CS220313B2 - Method of producing new naphtyridine derivatives - Google Patents

Description

The invention relates to a process for the preparation of novel naphthyridine derivatives in the form of racemates or optical isomers of the general formula I

in which

R1 is hydrogen, C1-C4 alkoxy, 2-oxopropyl, 2-hydroxypropyl, 3-oxobutyl, 3-hydroxybutyl, cyclopropylmethyl, benzyl, halobenzyl, preferably fluorobenzyl or chlorobenzyl, acetyl group, a cyclopropylcarbonyl group, a benzoyl radical or a radical of the formula - (CH _{2) n} -R 'wherein n is 1 or 2 and R' is methoxycarbonyl, ethoxycarbonyl or cyano, and

R2 represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, with the exception of compounds in which either

R 1 is hydrogen and R 2 is methoxy at the 10-position, or

R1 and R2 are hydrogen atoms as well as their addition salts with pharmaceutically acceptable acids.

The principle of the preparation of the novel naphthyridine derivatives by the process according to the invention is that the tryptamine derivative of the general formula II

in which

R2 is as hereinbefore defined, it condenses with glutaric acid having a alpha group in the alpha position of formula III

HOOC \

c = o

CH2]

CH2 /

The intermediate intermediate HOOC (III) is cyclized in hydrochloric acid and ethanol to give the compound of formula IV

in which

R 2 is as defined above, which is then reacted with either an aldehyde of formula R 9 CHO in which R 5 is hydrogen, C 1 -C 3 alkyl, cyclopropyl, phenyl or halophenyl, in an acidic medium, or with an acid of formula R 9 COOH wherein R 8 is as defined above, in the presence of sodium borohydride, or with a halide of the formula R 1, wherein R 1 is as defined above and X is a halogen atom, in the presence of sodium carbonate, or a compound of the formula CH 2 = CH-R ', wherein R' is as defined above, or with an acyl halide of formula

R 10 COX, wherein R 10 represents a methyl, cyclopropyl or phenyl group and X represents a halogen atom, and the compounds obtained are optionally converted into addition salts and / or optical isomers.

The compounds of formula I and their salts are useful as medicaments in human and veterinary medicine.

All compounds produced by the process of the present invention can form two optical isomers, (+) and (-), since the carbon atom at the 3a position is asymmetric. In the following examples, racemates of the compounds are obtained.

The two isomers, cis and trans, can be separated by column chromatography.

The production of the compounds according to the invention starts from tryptamine or one of its derivatives, which is condensed with glutaric acid with a keto group in the alpha position. Thereafter, cyclization is carried out to form the indolo [3,2,1-de] '[1,5] -naphthyridine nucleus, and eventually various reactions are carried out to introduce the desired substituents into the nucleus or to convert existing substituents or change the degree of saturation .

The reaction schemes below illustrate the main routes for obtaining compounds of Formula I.

CYCLING

Scheme A - R 1 = H

HOOC

CHjCH. +.

' ^nh zc ~ o <CH

HC1 / C _Z H _S OH _--->

COOH in ¹ / _Z CH

HOOC- CH _Z

DETAILED PROCEDURES - VARIANTS

Scheme B

or chemical hydrogenation

Scheme C

Scheme E

Scheme F

O

WITH

Scheme J

The reduction is preferably carried out in a lower alcohol with an alkali borohydride at room temperature.

The resulting two diastereoisomers are separated by chromatography.

In the foregoing schemes, R 1, R 5, R 'and n are as defined for formula (I), R 8 is hydrogen, C 1 -C 3 alkyl, cyclopropyl, phenyl or halophenyl and Rvi is methyl, cyclopropyl or phenyl and X is halogen especially chlorine, bromine or iodine.

The following examples illustrate non-limiting embodiments of the invention and provide details of the procedures outlined in Schemes A to J.

The procedure of Scheme A (the first cyclization method was carried out essentially as described by Táborský and McLacs (j. Med. Chem. 1964, 7, 135) for related compounds) will therefore not be mentioned here.

IR and NMR spectra as well as analyzes confirm the structures of the compounds.

EXAMPLE 1 1,2,3,3a, 4,5-Hexahydro-3-methyl-6H-indolo [3,2,1-di ₍ [1,5 l-naphthyridin-6-one and its methanesulfonate) (Procedure Bj [R 1 = CH 3, R a = H]

To a 50 mL flask was added 2.26 g (0.010 mol) of 1,2,3,3a, 4,5-heahydro-6H-indolo [3,2,1-de] [1,51-naphthyridine- 6-one (obtained according to Scheme A) 3 g (0.059 mol) of 98% formic acid and 2.5 g (0.024 mol) of 30% formaldehyde.

The solution obtained is heated to boiling and then allowed to stand at room temperature for 16 hours. The reaction mixture was poured into 250 ml of water, and this was washed twice with 100 ml of benzene. The aqueous phase is then basified with sodium carbonate and the product crystallizes.

The product was recrystallized from a minimum amount of diisopropyl ether to give 1.2 g, 2,3,3a, 4,5-hexahydro-5-methyl-6H-indolo [3,2,1-del [1,5] naphthyridine-6. mp 95 ° C. The yield was 50% and the structure was confirmed by IR and NMR spectra.

To prepare the methanesulfonate, 5 g (0.0208 mol) of the preceding compound is suspended in 50 ml of methanol, and 2.110 g of methaosulfonic acid (i.e. a 10% excess) are added. The resulting solution was stirred for 15 minutes, and 500 ml of anhydrous diethyl ether was added dropwise, causing a rich crystallization. After stirring for 1 hour, the mesylate crystals are aspirated and recrystallized from a minimum amount of isopropanol. There are obtained 6.3 g of 1,2,3,3a, 4,5-hexahydro-3-methyl-6H-indolof 3,2,1-de-11,5-naphthyridin-6-one methanesulfonate, mp 188 ³ C. Yield 85%.

Example 2 1,2,3,3a, 4,5-hexahydro-3-cyclopropylmethyl-6H-indolo [3,2,1-de] [1,5] naphthyridin-6-one (Procedure C j)

A three-necked 1 liter flask equipped with a stirrer was charged with a solution of 33.8 ml (0.430 mol) of cyclopropanecarboxylic acid in 500 ml of benzene and added in small portions of 5 g (0.130 mol) of sodium borohydride such that the temperature did not exceed 25 ^° C. This addition takes about 4 hours. The mixture was then allowed to stand at room temperature overnight.

Next day, the solution is added all at once

5.5 g (0.0243 mol) of 1,2,3,3a, 4,5-diethydro-6H-indolo [3,2,1-de] [1,51-naphthyridin-6-one] and the mixture is heated to boiling for 5 hours.

After cooling, 500 ml of water and sodium carbonate are added to the reaction mixture until alkaline pH. The benzene phase is separated from the aqueous phase, which is extracted twice with 100 ml of benzene each and the extracts are added to the original extract. This solution was washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue is an oil which crystallizes upon addition of diisopropyl ether. The product was recrystallized twice from the minimum amount of the same ether to give 3.2 g of 1,2,3,3a, 4,5-hexahydro-5-cyclopropylmethyl-6H-indolo (3,2,1-del, 5-naphthyridin-6-one, mp 126 ° C.

Example 3 1,2,3,3a, 4,5-hexahydro-3- (2-cyanoethyl) -6H-indolo [3,2,1-de] [1,5] naphthyridin-6-one (procedures D and E) (R = - CH-CH ₂ -C = N, R2 = H)

1. Procedure D

To a 250 mL flask was charged with stirring 5 g (22 mmol) of 1,2,3,3a, 4,5-hexahydro-6H-indolo [3,2,1-de] [1,5] naphthyridine-6- It was dissolved in 100 ml of methyl ethyl ketone as well as 4.7 g (44 mmol) of sodium carbonate and the mixture was refluxed for 1 hour. Subsequently, 8 g (60 mmol) of bromopropionitrile and 5 g (30 mmol) of potassium iodide are added to the suspension and boiling is continued for 48 hours. The reaction mixture is cooled, the mineral salts are filtered off, the filtrate is evaporated to dryness to give a residue which, after chromatography on a Merck 7734 silica gel column with benzene ethanol 7: 3, yields 4.3 g of the compound, m.p. about 155 ° C.

After two hot and cold crystallizations, 2.7 g (44% yield of 1,2,3,3a, 4,5-hexahydro-3- (2-cyanoethyl) -6H-indolo [3,2,1]) were isolated. -de] [1,5] naphthyridin-6-one, mp 156-157 ° C.

2. Procedure E

To a 100 mL stirred flask under nitrogen was charged 4.52 g (0.020 mol) of 1,2,3,3a, 4,5-hexahydro-6H-indolo [3,2,1-de ₍ ] [1,5] naphthyridin-6-one suspended in 30 ml of absolute ethanol and 3 ml of acrylonitrile.

The mixture was then refluxed for 24 hours. On cooling, crystallization occurs. The crystals are aspirated and recrystallized from a minimum amount of anhydrous ethanol. 3.4 g of 1,2,3,3a, 4,5-hexahydro-3- (2-cyanoethyl) -6H-indolo [3,2,1-de [1,5] naphthyridin-6-one are obtained. This compound has the same properties as the compound obtained by Method D.

Example 4 1,2,3,3a, 4,5-hexahydro-3-benzyl-6H-indolo [3,2,1-dej [1,5] naphthyridin-6-one (Method F) (Rt = CsIHCO, Rz) - II)

A solution of 4 g (0.017 mol) of 1,2,3,3a, 4,5-hexahydro-6H-indolo [3,2,1-de] [1,5] naphthyridin-6-one is placed in a 250 ml flask. in 100 ml of anhydrous tetrahydrofuran, 2 ml of pyridine and 4 ml of benzoyl chloride and the mixture is stirred at 20 ^° C for 16 hours.

The pyridine hydrochloride formed during the reaction is filtered off with suction, the filtrate is washed with water until the wash water is neutral. The filtrate was dried over sodium sulfate, filtered and evaporated to dryness. The crystals obtained are dissolved in petroleum ether and recrystallized from a minimum amount of methanol. 4.8 g (82% yield) of 1,2,3,3a, 4,5-hexahydro-3-benzoyl-6H-indolo [3,2,1-de] [1,5] naphthyridine-6 are obtained. mp 171-172 ° C.

EXAMPLE 5 1,2,3,3a, 4,5-Hexahydro-3,6-dimethyl-6-hydroxy-6H-indolo [3,2,1 d] [1,5] naphthyridine (Method G) (Ri = CH 3, R 2 = H)

Methyl magnesium iodide is prepared in a conventional manner from 5 g of magnesium shavings, 75 ml of anhydrous diethyl ether and 11 ml (25 g or 0.420 mol) of methyl iodide.

To the obtained solution, cooled to 0 ° C, was added dropwise and under nitrogen a solution of 5 g (0.028 mol) of 1,2,3,3a, 4,5-hexahydro-3-methyl-6H-indolo [3,2, 1-dehydro- [1,5] naphthyridin-6-one in 50 ml of anhydrous tetrahydrofuran. The addition was carried out so that the temperature did not rise above 5 ° C. When the addition is complete, the reaction mixture is stirred for 1 hour 30 minutes at 0 ^° C. Excess magnesium is destroyed by the slow addition of ice water and the mixture is finally poured into 1000 ml of saturated aqueous ammonium chloride solution to crystallize. The product was recrystallized from a minimum amount of ethyl acetate to give 2.5 g (47% yield) of 1,2,3,3a, 4,5-heahydro-3,6-dimethyl-6-hydroxy-6H-indolo [3]. 2,1,1-di] [1,5] naphthyridine, mp 194 ° C.

Example 6 1,2,3,3a-tetrahydro-3,6-dimethyl-4H-indolo [3,2,1-de] t [1,5] naphthyridine (Procedure H) (R 1 = CH 3, R 2 = H )

To a 250 mL flask was added 4 g (0.0156 mol) of 1,2,3,3a, 4,5-hexahydro-3,6-dimethyl-6-hydroxy-6H-indolo [3,2,1-de]. [1,5] naphthaline, 60 ml of benzene and 60 ml of pyridine are stirred until complete dissolution. 4 ml of phosphorus oxychloride are then added, the flask is sealed with a chloro-calcium tube and stirring is continued for 2 hours at 25 ° C. The precipitate obtained is poured into 1500 ml of water. The organic phase is decanted, the aqueous phase is extracted twice with 200 ml of benzene, the organic phases are combined, washed with water, dried over sodium sulphate, filtered and finally evaporated to dryness. A residue is obtained in the form of a resin which is first treated with petroleum ether; then crystallized from the minimum amount of diisopropyl ether to give 1.2 g (32% yield) of 1,2,3,3a tetrahydro-3,6-dimethyl-4H indole-3,2,1-de] [1,5] - mp 89 ° C.

The compounds prepared according to the invention were subjected to pharmacological examination.

1. Toxicity

The lethal dose of 50 (LD 50) compounds was determined on mouse strain CD 1 by a graphical method.

The results are shown in Table II for a certain number of representative compounds.

2. Hypobaric anoxia

CD1 strain mice were maintained in an oxygen-depleted atmosphere by reducing the pressure to 25.33 kPa corresponding to 5.25% oxygen.

Animal survival time was recorded. This time is prolonged after administration of agents capable of promoting tissue oxidation, particularly brain tissue. The test compounds are administered intraperitoneally in several doses, 10 minutes before the start of the experiment. Percentage of prolongation of survival time calculated relative to values obtained with control animals. The median active dose is one that extends the survival time by 100%, determined graphically.

The results are shown in Table II for a certain number of representative compounds.

3. Effect on the duration of “sleep” induced by sodium 4-hydroxybutyrate

This effect was determined by the effect of the compounds on the duration of "sleep" induced by sodium 4-hydroxybutyrate (GHB) in rats.

The animals used are male Charles Rlver rats weighing 200 ± 20 g. Alloforin is administered at a dose of 1 mg / kg by the intraperitoneal route and subjected to artificial respiration using a mask on the muzzle (respiratory rate: 50 / min; breath volume: 14 ml) . Before the experiment, esophagus is ligated to prevent air from entering the stomach.

The cortical frontal-parietal and occipital electrodes allow recording of electrocorticographic activity using a Grass Model 79 P polygraph at a speed of 6 mm / s. The animal is prepared for experimentation by local anesthesia (2% xylocaine). The rats are maintained at a constant temperature (37.5 ° C) throughout the experiment. Ten minutes after completion of the rat preparation, a dose of 200 mg / kg sodium 4-hydroxybutyrate was injected intravenously into the tail vein.

Doses of 10 and 30 mg / kg of test compounds are administered to the animal intraperitoneally 3 minutes after the administration of sodium 4-hydroxybutyrate.

Recording is performed at 15 ml intervals 75 minutes after injection of "GHB". During this analysis period, the total duration of sleep is determined. A series of 15 control animals make it possible to refine the duration of 'sleep after GHB'.

Statistical analysis of the results was performed using the Mann-Whitney U-test.

The results are shown in Table III.

Pharmacological study of the compounds indicates that they are effective in the test hypobaric yes ^- ie in mice, and that are only slightly toxic and have a significant influence on the test excitation "sleep" induced 4-hydroxybutyrate sodium.

The compounds according to the invention, which simultaneously have antianoxic and psychotropic activity, can be used in therapy for the treatment of wakefulness disorders, in particular in combating problems attributable to vascular disorders of the brain and cerebral sclerosis in geriatrics, and treating depressive conditions.

TABLE I

m.p. = methanesulfonate

Compound number Rl R2 Method Base or salt Melting point, ° C 2 (BC) CH3 H (B) base m. 95 188 3 C2H5 H (B) base 114 4 (Ex.2) “CH _Z --- O H C base 126 5 C8H5CH2— H D base m. 174 227—230 6 (Ex. 3) —CH2CH3CN H DE base 156 7 (Ex. 4) CeíDCO— H F base 171—172 11 H CHa (9) AND base 170—172 12 n-C 7 H 7 H (B) base 111—113 13 I-C3H7 H D base 161 14 CHaCO— H F base 174 15 Dec About what- H F base 134 16 0 H D base 160

Merging- Ri R2 Method Base or salt Melting point, to the number Noc: 2 ° C 17 H D base 165 18 H D base 148 19 Dec -CH 2 - CH 2 - COOCH 3 ; h E base m. 122—125 213—215 20 May CH3 CII3 (9) (B) base 108—109 33 —CH2CH2COCH3 H E base 100 ALIGN! 34 - CH2COOC2H5 - H D m. 203 35 —CH2CH2CHOHCH3 H J base isomer A 144 base isomer B 115 38 CH3 CH3O (9) (B) m. 245—246 52 H Cl (10) AND base 161—163 53 CH3 Cl (10) (B) base 118—119 54 H F (10) AND base 123—125 55 CHj F (10) (B) base 146—147 56 —CH2 —CH2COCH3 Cl (10) E base 135—136 57 —CH2 —CH2COCH3 F (107) E base 124—125 62 —CH2COCH3 H D base 135—136 63 —CH2CHOHCH3 H J base isomer A 164.5—165.6 base isomer B 142—143 64 * -CH 2, CH 2 —COCH 3 CHs (10) D base 120—121 65 H Cl (11) AND base 145—146 66 CH3 ci (9) (B) base 168—169 67 -CH 2 —CH 2 —COCH 3 F (10) D base 140—142 68 -CH 2 - CH 2 - COCH 3 Cl (10) D base 113—114 69 CH3 CHs (9) (B) base 145—151 rozkl. 70 C2H5 Cl (10) D base 124—125 72 H Cl (9) AND base 195—196 73 H CH3 (7) AND base 76—78 Pharmaceutical preparations containing com- mon for theirs administration, can be cheniny manufactured according to the invention in particular orally or parenterally.

or a salt thereof as an active ingredient in combination with conventional excipients suitable daily dosages of 10 to 100 mg.

can range from

TABLE II

Compound Acute toxicity DL 50 Hypobaric anoxia i.

(mg / kg i.p.

2 (base) 85 6 2 (m. p.) 52 4,5 3 58 9 1 (m. cisj 170 4 33 170 8 35 (base isomer A) 150 9 38 65 8 52 165 9.5 53 150 8 62 190 10

Compound Toxicity mg / kg TABLE III Activity Overall Deviation i. v. i. number of doses duration in min in% animals mg / kg i.p. with regard to controls

Control 11 105 155 15 Dec 6 30 54.12 ± 2.07 34.08 ± 1.21 —37 19 m. 103 680 6 30 38.59 ± 1.20 —28 52 110 165 6 30 32.35 ± 5.02 —40 6 10 37.34 ± 3.35 54 - 100 ALIGN! 6 30 28.28 ± 4.28 —47 6 10 40.01 ± 5.00 —26 56 - 575 6 30 30.39 ± 3.01 —43 6 10 43.07 ± 3.26 —20 63 isomer A 75 125 6 30 34.52 ± 2.14 —36 65 - 54 6 10 34.51 ± 1.42 —36 69 - 88 6 10 29.46 ± 1.27 —45

SUBJECT

Claims (6)

VYNALEZU A process for the preparation of novel naphthyridine derivatives of the general formula wherein: R1 is hydrogen, C1-C4alkyl, 2-oxopropyl, 2-hydroxypropyl, 3-oxobutyl, 3-hydroxybutyl, cyclopropylmethyl, benzyl, halobenzyl, preferably fluorobenzyl or chlorobenzyl, an acetyl group, a cyclopropylcarbonyl group, a benzoyl group or a group of the formula - (CH 2 -R ', where n is 1 or 2 and R' represents a methoxycarbonyl, ethoxycarbonyl or cyano group, and R2 represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, with the exception of compounds in which either R 1 is hydrogen and R 2 is methoxy at the 10-position, or R1 and R2 are hydrogen atoms and their addition salts with pharmaceutically acceptable acids and / or optical isomers, characterized in that the tryptamine derivative of the general formula II CH-CH _Z NH _Z (II) wherein Ra is as hereinbefore defined, it condenses with α-ketoglutaric acid of formula III HOOC C = O CHz CHz / The intermediate intermediate HOOC (III) is cyclized in hydrochloric acid and ethanol to give the compound of formula (IV): R2 is as hereinbefore defined, which optionally is reacted either with an aldehyde of the formula R @ 9 CHO in which R @ 8 is hydrogen, C1 -C3 alkyl, cyclopropyl, phenyl or halophenyl, in an acidic medium or with an acid of the formula R 9 COOH, wherein R 9 is as defined above, in the presence of sodium borohydride, or a halide of the formula R 1X, wherein R 1 is as defined above and X is a halogen atom, in the presence of sodium carbonate, or a compound of the formula R ', wherein R' is as defined above, or with an acyl halide of the formula R10COX, wherein R10 is methyllo220313 X is a halogen atom, and the resulting racemic mixture is optionally resolved into the optical isomers and / or the resulting compounds are optionally converted into the addition salts with pharmaceutically acceptable acids. 2. The process of item 1 for producing novel naphthyridine derivatives of the general formula R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a cyclopropylmethyl group, a benzyl group, a halobenzyl group, an acetyl group, a cyclopropylcarbonyl group, a benzoyl group or a group of the formula -CH 2 -CH 2; wherein R 'represents a methoxycarbonyl group or a cyano group, R? represents a hydrogen atom or a methyl group, and their addition salts with pharmaceutically acceptable acids and / or optical isomers, characterized in that tryptamine or a derivative thereof is condensed with acetoglutaric acid of formula III, the obtained intermediate is cyclized to give indolo [3,2, The 1-de] [1,5] naphthyridine compounds of formula (IV) and optionally introduce the above substituents or modify the existing substituents within the above substituents, or modify the degree of saturation of the molecule within the above substituents, and form the racemic the mixture is optionally resolved into optical isomers and / or the compounds obtained are optionally converted into addition salts with pharmaceutically acceptable acids. 3. The process of item 1 for producing the novel naphthyridine derivatives of the general formula [Indolo [3,2,1-de] [1,5] naphthyridine compound of the general formula (IV) and optionally introducing the above substituents into the resulting nucleus or modifying the existing substituents in the and the resulting racemic mixture is optionally resolved into the optical isomers and / or the resulting compounds are optionally converted into pharmaceutically acceptable acid addition salts. 4. The process of item 1 for producing novel naphthyridine derivatives of the general formula wherein: R 1 represents a hydrogen atom, a C 1 -C 4 alkyl group, a cyclopropylmethyl group, a 3-oxobutyl group, a 3-hydroxybutyl group or an ethoxycarbonylmethyl group, and R? represents a halogen atom, and their addition salts with pharmaceutically acceptable acids and / or optical isomers, characterized in that the triptamine of the formula II is condensed with the .alpha.-ketoglutaric acid of the formula III, the obtained intermediate is cyclized to give indolo [3,2,1] -de] [1,5] naphthyridine compounds of the general formula IV and optionally the above substituents are introduced into the resulting nucleus, or existing substituents are modified within the above-mentioned substituents, or the degree of saturation of the molecule within the above-mentioned substituents is modified, and the racemic formed the mixture is optionally resolved into optical isomers and / or the resulting compounds are optionally converted into addition salts with pharmaceutically acceptable acids. 5. The process of item 1 for producing novel naphthyridine derivatives of the general formula wherein: R1 represents a hydrogen atom, a (C1-C4) alkyl group, a cyclopropylmethyl group, a 3-oxobutyl group, 3-hydroxybutyl or ethoxycarbonylmethyl, R? represents a hydrogen atom or a methoxy group, and their addition salts with pharmaceutically acceptable acids and / or optical isomers, characterized in that the tryptamine of the formula II is condensed with the α-ketoglutaric acid of the formula III, the obtained intermediate is cyclized to form R 1 is hydrogen, C 1 -C 4 alkyl, 3-oxobutyl, 3-hydroxybutyl, cyclopropylmethyl, benzyl, halobenzyl, acetyl, cyclopropylcarbonyl, benzoyl, or -CH 2 - CH 2 -R 'in which R' represents a methoxycarbonyl group, an ethoxycarbonyl group or a cyano group and R? represents a halogen atom, methyl A 229313 group or an ethyl group, and their addition salts with pharmaceutically acceptable acids and / or optical isomers, characterized in that tryptamine or a derivative thereof of the general formula (7) is CH _T CH? I, < M / 7 /? in which R represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 3 -C 5 cycloalkyl group or a benzyl group optionally substituted by a halogen atom, and R 2 is as hereinbefore defined, condenses with the α-ketoglutaric acid derivative of the formula III, then cyclized to give the indolo [3,2,1-de] [1,5] naphthyridine compound of the formula IV, optionally introduced into the core above said substituents or modifying already existing substituents or the degree of saturation of the molecule within the aforementioned substituents, and the resulting racemic mixture is optionally resolved into optical isomers and / or the resulting compounds are optionally converted into pharmaceutically acceptable acid addition salts. 6. The process of item 6 for producing novel naphthyridine derivatives of the general formula wherein: R1 is 2-oxopropyl or 2-hydroxypropyl; and R 2 represents a hydrogen atom, a halogen atom, a methyl group or a methoxy group, and their addition salts with pharmaceutically acceptable acids and / or optical isomers, characterized in that the naphthyridine is of the formula: Rž is as defined above, reacted with 2-oxopropyl chloride and the ketone obtained is optionally reduced and the resulting racemic mixture is optionally resolved into optical isomers and / or the resulting compounds are optionally converted into addition salts with pharmaceutically acceptable acids.