NO842700L - PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE NAFTYRIDINES - Google Patents

Description

The present invention relates to an analog method for the production of therapeutically active hexahydro-indolo-naphthyridines in the form of racemates or enantiomers, with formula (I)

in which

Z represents one oxygen atom or two hydrogen atoms,

or R_ or R-. or R^ represents the methyl radical while the others are hydrogen atoms,

as well as their pharmaceutically acceptable acid addition salts, and the invention is characterized by either reacting a tryptamine of formula (II)

wherein R 1 and R 2 have the above meaning, with a diacid of formula (III)

wherein R_ and R^ have the above meaning, in aqueous hydrochloric acid environment to obtain a compound (I) in which Z represents an oxygen atom and, if desired, this compound is reduced to obtain a compound (I) in which Z represents two hydrogen -atoms, or

that a tryptamine of formula (II)

in which R^ and R2 have the above meaning and in which the Nf^ group is optionally benzylated, with an acid chloride of formula (IV)

in which R, and R^ have the above meaning, for

obtaining a compound of formula (V)

wherein R 1 , R 2 , R 2 and R 2 have the above-mentioned meaning, which is subjected to cyclization to the compound (I) in which Z represents an oxygen atom and, if desired, this compound is reduced to obtain the compound (I) in which Z represents two hydrogen atoms and the benzyl group in the 3-position are removed.

These features of the invention appear in the patent claim.

The compounds that can be prepared by the invention have therapeutic applications.

The preferred compounds are those in which Z represents two hydrogen atoms.

The procedure is illustrated using the reaction scheme listed below.

Tryptamine (II) is reacted with 2-oxo-pentanoic acid (III) in an aqueous hydrochloric acid environment to obtain a compound (I) in which Z is 0. When this is reduced, e.g. by means of AlCl^ and LiAlH^ a compound (I) is obtained in which Z represents two hydrogen atoms.

The tryptamine (II) is reacted with the 4-chloro-4-oxo-butanoic acid ethyl ester (IV) in the presence of pyridine, after which the double cyclization of the compound (V) is carried out first with the aid of POCl3 followed by the addition of KBH^/ AcOH and finally by adding 4N hydrochloric acid. A compound (I) is obtained in which Z is 0. This can be reduced, e.g. using AlC13 and LiAlH^ to obtain a compound (I) in which Z represents two hydrogen atoms.

Instead of the primary tryptamine of formula (II), tryptamine protected with a benzyl group (-NH-Cr^-CgHj- instead of -NH2) can be used. This benzyl group can be removed from the 3-position at the end of the process, e.g. by means of catalytic hydrogenation.

The following examples illustrate the invention.

Analyzes and spectra IR and RNM confirm the structure of the compounds.

EXAMPLE 1 2,2-Dimethyl-1,2,3,3a,4,5-6H-hexahydro-indolo-[3,2,1-de][naphthyridin-1,5]-6-one and its hydrochloride. 1. N-[2-(3-1H-indolyl)-1,1-dimethyl-ethyl]-4-amino-4- oxo-butanoic acid ethyl ester. 27.2 ml of 4-chloro-4-oxo-butanoic acid ethyl ester and 50 ml of CP^C^ are filled into a flask. Stir and add 30 g of α,α-dimethyltryptamine in solution in 500 ml of CH2C12 and 13.35 ml of pyridine over the course of 5 minutes. Stir at normal temperature for 1 hour and add 150 ml IN hydrochloric acid and stir. The organic phase is separated and washed with 2 x 150 ml IN hydrochloric acid. The organic phase is dried after which the solvent is driven off. An oil is obtained which is chromatographed on silica. After elution with a CH2Cl2/acetone (8:2) mixture, 4^[2-(3-1H-indolyl)-1,1-dimethyl-ethyl]-amino-4-oxo-butanoic acid ethyl ester is obtained, which is used■directly in the following step. 2. 2,2-dimethyl-1,2,3,3a,4,4,5-6H-hexahydro-indolo- [3, 2, 1-de] [naphthyridin-1,5]-6-one and its hydrochloride.

28 g of the compound obtained under section 1 are introduced into a flask and 100 ml of CH^CN are added. 6.46 ml of POCl3 are added and heated at the reflux temperature for 2 hours. CH2CN is driven off and 100 ml of ethanol is added. The ethanol is distilled off and 200 ml of ethanol and 40 ml of acetic acid are added to the mixture. 4.4 g of KBH^ are added and it is stirred for 30 min. The solvent is distilled off, 200 ml of water is added and the mixture is left at room temperature overnight.

Add 500 ml of CH2Cl2 and make alkaline with it

dilute ammonia. The organic phase is separated and the aqueous extract is washed with 2 x 200 ml CH 2 Cl 2 . The extracts are combined and the solvent is driven off. An oil is obtained which is used directly in the following step.

To 28.1 g of this oil, 500 ml of 4N hydrochloric acid and 50 ml of ethanol are added. It is heated at the reflux temperature for 6 hours and cooled in an ice bath. It is made alkaline with ammonia and the organic phase is extracted with ethyl acetate, the organic phases are dried and the solvent is driven off.

An oil is obtained which is chromatographed on silica. After elution with ethyl acetate and then with a mixture CHCl3/EtOH (8:2), an oil is obtained which is added to 50 ml of ether. Hydrochloric acid gas is bubbled through, suction is applied to a filter and the precipitate formed, which is the hydrochloride of the compound, is dried.

Temp. >260°C.

EXAMPLE 2 2,2-Dimethyl-2,3,3α,4,5,6-hexahydro-1H-indolo-[3,2,1-de][naphthyridine-1,5 and its methanesulfonate.

To a solution of 4.1 g of AlCl^ in 38 ml of ether, 1.73 g of AlLiH^ are added. After stirring, 25 ml of tetrahydrofuran (THF) and little by little 4.4 g of the compound obtained in example 1 are added. A further 25 ml of THF is added and stirred at normal temperature for 1 hour. One cools down in an ice bath. 7.5 ml of water, 7.5 ml of soda ash, 750 ml of water and then 200 ml of ethyl acetate are added and filtered. The organic phase is separated, the aqueous phase is extracted with 3 x 150 ml of ethyl acetate. The latter is distilled off and an oil is obtained to which 150 ml of ether is added.

1.6 g of methanesulfonic acid in solution is added to the solution

in 15 ml of ethanol and a white solid is obtained which is recrystallized from ethanol.

Temp. = 226 - 227°C.

EXAMPLE 3 5,5-Dimethyl-1,2,3,3a,4,5-6H-hexahydro-indolo-[3,2,1-de][naphthyridin-1,5]-6-one and its hydrochloride .

26.6 g of 2,2-dimethyl-4-oxo-pentanediic acid and 24.47 g of tryptamine are reacted in solution in 390 ml of 4N hydrochloric acid. The reflux temperature is maintained with stirring for 7 hours and 30 minutes. and the mixture is set aside overnight at ordinary temperature.

It is made alkaline with dilute ammonia and then 1.2 1 ethyl acetate is added. The organic phase is decanted and the ethyl acetate is driven off. After chromatography on silica with elution with a 95/5 mixture of CH2C12/CH3OH, a solid is obtained which is dissolved in 150 ml of ether, after which 50 ml of hydrochloric acid ether is slowly added. After stirring, filtering and drying under vacuum above<p>4°1os, the compound melts at 220°C (decomposition).

EXAMPLE 4 5,5-Dimethyl-2,3,3a,4,5,6-hexahydro-1H-indolo-[3,3,1-de] [naphthyridine-1,5] and its methanesulfonate.

In a round-bottomed flask containing 1.4 g of AlCl3, 22 ml of ether,

0.65 g of AlLiH4 and 22 ml of THF are added slowly at ordinary temperature with stirring 1.63 g of a compound obtained in example 3.

The reaction mixture is kept at room temperature for 1 hour, after which it is cooled in an ice bath.

50 ml of water, 1 ml of concentrated NaOH and 100 ml of ethyl acetate are added. The reaction mixture is stirred and filtered. The filtrate is collected and the organic phase is separated. The solvent is driven off and crystals are obtained. 1.17 g of the base obtained is dissolved in 30 ml of isopropanol. A solution of 0.52 g of methanesulfonic acid in 5 ml of ethyl acetate is added and a solid is obtained which, after recrystallization from isopropanol, melts at 218°C.

EXAMPLE 5 1,1-Dimethyl-1,2,3,3a,4,5-6H-hexahydro-indolo-[3,2,1-de][naphthyridin-1,5]-6-one and its hydrochloride.

1.88 g (0.01 mol) of 3,3-dimethyltryptamine in solution in 20 ml of 3N hydrochloric acid is reacted with 1.7 g (0.012 mol) of 2-oxo-pentane diacid.

The reaction mixture is heated at 110°C for 4 hours, the precipitated hydrochloride is filtered off, dried and recrystallized from ethanol.

Temp. >300°C.

EXAMPLE 6 1,1-Dimethyl-2,3,3a,4,5,6-hexahydro-1H-indolo-[3,2,1-de] [naphthyridine-1,5] and its methanesulfonate.

In a round flask containing 15 ml of THF, 0.53 g of AlCl^ and 0.23 g of AlLiH^, 0.58 g (0.002 mol) of the previously obtained compound are added in small portions. The reaction mixture is kept at room temperature for 1 hour. 3.1 ml of soda solution is added and then 50 ml of water and 50 ml of ethyl acetate. The reaction mixture is stirred, filtered, decanted, washed with water, dried over Na 2 SO 4 and evaporated to dryness.

The obtained base is dissolved in a minimum of ethanol and 0.16 g (1.6 mmol) of methanesulfonic acid is added. The salt is precipitated and recrystallized from ethanol.

Temp. = 212 - 214°C.

EXAMPLE 7 4,4-Dimethyl-1.2.3.3a.4.5-6H-hexahydro-indolo-[3,2,1-de] [naphthyridine-1,5] and its hydrochloride. 1. N-[2-(3-1H-indolyl)-ethyl]-N-benzyl-4-amino-4-oxo-3,3-dimethyl-butanoic acid ethyl ester.

Into a 1 L round bottom flask equipped with isobar ampoule, nitrogen purge tube, condenser, calcium chloride trap, magnetic stirrer and an oil bath for heating, is placed 30.06 g (0.12 mol) of 3-(2-benzylamino-ethyl)- indole, 200 ml of anhydrous tetrahydrofuran, 11.07 i.e. 12.28 ml (0.14 mol) of pyridine and then add slowly at room temperature 26.83 g (0.14 mol) of 4-chloro-4-oxo-3 ,3-dimethyl-butanoic acid ethyl ester. It is then heated under reflux for 7 hours, cooled, insoluble substance is separated by filtration and the filtrate is evaporated. The obtained brown oil is mixed with 200 ml of ethyl acetate, 200 ml of 1N hydrochloric acid is added, the organic phase is separated, washed with water and then with 100 ml of 5% sodium bicarbonate solution and then again with water, dried over MgSO^ and concentrated by evaporation. There remains 40.66 g of a brown oil which is purified by chromatography on silica eluting with a 98/2 mixture of methylene chloride/ethyl acetate.

14.5 g of ochre-coloured crystals are obtained, which are used

as they are.

2. 4,4-dimethyl-3-benzyl-1,2,3,3a,4,5-6H-hexahydro-indolo-[3,2,1-de] [naphthyridin]-6-one. 1 the same apparatus as previously placed 14.5 g of the crystals obtained, 120 ml of anhydrous acetonitrile and 2 7.3 g, i.e. 16.4 ml of phosphorus oxychloride. It is heated under reflux for 8 hours and cooled.

The mixture is evaporated, poured into a 1 1 beaker, 50 ml of water, 50 ml of ethanol are added, cooled to 0°C and the mixture is made basic using concentrated ammonia and 12 g of potassium borohydride are added in portions. One stirs for 30 min. at ordinary temperature and then add 200 ml of water and 100 ml of ethyl acetate, the organic phase is separated, washed with water and dried over MgSO^.

By evaporation, 11.3 g of a thick yellow oil is obtained. This is purified by chromatography on silica eluting with a 98/2 mixture of methylene chloride/methanol.

5.91 g of a yellow oil is then obtained, which is used as it is

is in the following.

3. 4,4-dimethyl-3-benzy1-1,2,3,3a,4,5-6H-hexahydro-indolo-[3,2,1-de] [naphthyridine].

In the same apparatus as in the preceding, 5.26 g of AlCl^/80 ml of tetrahydrofuran, 2.3 g of AlLiH^ are placed and slowly 5.91 g of the oil obtained in the preceding dissolved in 60 ml of tetrahydrofuran are added. The mixture is slowly brought to the reflux temperature and held at this temperature for 4 hours and set aside overnight. To be sure to utilize the entire starting product, 1 g of AlLiH^ is added again and reflux is repeated for 2 hours. After cooling to 0°C, 200 ml of water, 10 ml of concentrated ammonia and 100 ml of ethyl acetate are slowly added. One filters to remove the inorganic products, the organic phase is separated, washed and dried and evaporated under vacuum.

4.71 g of a yellow oil is obtained which is purified by chromatography on silica eluting with methylene chloride.

One then recovers 0.81 g of an oil which is used as it is

is in the following.

4. 4,4-dimethyl-1,2,3,3a,4,5,-6H-hexahydro-indolo [3,2,1-de] [naphthyridine].

Into a 250 ml Parr flask is placed 0.5 g of the oil obtained above, together with 20 ml of ethanol, 4 ml of acetic acid and 0.05 g of 10% palladium and charcoal.

A hydrogenation is carried out at 50°C under approximately 0.35 MPa for 1 hour. The catalyst is then separated by filtration, the solvent is evaporated, 30 ml of water are added to the remaining oil and then 10 ml of 10% ammonia and 50 ml of ethyl acetate. The phases are separated, washed and the organic phase is dried and evaporated under vacuum. 0.37 g of orange-coloured crystals remain, which are taken up in 15 ml of ethyl acetate and then 5 ml of hydrochloric acid ether are added slowly in an ice bath. The formed precipitate is stirred for 1 hour at 0°C, filtered on a glass filter, washed with ethyl acetate and dried under vacuum at 80°C. 0.31 g of hydrochloride is then obtained.

Temp. = 258 - 259°C.

In accordance with the invention, the following compounds are produced

Compounds prepared in accordance with the invention were subjected to a pharmacological investigation.

1. TOXICITY

Lethal dose 50 (LD 50) of the compounds is determined in mice

of the stem CDl using the graphical method. LD 50 is from 30 to 100 mg/kg by i.p. supply.

2. HYPOBAR HYPOXIA

Mice of the strain CD1 are maintained under an oxygen-poor atmosphere by means of a partial vacuum

(190 mm of mercury corresponding to 5.25% oxygen).

The survival time of the animals is noted. This time increases

by means of agents that can favor tissue oxygenation and especially cerebral oxygenation. The investigated compounds are administered in several doses intraperitoneally for 10 min. before the experiment. The percentage increase in survival time compared to values obtained among the control animals is calculated. The mean active dose (MAD) that increases survival time by 100% is determined graphically. The MAD is approximately 2 to 10 mg/kg by i.p. supply.

3. COMPLETE CEREBRAL ISCHEMIA

The compounds prepared according to the invention were subjected to the complete cerebral ischemia test in mice. Ischemia is due to cardiac arrest induced by rapid intravenous injection of MgC^. In this test, the "survival time" is measured, i.e. the interval between the injection time for MgCl2 and the last respiratory movement that can be observed for each mouse.

The last movement is considered the final indication of a function of the central nervous system.

The respiratory arrest appears approximately 19 sec. after the injection of MgC^-

Male mice (Charles River CDl) are examined in groups of 10.

The mice are given food and drink ad libitum before the experiments. The survival time is measured in 10 min. after intraperitoneal administration of the compounds obtained in accordance with the invention. The results are given in terms of the difference between the survival time measured for a group of 10 mice that had received the compound and the survival time measured in a group of 10 mice that had received the liquid vehicle.

The ratios between the modifications for the survival time

and the dose of the compound is plotted graphically using a semi-logarithmic curve.

This curve allows calculation of the effective dose for 3 sec.

(DE^")/ie the dose (in mg/kg) which produces a 3 sec increase in survival time compared to the control group of 10 untreated mice.

An increase of 3 sec. in the survival time is at the same time statistically significant and reproducible.

DE^" of the compounds produced in accordance with the invention varies from 2.2 to 7.4 mg/kg by i.p. administration.

The pharmacological investigation of the compounds

produced in accordance with the invention show that they are active in the hypobaric hypoxia test in mice while they are only slightly toxic.

The compound produced in accordance with the invention has an anti-anoxia effect and an anti-ischemia effect which can be used in the field of therapy for the treatment of vigilance disorders, in particular to combat behavioral disorders which can be caused by cerebral vessel damage and cerebral sclerosis in geriatrics, as well as for the treatment of unconsciousness resulting from cranial injuries, and for the treatment of metabolic encephalopathies.

The compounds obtained in accordance with the invention can be used together with all usual additives for their administration, especially for oral or parenteral administration.

The compounds can thus be administered orally and parenterally.

The daily dose can amount to 10 to 100 mg.

Claims (1)

Analogy process for the preparation of therapeutically active hexahydro-indolo-naphthyridines in the form of racemates or enantiomers of formula (I) in which Z represents one oxygen or two hydrogen atoms, or R2 or R^ or R^ represents the methyl radical while the others are hydrogen atoms, as well as their pharmaceutically acceptable acid addition salts, characterized in that a tryptamine with formula (II) in which R^ and R~ have the above meaning, is reacted with a diacid of formula (III) in which Ro and R^ have the above meaning, in an aqueous hydrochloric acid environment to obtain a compound (I) in which Z represents an oxygen atom, and if desired, this compound is reduced to obtain a compound (I) in which Z represents two hydrogen atoms, or that a tryptamine of formula (II) in which R 1 and R 2 have the above meaning and in which the group NH 2 is optionally benzylated, is reacted with an acid chloride of formula (IV) in which R., and R^ have the above meaning, for obtaining a compound of formula (V ) in which R^ , R2 , R^ and R^ have the above meaning, and the compound of formula (V) is cyclized to the compound (I) in which Z represents an oxygen atom, and if desired, this compound is reduced to obtain the compound (I) in which Z represents two hydrogen atoms, and the benzyl group in the 3-position is removed.