 169-171°C.

The same compound with m.p. 71-72°C is obtained with the same yield by using formic acid methyl ester, formic acid n-propyl ester, formic acid n-butyl ester, formic acid n-amyl ester and formic acid benzyl ester instead of formic ethyl ester.

Example 5

Rac. 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl-1H- indo1- 1- carboxaldehyde

5.0 g of 2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-3H-indole (compound of formula III with m.p. 102°C) is dissolved in 80 ml of formic acid (99% ig) and hydrogenates in the presence of 1.0 g of 10% palladium-charcoal catalyst at 35°C and 5 bar hydrogen pressure. After complete hydrogen absorption, the catalyst is filtered off and the filtrate is heated for 3 hours until boiling. The solution is then evaporated, the residue is dissolved in water, potassium carbonate is added to the solution and the base is titrated. This is isolated as described in example 4.

Yield: 2.5 g, m.p. 71-72°C.

Example 6

Rac. 2,. 3- dihydro- 2- methyl 1- 3- [ 2- (dimethylamino) - propyl] - 3- phenyl-1H- indole- 1- corboxaldehyde

Dissolve 2.0 g of carbonyldiimidazole in 40 ml of anhydrous methylene chloride and add 1.0 g of 99% formic acid in 5 ml of methylene chloride. The reaction mixture is allowed to stand for 1 hour at room temperature, then 2.8 g of 2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole, dissolved in 10 ml of methylene chloride, and let it all stand for 24 hours at room temperature. The solution is then evaporated, the residue is distributed between cold potassium carbonate solution and ether and the desired base is isolated as described in example 4.

Yield: 1.5 g, m.p. 71-72°C.

Oak sample 7

(+)- 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl- 1H- indole- 1- boxaldehyde

The procedure is as described in example 1, with the difference that the starting material is (+)-2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole ( oily base, described in German official publication 1,931,477, example 2b) instead of the racemate.

The optically active base formed is transferred - to the methanesulfonate which has a melting point of 178-180°C.

[ct]^ +<9>6° (c = 1.1 dm, pure ethanol) .

Example 8

(-)- 2, 3- dihydro- 2- methyl- 3-[ 2-( dimethylamino)- propyl]- 3- phenyl- 1H- indole- 1- corboxaldehyde

Produced analogously to example 1, except that

one uses (-)-2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole (oily base, described in German official publication 1,931,477, example 2c) as starting material instead of the racemate. The methanesulfonate has a melting point of 178-180°C.

[α]^° = -97.4° (c = 1.1 dm, pure ethanol).

Claims (6)

Analogous process for the preparation of therapeutically active racemic 2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]- 3-phenyl-1H-indole-1-carboxaldehyde of formula I with melting point 71-72°C, characterized by the following <1> H-NMR data: (d6,-DMSO, 90 MHz, TMS as internal standard): a) 400 K: 6 = 8.63 (1H-s, CHO); 7.0-7.7 (9H-m, aromatic. H) ; 4.65 (1H-q, 2-H, J = 6 Hz); 1.76-2.5 (3H-m, protons 11" and 2'); 2.03 (6H-s, N(CH3 )2 ); 1.38 (3H-d, 2-CH3 , J = 6 Hz); 0.66 (3H-d, CH3 in the side chain, J = 6 Hz) b) 300 K: 6 = 8.4.8 and 8.82 (each s, together 1H); 7.6-8.05 (lH-m, aromatic. H); 7.0-7.5 (8H-m, aromatic. H) ; 4.52 and 4.86 (each q, together 1H, J = 6 Hz); 1.7-2.75 (9H-m) ; 1.37 and 1.22 (each d, together 3H, J = 6.Hz); 0.5-0.8 (3H-m, possibly doublet) and its enantiomers and the physiologically compatible salts with inorganic or organic acids, characterized by that a) the corresponding 2,3-dihydro-2-methyl-3-[2-(dimethylamino)-propyl]-3-phenyl-1H-indole of formula II is formylated, orb) the 3H-indole forbyridation with formula III is reductively formylated with hydrogen and formic acid in the presence of a noble metal catalyst, and optionally the compound thus obtained is transferred to a physiologically compatible salt with inorganic or organic acids.