CA1162544A - Naphthyridine derivatives - Google Patents
Naphthyridine derivativesInfo
- Publication number
- CA1162544A CA1162544A CA000390531A CA390531A CA1162544A CA 1162544 A CA1162544 A CA 1162544A CA 000390531 A CA000390531 A CA 000390531A CA 390531 A CA390531 A CA 390531A CA 1162544 A CA1162544 A CA 1162544A
- Authority
- CA
- Canada
- Prior art keywords
- naphthyridine
- acid addition
- alkyl
- acceptable acid
- hexahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/16—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
A B S T R A C T
"NAPHTHYRIDINE DERIVATIVES"
2,3,3a,4,5,6-Hexahydro-1H-indolo[3,2,1-de]-[1,5-naphthyridine] derivatives of the general formula:
in which R1 is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, are new compounds useful in therapy as they possess an anti-anoxia action and a psychotropic action.
They can be prepared by reduction of the carbonyl group of corresponding 1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one derivatives, which are known compounds, to methylene.
"NAPHTHYRIDINE DERIVATIVES"
2,3,3a,4,5,6-Hexahydro-1H-indolo[3,2,1-de]-[1,5-naphthyridine] derivatives of the general formula:
in which R1 is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, are new compounds useful in therapy as they possess an anti-anoxia action and a psychotropic action.
They can be prepared by reduction of the carbonyl group of corresponding 1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one derivatives, which are known compounds, to methylene.
Description
t ~ 625~
DESCRIPTION
"NAPHT~ IDINE DERIVATIVES"
The present invention relates to
DESCRIPTION
"NAPHT~ IDINE DERIVATIVES"
The present invention relates to
2,3,3a,4,5s6-hexahydro-lH-indolo[3,2,1-de]C1,5-naphthyrldine~ derivatives, their addition salts with pharmaceutically acceptable acids, their preparation and pharmaceutical compositions containing -them.
The naphthyridine derivatives of the present invention are those compounds of the general formula:
~ 3NH
1 o~J<R 2 R ~ (I) 1 9 ~ N~ "
in which Rl is in the 9- or 10-position and represents a hydrogen atom. a halogen atom or a Cl ~ alkyl or Cl ~ alkoxy radical and R2 represents a hydrogen atom or a Cl 4 alkyl radical, and pharmaceutically acceptable acid addition salts thereof.
~hese compounds contain an asymmetric carbon atom in the 3a-position. The racemates and the optically active isomers of the com~ounds of general formula ~I) form part of the present invention.
~ J~4~
The preferred cornpounds of the invention are those in which Rl represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and R2 represents a hydro~en atom or the methyl radical and, more particularly, those in which Rl represents a hydrogen, fluorine, chlorine or bromine atom and R2 represents a hydrogen atorn.
The compounds of general formula (I) can be prepared, for example, by reducing the compounds of the general formula:
~ ~IEI R
in which Rl and R2 are as hereinbefore defined, or an acid addition salt thereof, e.g. the hydrochloride.
The compounds of general formula (II) have already been described in the literature, in particular by R.G. Taborsky et al., J. Med. Chem. 7 (2). 135-41 (1964).
by G. Hahn et al., Ber. 71B, 2163-7S (1933), in French Patent 2434165 and by ourselves in Canadian Patent 1072960.
~ 3~5~4 rFhe process of the invention consists in reducing the compounds of general formula (II) in accordance with a conventional method for the conversion of the carbonyl group (~ C=0) to me-thylene (i.e. -CH2-), for example by treating a compound of general formula (II) with a hydride, such as lithium aluminium hydride. in the presence of a Lewis acid such as aluminium chloride. The reaction is generally carried out at a temperature of from -40 to +80C in an organic solvent such as an anhydrous ether.
Pharmaceutically acceptable acid addition salts of the naphthyridine derivatives of general formula (I), e.g~ methanesulphonates, mandelates, fumarates, citrates and hydrochlorides, may be obtained by methods known per se, for example by treatment of the naphthyridine base in a solvent medium, e.g. an ether, with the appropriate acid in a solvent medi~n. e.g. an alkanol.
By the term~methods known per se' as used in this specification is meant methods heretofore used or described in the literature.
The following Examples illustrate the preparation of naphthyridine derivatives of the present invention.
The analyses and the IR and NMR spectra confirm the structure of the compounds.
~ 1 62~
.
2,3,3a,~,5,6-Hexahydro~lH -indol~3,2.1-de][1,5-naphthyr ~ and its methanesulphorlate 5.4 g (0.04 mol) of aluminium chloride are placed in a one litre three-necked flask. 50 ml of anhydrous diethyl ether are added all at once.
2.3 g (0.06 mol) of lithium aluminium hydride are added gradually to the solution obtained. The suspension obtained is stirred for 10 minutes.
A suspension of 5.3 g (0.02 mol) of 1.2,3,3a,4,5-hexa-hydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one hydrochloride in 70 ml of anhydrous tetrahydrofuran is added gradually thereto. The mixture is stirred at ambient temperature for 30 minutes. It is then cooled in an ice-bath and 10 ml of water are added slowly.
The mixture is stirred for 10 minu-tes and 10 ml of sodium hydroxide solution (d = 1.38), 150 ml of ethyl acetate and 100 ml of water are then added successively.
The mixture is stirred for 15 minutes. The organic phase is decanted. The aqueous phase is extracted twice with 60 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated ln vacuo on a water-bath. This yields an oil, which is dried by aæeotropic distillation with toluene. The base obtained is pure according to thin layer chromatography.
~ ~ ~2~
This oil is soluhilised in 80 ml of anhydrous diethyl e-ther. A solution of 2 g (0.02 mol) of methanesulphonic acid in 20 ml of ethanol is added.
The mixture is stirred for 30 minutes at ambient temperature. The white precipitate obtained is filtered off, washed with diethyl ether and dried in a desiccator. The methanesulphona-te salt of the naphthyridine produc-t is recrys-tallised from 80 ml of ethanol. Its melting point is 246-248C.
10-Chloro-2,3,3a,4,5,6-hexahydro-lH-indolo-.~. .. _ _ [3,2,1-de~[1,5-naphthyridine~ and its methane-. . . _ . _ _ _ _ sulphonate 2.25 g (0.0168 mol) of anhydrous aluminium chloride, 25 ml of anhydrous diethyl ether and 0.96 g (0.0252 mol) of lithium aluminium hydride are placed in a 500 cc three-necked round-bottomed flask. A
suspension of 2.5 g (0.0084 mol) of 10-chloro-1,2,3,3a,~,5-hexahydro-6H-indolo[3,2,1-de][1,5-naphthyridine~-6-one hydrochloride in 60 ml of anhydrous tetrahydrofuran is added to the resulting suspension, whilst stirring. ~hen the introduction has ended, a grey solution is obtained, which is stirred for half an hour. The complete clisappearance of the starting material is monitored by thin layer chromatography.
The complex is destroyed by slowly adding 5 ml of water and then 15 ml of sodium hydroxide solution (d = 1.38). The mediurn is diluted with 150 ml of water and extraction is then carried out three times with 70 ml of ethyl acetate. The extract is washed with water and then dried over sodium sulphate.
It is filtered.
A solution of 0.9 g (0.0093 mol) of methanesulphonic acid in 2 ml of ethyl acetate is added to the filtrate. The resulting precipitte is filtered off, and recrystallised from about 50 ml of methanol in the presence of decolorising charcoal.
The mixture is filtered hot. The filtrate deposits crystals. These are fi]tered off and dried. The methanesulphonate of the naphthyridine product melts at 275-278C.
The following Table shows the compounds of the invention which were prepared by way of examples in accordance with the method described above.
~ 3 ~5~
TABLE
~ NH
R
g ~----N~ "
_ CompoundRl R2 Base Melting or point salt (C) 1 H H m.s. 246-248 (Example 1) lO_CN3 H baEe ~, 3
The naphthyridine derivatives of the present invention are those compounds of the general formula:
~ 3NH
1 o~J<R 2 R ~ (I) 1 9 ~ N~ "
in which Rl is in the 9- or 10-position and represents a hydrogen atom. a halogen atom or a Cl ~ alkyl or Cl ~ alkoxy radical and R2 represents a hydrogen atom or a Cl 4 alkyl radical, and pharmaceutically acceptable acid addition salts thereof.
~hese compounds contain an asymmetric carbon atom in the 3a-position. The racemates and the optically active isomers of the com~ounds of general formula ~I) form part of the present invention.
~ J~4~
The preferred cornpounds of the invention are those in which Rl represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and R2 represents a hydro~en atom or the methyl radical and, more particularly, those in which Rl represents a hydrogen, fluorine, chlorine or bromine atom and R2 represents a hydrogen atorn.
The compounds of general formula (I) can be prepared, for example, by reducing the compounds of the general formula:
~ ~IEI R
in which Rl and R2 are as hereinbefore defined, or an acid addition salt thereof, e.g. the hydrochloride.
The compounds of general formula (II) have already been described in the literature, in particular by R.G. Taborsky et al., J. Med. Chem. 7 (2). 135-41 (1964).
by G. Hahn et al., Ber. 71B, 2163-7S (1933), in French Patent 2434165 and by ourselves in Canadian Patent 1072960.
~ 3~5~4 rFhe process of the invention consists in reducing the compounds of general formula (II) in accordance with a conventional method for the conversion of the carbonyl group (~ C=0) to me-thylene (i.e. -CH2-), for example by treating a compound of general formula (II) with a hydride, such as lithium aluminium hydride. in the presence of a Lewis acid such as aluminium chloride. The reaction is generally carried out at a temperature of from -40 to +80C in an organic solvent such as an anhydrous ether.
Pharmaceutically acceptable acid addition salts of the naphthyridine derivatives of general formula (I), e.g~ methanesulphonates, mandelates, fumarates, citrates and hydrochlorides, may be obtained by methods known per se, for example by treatment of the naphthyridine base in a solvent medium, e.g. an ether, with the appropriate acid in a solvent medi~n. e.g. an alkanol.
By the term~methods known per se' as used in this specification is meant methods heretofore used or described in the literature.
The following Examples illustrate the preparation of naphthyridine derivatives of the present invention.
The analyses and the IR and NMR spectra confirm the structure of the compounds.
~ 1 62~
.
2,3,3a,~,5,6-Hexahydro~lH -indol~3,2.1-de][1,5-naphthyr ~ and its methanesulphorlate 5.4 g (0.04 mol) of aluminium chloride are placed in a one litre three-necked flask. 50 ml of anhydrous diethyl ether are added all at once.
2.3 g (0.06 mol) of lithium aluminium hydride are added gradually to the solution obtained. The suspension obtained is stirred for 10 minutes.
A suspension of 5.3 g (0.02 mol) of 1.2,3,3a,4,5-hexa-hydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one hydrochloride in 70 ml of anhydrous tetrahydrofuran is added gradually thereto. The mixture is stirred at ambient temperature for 30 minutes. It is then cooled in an ice-bath and 10 ml of water are added slowly.
The mixture is stirred for 10 minu-tes and 10 ml of sodium hydroxide solution (d = 1.38), 150 ml of ethyl acetate and 100 ml of water are then added successively.
The mixture is stirred for 15 minutes. The organic phase is decanted. The aqueous phase is extracted twice with 60 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated ln vacuo on a water-bath. This yields an oil, which is dried by aæeotropic distillation with toluene. The base obtained is pure according to thin layer chromatography.
~ ~ ~2~
This oil is soluhilised in 80 ml of anhydrous diethyl e-ther. A solution of 2 g (0.02 mol) of methanesulphonic acid in 20 ml of ethanol is added.
The mixture is stirred for 30 minutes at ambient temperature. The white precipitate obtained is filtered off, washed with diethyl ether and dried in a desiccator. The methanesulphona-te salt of the naphthyridine produc-t is recrys-tallised from 80 ml of ethanol. Its melting point is 246-248C.
10-Chloro-2,3,3a,4,5,6-hexahydro-lH-indolo-.~. .. _ _ [3,2,1-de~[1,5-naphthyridine~ and its methane-. . . _ . _ _ _ _ sulphonate 2.25 g (0.0168 mol) of anhydrous aluminium chloride, 25 ml of anhydrous diethyl ether and 0.96 g (0.0252 mol) of lithium aluminium hydride are placed in a 500 cc three-necked round-bottomed flask. A
suspension of 2.5 g (0.0084 mol) of 10-chloro-1,2,3,3a,~,5-hexahydro-6H-indolo[3,2,1-de][1,5-naphthyridine~-6-one hydrochloride in 60 ml of anhydrous tetrahydrofuran is added to the resulting suspension, whilst stirring. ~hen the introduction has ended, a grey solution is obtained, which is stirred for half an hour. The complete clisappearance of the starting material is monitored by thin layer chromatography.
The complex is destroyed by slowly adding 5 ml of water and then 15 ml of sodium hydroxide solution (d = 1.38). The mediurn is diluted with 150 ml of water and extraction is then carried out three times with 70 ml of ethyl acetate. The extract is washed with water and then dried over sodium sulphate.
It is filtered.
A solution of 0.9 g (0.0093 mol) of methanesulphonic acid in 2 ml of ethyl acetate is added to the filtrate. The resulting precipitte is filtered off, and recrystallised from about 50 ml of methanol in the presence of decolorising charcoal.
The mixture is filtered hot. The filtrate deposits crystals. These are fi]tered off and dried. The methanesulphonate of the naphthyridine product melts at 275-278C.
The following Table shows the compounds of the invention which were prepared by way of examples in accordance with the method described above.
~ 3 ~5~
TABLE
~ NH
R
g ~----N~ "
_ CompoundRl R2 Base Melting or point salt (C) 1 H H m.s. 246-248 (Example 1) lO_CN3 H baEe ~, 3
3 10-CH30 H m.s. 248-250 _ _ 10-F H HCl >300 10-Cl H base 142-3 (Example 2) m.s. ~75-8 6 H CEI3 m. 9 . )~0 7 9-Cl H m.s. 251-253 10-Br H m.s. 265 9-CH30 H m.s. 214-6 (m.s. = methanesulphonate) I :~ 625~4 The compourlds of the invention formed the subject of a pharmacological study.
1. TOXICITY
The 50% le-thal dose (LD 50) o~ the compounds is determined on mice of the CDl strain by a graphical method. The LD 50 is from 120 to 500 mg/kg, administered intraperitoneally.
2. HYPOXIA CAUSED BY PRESSURE REDUCTION
Mice of the CDl strain axe kept in an oxygen-depleted atmosphere produced by _reating a partialvacuum (190 mm of mercury, corresponding to r3.25% of oxyyen).
The survival -time of the animals is noted.
This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain. The compounds studied are administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals,are calculated. The mean active dose (MAD), that is to say the dose which increases the survival time by 100%, is determined graphically. Tne MAD is from 10 to 15 mg/kg.
3. ACTION ON THE DURATION OF THE "SLEEP" INDUCED BY
SODIUM 4-HYDRoxBuTYRArrE
This action was determined by the influence ~ ~ 6~54~
of a compound on the duration of the "sleep" induced in curarised rats hy sodium 4-hydroxybutyrate (GMB).
The animals used are male rats of the Charles River strain, weighing 200 + 20 g The animals, which have been curarised with alloferine at a rate of 1 mg/kg, administered intraperitoneally, are placed under artificial respiration with the aid of a mask applied to the snout (breathing rate: 50/minute, breathing volume: 14 cc).
The oesophagus is ligated beforehand in order to prevent air from entering the stomach.
Fronto-parietal and fronto-occipital cortical electrodes make it possible to record the electrocorticographic activi-ty on a model 79 P Grass polygraph at a speed of 6 mm/second.
The animal is prepared under local anaesthetic (2% strength xylocaine). The rats are kept at constant temperature (37.5C) throughout the experiment. Ten minutes after the rat has been prepared, a 200 mgjkg dose of sodium 4-hydrox~butyrate is injectecl intravenously into the tail.
A 10 mg/kg dose o the compound to be studied is administered intraperitoneally, 3 minutes after the administration of the sodium 4-hydroxybu-tyrate.
The graphs are evaluated at 15-minute intervals for 75 minutes after the injection of the 1 ~62S4~
"GHB". During this peri.od of analysis, the total.
duration of -the "sleep" is determined. A series of 15 controls makes it possi~le to specify the duration of the "G~IB sleep".
Statis-tical analysis of the results is carried out using the Mann-Whitney "U" test.
The reduction in the duration of the "sleep"
is from 25 to 40%.
The pharmacological study of the compounds of the invention shows that -they are active in the test for the hypoxia caused in mice by pressure reduction, whilst at the same time being only slightly toxic, and that they exert a significant waking action in the test for the "sleep" induced by sodium 4-hydroxybutyrate.
The compounds of the invention, which possess an anti-anoxia action and a psychotropic action, can be used in therapy for the treatment of vigilance disorders, in particular for combating the behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, for the treatment of metabolic encephalopathies and for the treatment of depressive states.
I ~fi254~
The invention consequently includes pharmaceu-tical compositions containing, as active ingredient, a naphthyridine derivative of genera]
formula (I), or a pharmaceu-tically acceptable acid addition salt thereof, in association with any excipients which are suitable for their administration, in particular their oral or parenteral administration.
~ he methods of administration can be oral and parenteral.
The daily posology can range from 10 to 100 mg of naphthyridine derivative. The dosage units can therefore contain, for example, 2 to 50 mg doses of active substance associated with customary excipients, and can be presented in the form of tablets, coated tablets, capsules, suspensions or solutions to be taken orally or in~ected.
Particularly preferred naphthyridine derivatives of the invention are 2,3,3a,4,5,6-hexahydro-lM-indolo[3,2,1-de][1,5-naphthyridine~, 10-chloro-2,3,3a,4,5/6-hexahydro-lEI-lndolo[3,2,1-de]-[1,5-naphthyridine], 10-fluoro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][1,5-naphthyridine~ and 10-bromo-2,3,3a,4,5,6-hexahydro-l~I-indolo[3,2~1-de]-[1,5-naphthyridine], and their pharmaceutically acceptable acid addition salts.
1. TOXICITY
The 50% le-thal dose (LD 50) o~ the compounds is determined on mice of the CDl strain by a graphical method. The LD 50 is from 120 to 500 mg/kg, administered intraperitoneally.
2. HYPOXIA CAUSED BY PRESSURE REDUCTION
Mice of the CDl strain axe kept in an oxygen-depleted atmosphere produced by _reating a partialvacuum (190 mm of mercury, corresponding to r3.25% of oxyyen).
The survival -time of the animals is noted.
This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain. The compounds studied are administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals,are calculated. The mean active dose (MAD), that is to say the dose which increases the survival time by 100%, is determined graphically. Tne MAD is from 10 to 15 mg/kg.
3. ACTION ON THE DURATION OF THE "SLEEP" INDUCED BY
SODIUM 4-HYDRoxBuTYRArrE
This action was determined by the influence ~ ~ 6~54~
of a compound on the duration of the "sleep" induced in curarised rats hy sodium 4-hydroxybutyrate (GMB).
The animals used are male rats of the Charles River strain, weighing 200 + 20 g The animals, which have been curarised with alloferine at a rate of 1 mg/kg, administered intraperitoneally, are placed under artificial respiration with the aid of a mask applied to the snout (breathing rate: 50/minute, breathing volume: 14 cc).
The oesophagus is ligated beforehand in order to prevent air from entering the stomach.
Fronto-parietal and fronto-occipital cortical electrodes make it possible to record the electrocorticographic activi-ty on a model 79 P Grass polygraph at a speed of 6 mm/second.
The animal is prepared under local anaesthetic (2% strength xylocaine). The rats are kept at constant temperature (37.5C) throughout the experiment. Ten minutes after the rat has been prepared, a 200 mgjkg dose of sodium 4-hydrox~butyrate is injectecl intravenously into the tail.
A 10 mg/kg dose o the compound to be studied is administered intraperitoneally, 3 minutes after the administration of the sodium 4-hydroxybu-tyrate.
The graphs are evaluated at 15-minute intervals for 75 minutes after the injection of the 1 ~62S4~
"GHB". During this peri.od of analysis, the total.
duration of -the "sleep" is determined. A series of 15 controls makes it possi~le to specify the duration of the "G~IB sleep".
Statis-tical analysis of the results is carried out using the Mann-Whitney "U" test.
The reduction in the duration of the "sleep"
is from 25 to 40%.
The pharmacological study of the compounds of the invention shows that -they are active in the test for the hypoxia caused in mice by pressure reduction, whilst at the same time being only slightly toxic, and that they exert a significant waking action in the test for the "sleep" induced by sodium 4-hydroxybutyrate.
The compounds of the invention, which possess an anti-anoxia action and a psychotropic action, can be used in therapy for the treatment of vigilance disorders, in particular for combating the behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, for the treatment of metabolic encephalopathies and for the treatment of depressive states.
I ~fi254~
The invention consequently includes pharmaceu-tical compositions containing, as active ingredient, a naphthyridine derivative of genera]
formula (I), or a pharmaceu-tically acceptable acid addition salt thereof, in association with any excipients which are suitable for their administration, in particular their oral or parenteral administration.
~ he methods of administration can be oral and parenteral.
The daily posology can range from 10 to 100 mg of naphthyridine derivative. The dosage units can therefore contain, for example, 2 to 50 mg doses of active substance associated with customary excipients, and can be presented in the form of tablets, coated tablets, capsules, suspensions or solutions to be taken orally or in~ected.
Particularly preferred naphthyridine derivatives of the invention are 2,3,3a,4,5,6-hexahydro-lM-indolo[3,2,1-de][1,5-naphthyridine~, 10-chloro-2,3,3a,4,5/6-hexahydro-lEI-lndolo[3,2,1-de]-[1,5-naphthyridine], 10-fluoro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][1,5-naphthyridine~ and 10-bromo-2,3,3a,4,5,6-hexahydro-l~I-indolo[3,2~1-de]-[1,5-naphthyridine], and their pharmaceutically acceptable acid addition salts.
Claims (20)
1. A process for the preparation of a naphthyridine derivative of the general formula:
(I) in which R1 is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing the carbonyl group of a compound of the general formula:
(II) (wherein R1 and R2 are as hereinbefore defined), or an acid addition salt thereof, to methylene, and when required, converting a naphthyridine derivative of general formula (I) so obtained into a pharmaceutically acceptable acid addition salt.
(I) in which R1 is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing the carbonyl group of a compound of the general formula:
(II) (wherein R1 and R2 are as hereinbefore defined), or an acid addition salt thereof, to methylene, and when required, converting a naphthyridine derivative of general formula (I) so obtained into a pharmaceutically acceptable acid addition salt.
2. A process according to claim 1 in which a hydride, in the presence of a Lewis acid, is used for the reduction.
3. A process according to claim 1 in which the reduction of the carbonyl group to methylene is carried out with lithium aluminium hydride in the presence of aluminium chloride.
4. Naphthyridine derivatives, in the form of racemates or enantiomers, of the general formula:
in which R1 is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process claimed in claim 1.
in which R1 is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process claimed in claim 1.
5. A process according to claim 1 wherein R1 repre-sents a hydrogen or halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents an alkyl radical.
6. Naphthyridine derivatives as defined in claim 4 in which R1 represents a hydrogen or halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents an alkyl radical, and pharmaceutically acceptable acid addition salts thereof, when prepared by the process claimed in claim 5.
7. A process according to claim 1 wherein R1 represents a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical.
8. Naphthyridine derivatives as defined in claim 4 in which R1 represents a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, and pharmaceutically acceptable acid addition salts thereof, when prepared by the process claimed in claim 7.
9. A process according to claim 1 wherein R1 represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and R2 represents a hydrogen atom or the methyl radical.
10. Naphthyridine derivatives as defined in claim 4 in which R1 represents represents a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, and pharmaceutic-ally acceptable acid addition salts thereof, when prepared by the process claimed in claim 9.
11. A process according to claim 1 wherein R1 repre-sents a hydrogen, fluorine, chlorine or bromine atom and R2 represents a hydrogen atom.
12. Naphthyridine derivatives as defined in claim 4 in which R1 represents a hydrogen, fluorine, chlorine or bromine atom and R2 represents a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof, when prepared by the process claimed in claim 11.
13. A process according to claim 1 wherein the compound of formula II is 1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one hydrochloride.
14. 2,3,3a,4,5,6-Hexahydro-1H-indolo[3,2,1-de]-[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 13.
15. A process according to claim 1 wherein the compound of formula II is 10-chloro-1,2,3,3a,4,5-hexahydro-6H-indolo [3,2,1-de][1,5-naphthyridine-6-one-hydrochloride.
16. 10-Chloro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de]
[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 15.
[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 15.
17. A process according to claim 1 wherein the compound of formula II is 10-fluoro-1,2,3,3a,4,5-hexahydro-6H-indolo [3,2,1-de][1,5-naphthyridine-6-one-hydrochloride.
18. 10-Fluoro-2,3,3a,4,5,6-hexahydro-1H-indolo[3,2,1-de]
[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 17.
[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 17.
19. A process according to claim 1 wherein the compound of formula II is 10-bromo-1,2,3,3a,4,5-hexahydro-6H-indolo [3,2,1-de][1,5-naphthyridine-6-one-hydrochloride.
20. 10-Bromo-2,3,3a,4,5,6-hexahydro-1H-indolo[3,2,1-de]
[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 19.
[1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts, when prepared by the process claimed in claim 19.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8024717A FR2494693A1 (en) | 1980-11-21 | 1980-11-21 | DERIVATIVES OF HEXAHYDRO-2,3,3A, 4,5,6 1H-INDOLO (3,2,1-DE) (NAPHTHYRIDINE-1,5), THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| FR8024717 | 1980-11-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1162544A true CA1162544A (en) | 1984-02-21 |
Family
ID=9248208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000390531A Expired CA1162544A (en) | 1980-11-21 | 1981-11-20 | Naphthyridine derivatives |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS57116070A (en) |
| AT (1) | AT379594B (en) |
| AU (1) | AU546924B2 (en) |
| BE (1) | BE891204A (en) |
| CA (1) | CA1162544A (en) |
| CH (1) | CH649549A5 (en) |
| DE (1) | DE3143179A1 (en) |
| DK (1) | DK515681A (en) |
| ES (1) | ES8207176A1 (en) |
| FR (1) | FR2494693A1 (en) |
| GB (1) | GB2087889B (en) |
| GR (1) | GR78026B (en) |
| IE (1) | IE52160B1 (en) |
| IL (1) | IL64328A (en) |
| IT (1) | IT1195292B (en) |
| LU (1) | LU83775A1 (en) |
| NL (1) | NL8105282A (en) |
| NO (1) | NO813945L (en) |
| NZ (1) | NZ199008A (en) |
| PT (1) | PT74019B (en) |
| SE (1) | SE8106918L (en) |
| ZA (1) | ZA818082B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2527210A1 (en) * | 1982-05-18 | 1983-11-25 | Synthelabo | ENANTIOMERS OF HEXAHYDRO-2,3,3A, 4,5,6 1H-INDOLO (3,2,1-DE) (NAPHTHYRIDINE-1,5), THEIR SEPARATION METHOD AND THEIR THERAPEUTIC APPLICATION |
| US4997831A (en) * | 1988-09-01 | 1991-03-05 | Glaxo Group Limited | Lactam derivatives |
| CN113214250B (en) * | 2021-04-28 | 2022-06-14 | 华南理工大学 | Synthetic method of fused hexahydro-1, 6-naphthyridine compound |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD129791A5 (en) * | 1976-04-13 | 1978-02-08 | Synthelabo | PROCESS FOR THE PREPARATION OF NAPHTYRIDINE DERIVATIVES |
| GB1550496A (en) * | 1976-12-31 | 1979-08-15 | Logeais Labor Jacques | 1,2,3,3a4,5-hexahydro-canthine derivatives a process for their preparation and their therapeutic applications |
-
1980
- 1980-11-21 FR FR8024717A patent/FR2494693A1/en active Granted
-
1981
- 1981-10-30 DE DE19813143179 patent/DE3143179A1/en not_active Withdrawn
- 1981-11-17 GR GR66585A patent/GR78026B/el unknown
- 1981-11-19 LU LU83775A patent/LU83775A1/en unknown
- 1981-11-20 GB GB8135005A patent/GB2087889B/en not_active Expired
- 1981-11-20 SE SE8106918A patent/SE8106918L/en not_active Application Discontinuation
- 1981-11-20 PT PT74019A patent/PT74019B/en unknown
- 1981-11-20 IE IE2722/81A patent/IE52160B1/en unknown
- 1981-11-20 IT IT25212/81A patent/IT1195292B/en active
- 1981-11-20 AT AT0501381A patent/AT379594B/en not_active IP Right Cessation
- 1981-11-20 NO NO813945A patent/NO813945L/en unknown
- 1981-11-20 ZA ZA818082A patent/ZA818082B/en unknown
- 1981-11-20 ES ES507317A patent/ES8207176A1/en not_active Expired
- 1981-11-20 AU AU77700/81A patent/AU546924B2/en not_active Ceased
- 1981-11-20 CH CH7460/81A patent/CH649549A5/en not_active IP Right Cessation
- 1981-11-20 JP JP56187652A patent/JPS57116070A/en active Pending
- 1981-11-20 DK DK515681A patent/DK515681A/en not_active Application Discontinuation
- 1981-11-20 CA CA000390531A patent/CA1162544A/en not_active Expired
- 1981-11-20 BE BE0/206615A patent/BE891204A/en not_active IP Right Cessation
- 1981-11-20 NZ NZ199008A patent/NZ199008A/en unknown
- 1981-11-20 IL IL64328A patent/IL64328A/en unknown
- 1981-11-23 NL NL8105282A patent/NL8105282A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NL8105282A (en) | 1982-06-16 |
| FR2494693A1 (en) | 1982-05-28 |
| GB2087889B (en) | 1984-01-25 |
| IE812722L (en) | 1982-05-21 |
| GR78026B (en) | 1984-09-26 |
| ES507317A0 (en) | 1982-09-01 |
| LU83775A1 (en) | 1983-09-01 |
| DE3143179A1 (en) | 1982-06-24 |
| ES8207176A1 (en) | 1982-09-01 |
| DK515681A (en) | 1982-05-22 |
| FR2494693B1 (en) | 1983-03-04 |
| IT1195292B (en) | 1988-10-12 |
| BE891204A (en) | 1982-05-21 |
| PT74019B (en) | 1983-12-07 |
| NZ199008A (en) | 1984-07-31 |
| CH649549A5 (en) | 1985-05-31 |
| PT74019A (en) | 1981-12-01 |
| ATA501381A (en) | 1985-06-15 |
| SE8106918L (en) | 1982-05-22 |
| AU7770081A (en) | 1982-05-27 |
| IL64328A0 (en) | 1982-02-28 |
| JPS57116070A (en) | 1982-07-19 |
| IE52160B1 (en) | 1987-07-22 |
| ZA818082B (en) | 1982-10-27 |
| GB2087889A (en) | 1982-06-03 |
| IT8125212A0 (en) | 1981-11-20 |
| NO813945L (en) | 1982-05-24 |
| AU546924B2 (en) | 1985-09-26 |
| IL64328A (en) | 1985-02-28 |
| AT379594B (en) | 1986-01-27 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |