IE873252L - Pyrrole derivatives. - Google Patents
Pyrrole derivatives.Info
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- IE873252L IE873252L IE873252A IE325287A IE873252L IE 873252 L IE873252 L IE 873252L IE 873252 A IE873252 A IE 873252A IE 325287 A IE325287 A IE 325287A IE 873252 L IE873252 L IE 873252L
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D471/02—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 two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D497/04—Ortho-condensed systems
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Abstract
Derivatives of formula (I), in which A forms with the pyrrole ring an isoindoline, 6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, 2,3,6,7- tetrahydro-5H-oxathiinno[1,4][2,3C]pyrrole or 2,3,6,7-tetrahydro-5H- dithiinno[1,4][2,3C]pyrrole nucleus and Het = naphthyridinyl, pyridyl or quinolyl which are unsubstituted or substituted by a halogen, alkyl (1-4 C), alkoxy (1-4 C), alkylthio (1-4 C) or CF3, and R = alkenyl (3- 10 C) with a straight or branched chain or alkyl which is unsubstituted or substituted by alkoxy, alkylthio, cycloalkyl (3-6 C), NH2, alkylamino, dialkylamino, alkylcarbonylamino (in which the amino part is optionally alkyl-substituted), 1- or 2-piperazinyl, piperidyl, piperidino, morpholino, pyrrolidinyl, 1-azetidinyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, (1-piperazinyl)carbonyl, piperidinocarbonyl, (1-pyrrolidinyl)carbonyl, phenyl, pyridyl, 1- imidazolyl, or else R = 2- or 3-pyrrolidinyl or 2-,3- or 4-piperidyl, it being understood that the alkyl radicals form a straight or branched chain and, unless specially mentioned, contain 1 to 10 C and that the piperazinyl, piperidino, piperidyl, pyrrolidinyl and azetidinyl radicals may be unsubstituted or substituted in any position by alkyl, alkylcarbonyl, benzyl or hydroxyalkyl or else may form a lactam functional group with the nitrogen atom of the ring, and, when they exist, their pharmaceutically acceptable salts and the optical isomers of the products of formula (I). <IMAGE> The products of formula (I) are useful as anxiolytics.
Description
6 i 3 The present invention relates to new pyrrole derivatives of general formulas 0 QCO-H in which A forms with the pyrrole ring an isoindoline ring-systemj. Het denotes a naphthyridinyl radical substituted with a halogen atom or a (1 to 4 C) alkyl or (1 to 4 C) alkyloxy radical and R denotes an alkyl radical which is unsubstituted or substituted with an alkyloxy or dialkylamino radical? with an alkylcarbonyl-amino radical (in which the amino portion can optionally be substituted with an alkyl radical), or with a piperidyl or piperidino radical, or alternatively R denotes a 4-piperidyl radical, on the understanding that the alkyl radicals are straight- or branched-chain radicals and contain, except where specifically stated, 1 to 10 carbon atoms, and that the piperidino and piperidyl radicals can be unsub3tituted or substituted at any position with an alkyl radical, as well as, where they exist, their pharmaceutically acceptable salts and the optical isomers of the products of formula (X).
Derivatives of isoindoline, of pyrrolo[3,4-b]~ pyrazine, of dithiino[ 2,3-c]pyrrole or of oxathiino-t2s3~c]pyrrols which are described in French Patents FR 2?101,081 and 2,115,045 or British Patent GB 1,468,497 are known as products possessing tranquillising and anticonvulsant properties. In European Patent Application EP 91,241, products of similar structure possessing anxiolytic properties are described.
In European Patent Applications EP-A~274,929 and EP-A-274,930, compounds very closely related structurally to the products which form the subject of the present invention, and which possess the same type of activity, are described.
According to the invention^ the products of general formula (I) in which Het is defined as abovet with the exception of denoting a 1,8-naphthyridin-2~yl radical substituted at the 7-position with an alkyloxy radical e and the other symbols are defined as above t, may be prepared by the action of an acid of general formula: R-COOH (II) or an alkali metal salt of this acid, in which R is defined as above, on a product of general formulas in which Het*' has the meanings given above for Het£. with the exception of denoting a 1,8-naphthyridin-2*-yl radical substituted at the 7-position with an alkyloxy radical{ and A is defined as above.
The reaction is generally performed in the presence of a condensing agent, such as 1,8-diazabicyclo-[5.4.0]undec-7-ene or 1■«, 5-diasahIcyclo[5.3.0]non-5-ene„ or a quaternary ammonium hydroxide, such as triethyl-benzylammonium hydroxide, in an organic solvent such as dimethylformamide at a temperature of between 20 and 100°Cf or simply,, when the alkali metal salt of the acid is used,, in dimethylformamide at a temperature of 20°C.
The products of general formula (III) may be prepared by chlorination of a product of general formulas 0 OH in which A and Het are defined as above.
The reaction is generally performed in the presence of a chlorinating agent such as sulphinyl chloride or phosphorus oxychloride, in the presence of catalytic amounts of dimethylformamide„ at a temperature 4 between 20"C and the refluxing temperature of the reaction mixture, or any other agent known to those versed in the art which enables a hydroxy radical to be converted to a chloro radical without affecting the 5 remainder of the molecule.
The products of general formula (IV) may be prepared by application or adaptation of the methods described in Belgian Patents 815,019 or 835,325.
According to the invention, the products of 10 general formula (I) may also be prepared by the action of a derivative of general formulas RCO-X (V) in which R is defined as above and X denotes a halogen atom such as a chlorine atom,, or alternatively denotes an 15 activated residue such as a l-imidasolyl radical or a radical R"C0»0- in which R" denotes an alkyl radical„ on a derivative of general formula (IV) defined as above.
The reaction is generally performed in an organic solvent such as chloroform or methylene chloride, or an 20 ether such as tetrahydrofuran or dioxane, or alternatively in dimethyl formamide at a temperature between 0°C and the refluxing temperature of the reaction mixture, in the presence of a base such as sodium hydride or an acceptor for acid such as triethylamine or pyridine. 23 According to the invention, the products of general formula (I) may also be prepared by the action of an alkali metal salt of an acid of general formula (II) on a product of general formulas 0 O-J(0R|)2 0 30 in which R4 denotes a straight- or branched-chain alkyl radical containing 1 to 4 carbon atoms or a phenyl radical and A and Het are defined as above.
The reaction is generally performed in an organic 5 solvent such as dimethyl formamide at a temperature of between 0 and 25°C.
The products of general formula (VI) may be prepared by the action of a product of general formulas 5 C1-P<0R«)2 (VII) 0 in which R<, denotes a straight- or branched-chain alkyl radical containing 1 to 4 carbon atoms or a phenyl radical, on a product of general formula (IV) in which Het and A are defined as above. 10 The reaction is generally performed in an organic solvent such as dimethyl formamide,, in the presence of a base such as an alkali metal hydride, e.g. sodium hydride at a temperature of between -5 and +25°C- It is not necessary to isolate the product of 15 general formula. (VI) in order to carry out. the process according to the invention. It is sufficient to perform the condensation of the products of general formula (VII) and (IV) as has just been stated, and then to add the alkali metal salt of the acid of general formula (II) to 20 the reaction mixture.
As may be realised by those versed in the art, some radicals falling within the definition of the symbol R are incompatible with the reactants employed during the reactions, and must be protected prior to carrying out 25 the processes, or some phases'of the processes, described above™ This is the case, in particular, when the radical R contains primary or secondary amino groups or hydroxyl groups which are capable of giving rise to side reactions. In this case, the said groups must be pro-30 tected by any method known to those versed in the art, and then unblocked after reaction.
The new products of general formula (I) may be purified by the usual known methods, e.g. by crystal-lization, chromatography or successive extractions in 35 acidic and basic medium.
The new products of general formula (I) may be converted to an addition salt with acids, by the action 6 of an acid in an organic solvent such as an alcohol,, a ketone, an ethar or a chlorinated solvent. The salt formed precipitates, where appropriate after concentration of its solution; it is separated by filtration or decantation.
The products of general formula (I) possess especially advantageous pharmacological properties , which reveal an anxiolytic, hypnotic, anticonvulsant, anti-epileptic and muscle relaxant activity. Thus, they show appreciable affinity in vitro for benzodiazepine receptor sites at concentrations whose values are between 0.4 and 200 nM according to the technique described by J«C. BLAMCHARD and L. JULOU, J. of Neurochemistry, 40e SOI (1983) modelled on the work of SQUIRES and BRAESTRUP, Mature, 266, 732 (1977).
In animals (mice), they have been shown to be active, at doses which are generally of between 0.3 and 200 mg/kg orally, with respect to pentetrassole-induced convulsions according to a technique closely allied to that of EVERETT and RICHARDS, J. Pharmacol., 81, 402 (1944).
The new products of general formula (I) and their salts possess, in addition^ low toxicity. Their oral LD50 is generally between 300 and 900 mg/kg in mice.
For medicinal use, the new products of general formula (I) may be employed as they are or in the state of ph&rmaceutically acceptable salts, i.e. salts which are non-toxic at the doses at which they are used.
As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with inorganic acids, such as hydrochlorides, sulphates, nitrates and phosphates, or with organic acids, such as acetates, propionates, succinates, benzoates, fumarates, maleates, methanesulphonates, isethionates, theophy11ineacetate s, salicylates, phenolpnthalinates and methylenebis(0-oxynaphthoates), or substitution derivatives of these compounds.
Of special value are the products of general formula (I) in which A forms with the pyrrole ring an 7 isoindoline ring-system, Het denotes a 1,8-naphthyridin-2-vl radical substituted with a halogen atom or a (1 to 4 C) alkyloxy radical and R denotes a straight- or branched-chain alkyl radical containing 1 to S carbon 5 atoms which is unsubstituted or substituted with an alkyloxy, dialkylamino, alkylcarbonylamino or piperidino radical£, or alternatively R denotes a 3-piperidyl (sic) radical,, on the understanding that the alkyl radicals are straight- or branched-chain radicals and contain, except 10 where specifically stated* 1 to 10 carbon atomse and that the piperidino and piperidyl radicals can be unsubsti-tuted or substituted at any position with one or more alkyl radicals.
The following products are of very special values 15 (RS) -2-(7-Chloro-l,8-naphthyridin-2-yl)-3-oxo~l~ isoindolinyl 4-acetamidobutyrate (RS)-2~(7-Chloro-l,8-naphthyridin-2~yl)-3-03S0~l-isoindolinyl l-propionyl-4-piperidinecarboxylate (RS)-2-(7-Methoxy-1,8-naphthyridin-2~yl)-3-oxo-l-20 isoindolinyl 5-methylhexanoate (RS)-2-(7~Chloro~l, 8-naphthyridin-2-yl)-3~oxo-l-isoindolinyl 3-diisopropylaminopropionate.
The examples which follow show how the invention may be put into practice. 25 EXAMPLE 1 3-Dimethylaminopropionic acid hydrochloride (9.2 g) and l,8-diazabicyclo[5.4.0]undec-7~ene (16.7 g) are added at a temperature in the region of 20°C to a solution {, Maintained under an argon atmosphere t, of 30 3 ~ch 1 oro-2 - ( 7 - c h 1 o r o - 1 # 8-naphthyr idin-2 - yl) -1 -isoindolinone (16.5 g) in anhydrous dimethylformamide (100 cc), and the suspension obtained is stirred for 24 hours at a temperature in the region of 20°C. Distilled water (200 cc) and dichloromethane (200 cc) are 35 then added. The aqueous phase is separated after settling has occurred and then re-extracted with dichloromethane (3 x 50 cc). The organic phases are combined, washed with distilled water (2 x 50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under 8 reduced pressure (2.7 kPa) at 80 °C. The residue obtained is dissolved in dichloromethana (100 cc) and the solution extracted with 1 N aqueous hydrochloric acid solution (2 x 100 cc). The aqueous phases are combined, washed 5 with dichloromethana (50 cc), alkalinized with 10 N sodium hydroxide solution to a pH in the region of 11 and extracted with dichloromethane (2 x 150 cc). The organic phases are combined, washed with distilled water (2 x 30 cc), dried over magnesium sulphate, filtered and 10 then concentrated to dryness under reduced pressure (2.7 kPa) at SOeG, After the product thereby obtained has been recrystallised twice successively in ethanol, 2- (7-chloro-l f 8-naphthyridin~2-yl)-3-oxo-l-isoindolinyl 3-dimethylaiainopropionate (2.9 g), III». p. 150°C, is 15 obtained. 3-Dimethylaminopropionic acid hydrochloride may be obtained by the method described by CLARKE H.T., GILLESPIE H.B. and WEISSHAUS S.Z., J. Am. Chem. Soc., 55, 4571 (1933). 20 3-Chloro-2~(7-chloro-l„8-naphthyridin-2-yl)-1- isoindolinone may be prepared in the following manner: sulphinyl chloride (200 cc) is added dropwise with stirring to 3~hydroxy~2- (7-jnethoxy-l,8-naphthyridin~2-yl)-1-isoindolinone (15-5 g). The reaction mixture is 25 heated to reflux with stirring for 1 hour,, then treated with dims thy 1 formamide (10.5 cc) and heated again to reflux for 3 hours, then cooled to a temperature in the region of S0eG and concentrated to dryness under reduced pressure (2.7 kPa) at 60°C. Dichloromethane (100 cc) is 30 added to the residue obtained, and the mixture is con centrated to dryness under reduced pressure (2./ kPa) at 60°C. Dichloromethane (100 cc) is added to the residual solid obtained and th© mixture is stirred for 10 minutes. The insoluble product is separated by filtration and 35 washed with dichloromethane (15 cc) and then with diiso-propyl ether (2 x 25 cc) and dried in the air. 3-Chloro-2- ( 7-chloro-l, 8-naphthyridin-2-yl) -1-isoindolinone (12»4 g), which has not melted at 300°C» is thereby obtained. 9 3-Hydroxy~2- (7-methoxy-i,8~naphthyridin-2~yl) -1-isoindolinone may be prepared by the method described in Belgian Patent 815,019.
EXAMPLE 2 5 Working in a manner similar to that described in Example 1, but starting with 3~chloro-2~(7-chloro~lt, 8-naphthyridin~2-yl)-l-isoindolinone (8.25 g) £, 4-dimethyl-aminobutanoic acid hydrochloride (4.25 g) and lt,8~diasa-bicyclo[5.4.0]undec-7~ene (7.6 g), 2~(7-chloro~l,8-10 naphfchyridin-2-yl)-3-oxo-l~isoindolinyl 4-dimethylamino-butanoate (4.1 g)£, m.p. 148°C, is obtained. 4-Dimethylaminobutanoic acid may be prepared by the method described by C. HARRIES and P. DUVBL, Liebigs Ann. Chem., (1915) 410, 54. 15 EXAMPLE 3 4-Methylpentanoic acid (2.4 g) and 1£,8-diasa-bicyclo[5»4.0]undee-/-ene (3.05 g) are added at a temperature in the region of 20°C to a solution, maintained under an argon atmosphere, of 3«chloro~2-(7-chloro-l,8-20 naphthyridin-2-yl)-l-isoindolinone (6.8 g) in anhydrous dimethylformamide (60 cc), and the suspension obtained is stirred for 24 hours at a temperature in the region of 20°C. Distilled water (500 cc) and dichloromethane (150 cc) are then added. Th® aqueous phase is separated 25 after settling has occurred and then re-extracted with dichloromethane (2 x 150 cc). The organic phases are combined, washed with distilled water (3 x 50 cc), dried over magnesium, sulphatet filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60°C. The 30 oily residue is purified by chromatography on silica gel (150 g) contained in a column 3.5 cm in diameter [eluant: dichloromethane/meth&nol (98s2 by volume)]. Elution is first performed with 200 cc of solvent: the corresponding eluate is discarded; slution is then performed with 35 900 cc of solvent: the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40 eC. After recrystallisaticm in ethanol, 2-(7-chloro-1,8-naphthyridin~2-yl)-3-oxo-l-isoindolinyl 4-methyl-pentanoate (4 g), m.p. 147"C, is obtained. i 0 EXAMPLE 4 Working as in Example 1, but starting with 3-chloro-2~(7-chloro-l» 8-naphthyridin-2-yl)-1-isoindolinone (9-9 g) in anhydrous dimethylformamide 5 (100 cc)f l-methyl-3-piperidinecarboxylic acid hydrochlo ride (5.4 g) and lf8-diag;abicyclo[5.4»0]undec=7-ene (10.7 g), a product (11.3 g), m.p. about 70°Cff is obtained after precipitation in water (1000 cc)f filtration and drying in the air. The solid obtained is 10 dissolved in ethanol (40 cc). A solution of fumaric acid (3 g) in ethanol (30 cc) is added to the hot solution obtained. The crystallised product obtained is separated by filtrationr washed with ethanol (15 cc) and dried under reduced pressure (0.07 kPa) at 45°C. 2-(7-Chloro-15 1,8-naphthyridin-2 ~y 1)-3-oxo~l-isoindolinyl 1-methyl-3-piperidinacarboxylate acid fumarate (9.8 g) f m.p. 211°Cl. is thereby obtained. 1-Methyl-3«piperidinecarboxylic acid hydrochloride may be prepared in the following manners ethyl 20 l-methyl»3~piperxdinecarbo3Eylate (17.1 g) is dissolved in 5 N aqueous hydrochloric acid solution (67 cc). After 6 hours under reflux,, the solution is concentrated to dryness and the residue re-crystallised in acetone. 1-Methyl-3-piperidinecarboxy1ic acid hydrochloride 25 (15.7 g), m.p. 186°Cf, is thereby obtained.
EXAMPLE 5 Working as in Example 1, but starting with 3-chloro-2-(7-chloro-l,8-naphthyridin-2-yl)~1~ isoindolinone (9.9 g) in anhydrous dimethylformamide 30 (100 cc), l-methyl-4-piperidinecarboxylic acid hydrochloride (5.4 g) and 1,8~diasabicyclo[5.4.0]undec~7~ene (10.7 g),, and after the residue obtained has been re-crystallised twice successively in ethanol and then in acetonitrile, 2-(7~chloro-l,8-naphthyridin-2-yl)-3-oxo-35 1-isoindolinyl l-methyl-4-piperidinecarbo:cylat® (5.6 g), m.p. 136 °C and then 157°C, is obtained,, 1 -Methyl - 4 -piper idinec arboxy1 ic a,c id hydrochloride may be prepared according to the method described in Example 4 for the preparation of I 1 1-methyl-3-piperidinecarhoxylic acid hydrochloride, but starting with ethyl X~methyl~4-piperidinecarhoxylate (8»6 g) and 6 N aqueous hydrochloric acid solution (33 cc). After reerystalligation in acetone,, 1-methyl- 5 4-piperidinecarboicylic acid hydrochloride (6.5 g), m.p. 231 aCt. is obtained.
Ethyl l-methyl-4~piperidinecarboxylate may be prepared in the following manners to a solution, maintained at a temperature in the region of 5eC# of ethyl 10 4-piperidinecarboscylate (15.7 g) in water (3 cc) , a 37% strength (weight/volume) solution (20.3 cc) of formaldehyde is added in the course of 15 minutes at the seuis temperature, followed, again in the course of 15 minutes, by formic acid (11.5 g)» The mixture is heated for 15 4 hours under reflux, then cooled, and brought to a pH in the region of 10 using 10 N aqueous sodium hydroxide solution. After extraction with methylene chloride (3 x 150 cc), washing the organic extracts with water, drying and concentration to dryness under reduced pres-20 sure (2,7 kPa) at 70 °C, ethyl l-methyl-4-piperidine-carboxylata (13.5 g) is obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
EXAMPLE 6 25 Working as in Example 1, but starting with 3-chloro-2» ( 7-ehloro-l 8- naphthyridin-2-yl) -1 -isaindolinone (6 ,, S g) in anhydrous dimethylformamide (70 cc), 3-diisopropylaminopropionic acid hydrochloride (4.4 g) and 1,8-diazabicyclo[5.4.0]undec-7~ene (7.45 g), 30 and after the residue obtained has been recrystallized successively, first in acetonitrile and then in ethanol, 2- (7-chloro-l, 8 - naphthyr idin- 2 -yl) -3-oxo-l-iaoindolinyl 3-diisopropylaminopropionate (2.7 g), m.p. 135°C, is obtained. 35 3-Diisopropylaminopropionic acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid, but starting with ethyl 3-diisopropylaminopropionate (5 g) and 6 N aqueous i s hydrochloric acid solution (35 cc) . After the product obtained has been recrystallised in acetone,. 3-diiso-propylaminopropionic acid hydrochloride (2 „ 3 g) e m.p. 170"C,. is obtained.
Ethyl 3-diisopropylaminopropionate may be obtained. in the following manners ethyl 3-bromopropionate (18.1 g) is introduced dropwise in the course of 30 minutes into a solution of diisopropylaraine (28,5 cc) and ethanol (40 cc) maintained at a temperature of 25°C-The suspension obtained is heated to reflux for 4 hours. After being cooled, the reaction mixture is taken up with water (100 cc) and 4 N aqueous hydrochloric acid solution (70 cc). After the mixture is washed with ethyl ether (100 cc), it is alkalinized to a pH in the region of 9 with 4 N aqueous sodium hydroxide solution. The oil formed is extracted with methylene chloride (3 x 150 cc). After being washed with water (2 x 100 cc) and dried, the methylene chloride solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. Ethyl 3-diisopropylaminopropionate (11.6 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
EXAMPLE 7 Triethylamina (27 cc) is added to a solution, maintained at a temperature in the region of 20°C, of 2- ( 7-methoxy-l,8-naphthyridin~2-yl)-3-hydroxy-l-iso~ indolinone (12.3 g) in methylene chloride (200 cc). 4-Methylpentanoy1 chloride (10.8 g) and 4-dimethylamino~ pyridine (50 mg) are then introduced dropwise in the course of 20 minutes, and the reaction mixture is then heated for 19 hours under reflux. The suspension obtained is poured into water (800 cc) and the solid obtained is separated by filtration and removed.The organic phase is separated after settling has occurred, washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is purified by chromatography on silica gel (0.063-0.2 mm; 150 g) contained in a column 2.7 cm in diameter (eluant: methylene chloride), ©luting 50-cc fractions. Fractions •1 3 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 400C- After the solid obtained has been recrystallised in aeetonitrile, 2 - (7 -methoxy-1 f 8-naphthyridin~2-yl) -3~oxo-l~isoindolinyl 5 4-methylpsntanoate (4.9 g), m.p. 133°C? is obtained. 4-Methylpentanoyl chloride may bs prepared according to F. KQGL and C.A. SALEMINK, Hac. Trav. Chim. 71, 779-97 (1952), EXAMPLE 8 10 Working as in Example 1, but starting with 3~chloro=2-( 7-chloro-1, Q-naphthyridin-2-yl) -l-iso~ indolinone (9.9 g) in anhydrous dimethylformamide (100 cc) t 5-methylhexanoic acid (3.9 g) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (4.6 g), and after recrystal-15 ligation in ethanol, 2«= (7-chloro-l t, 8-naphthyr±din-2»yl) -3-osco-l-isoindolinyl 5-methylh@xanoate (8 g), m.p. 132°Cf is obtained.
EXAMPLE 9 The procedure is as in Example 7, but starting 20 with 2-(7-methoxy-l,8-naphthyridin-2-yl)-3-hydroxy~l-isoindolinone (6-8 g) in methylene chloride (100 cc) ,, triethylamine (10.1 g), 5-methvlhexanoyl chloride (6.4 g) and 4-ddjnethylaminopyridine (50 mg). The residue obtained after treatment is purified by chromatography on silica 25 gel (Q.063-0.2 mm; 100 g) contained in a column 2.8 cm in diameter (eluant* methylene chloride), collecting 30-cc fractions. Fractions 19 to 94 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After the residue obtained has been recrystallized in heptane 30 (75 cc) , 2-(7-methoxy-l,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl 5~iaethylhexano&te (5.6 g), m.p. 105"C, is obtained.
EXAMPLE 10 Working as in Example 1, but starting with 35 3-chloro-2~(7-chloro-l,8-naphthvridin-2-yl)-1-iso-indolinone (29.7 q) in anhydrous dimethyl formamide (300 cc), 4-acetamidobutyric acid (13.1 g) and 1,8~diazabicyclo [5.4.0] undec-7-ene (13.7 g), 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl 1 4 4~acetoamidobutyrate (18 g), m.p. 18 6 ° C £ is obtained after recrystallization in acetonitrile.
EXAMPLE 11 The procedure is as in Example 1, but starting with 3-chloro-2~(7-chloro-l,8-naphthyridin-2-yl)-1-isoindolinone (4»95 g) in anhydrous dimethylformamide (60 cc)t, phenylacetic acid (2.05 g) and 1,8-diassahicyclo-[5»4.0]undec-7-ene (2.25 g). After reerystallisation in ethyl acetate, 2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl phenylacetate (4.4 g), m.p. 222-224°Cr is obtained.
EXAMPLE 12 Working as in Example lf but starting with 3-chloro-2- ( 7-chloro-l, 8-naphthyridin-2-yl) -l-iso~ indolinone (9.9 g) in anhydrous dimethylformamide (100 cc)f 3«(2,6-dimethylpiperidino)propionic acid hydrochloride (S.7 g) and 1 f8-diaaabicyclo[5.4*0]undec-7-ene (10.7 g) e 2-(7-chloro-l?8-naphthyridin-2-yl)-3~oxo-1-isoindolinyl 3-(2 ,S-dimethylpiperidino)propionate (S g), m.p. 159°C, is obtained after recrystallization in ethanol. 3-(2,S-Dimethylpiperidino)propionic acid hydrochloride may be obtained by •working according to the method described in Example 4 for the preparation of l-methyl-3-piperidinecarboxylic acid hydrochloride,, but starting with ethyl 3-(2,6-dimethylpiperidino)propionate hydrochloride (12.5 g) and S '1 aqueous hydrochloric acid solution (35 cc). 3-(2,, 6-Dimethylpiperidino)propionic acid hydrochloride, m.p. 215°C, is thereby obtained.
Ethyl 3-(2,6-dimethylpiperidino)propionate hydrochloride may be obtained by working according to the method described in Example 6 for th® preparation of ethyl 3-diisopropylaminopropionate, but starting with ethyl 3-bromopropion&te (18.1 g), 2,6-dimethylpiperidine (27 cc) and ethanol (30 cc). The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue obtained is taken up with water (50 cc) and 4 N aqueous hydrochloric acid solution (30 cc). The aqueous phase is washed with ethyl ether (2 x 80 cc) and neutralised with 4 N aqueous sodium hydroxide solution (40 cc). The insoluble oil is extracted with ethyl ether (3 x 120 cc)? the organic extracts are then washed with water (2 x 80 cc) and concentrated to dryness under 5 reduced pressure (2.7 kPa) at 40°C. The residue is dissolved in ethyl ether (100 cc) . A 4.5 N solution (13.4 cc) of gaseous hydrochloric acid in ethyl ether is added to the solution obtained. A product precipitates. It is separated by filtration,, washed and dried in the 10 air. Ethyl 3-(2,6-dimethylpiperidino)propionate hydro chloride (14.4 g),, m.p. 146°C, is thereby obtained. EXAMPLE 13 Working as in Example 1# but starting with 3-chloro-2-(7-chloro-l?8-naphthyridin-2- yl)-1-iso-15 indolinone (9.9 g) in anhydrous dimethyl formamide (100 cc) 4-piperidinobutyric acid hydrochloride (6.2 g) and 1,8~diazabicyclo[5.4.0]undec-7-ene (10.7 g), 2-(7-chloro-1„8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl 4-piperidinobutyrate (9.4 g) # m.p. 1666C,, is obtained 20 after'recrystallization in ethanol. 4-Piperidinobutyric acid hydrochloride may be obtained by working according to the raethod described in Example 4 for the preparation of l-methyl-3-piperidine-c&rboxylic acid hydrochloride, but, starting with ethyl 25 4-piperidinobutyrate (19,9 g) and 6 M aqueous hydrochloric acid solution (66.5 cc) * and by heating for 24 hours under reflux. 4-Piperidinobutyric acid hydrochloride (IS.3 g), m.p. 190°C, is thereby obtained.
Ethyl 4~piperidinobutyrate may be prepared by 30 working according to the method, described in Example 6 for the preparation of ethyl 3~diisopropylamino-propionate, but starting with ethyl 4-bromobutyrate (48,8 g), piperidine (42.5 g) and ethanol (75 cc). Th© reaction mixture is taken up with water (200 cc) and 4 M 35 aqueous hydrochloric acid solution (120 cc), After being washed with ethyl ether (150 ec)f the aqueous phase is alkalinized to a pH in the region of 9 with 4 M aqueous sodium hydroxide solution. The oil formed is extracted with methylene chloride (3 x 150 cc). The organic 1 6 extracts are combined, washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa) at 70°C. Ethyl 4~piperidinobutyrate (47 g) is thereby obtained in the form of an oil, which is employed in the 5 crude state in the subsequent syntheses.
EXAMPLE 14 Working as in Example 1, but starting with 3-chloro~2-( 7-chloro-l, 8-naphthyridin-2~yl) -1-iso-indolinone (9.9 g) in anhydrous dimethylformamide 10 (100 cc), 4-propionamidobutanoic acid (4.8 g) and l,8-diagabicyelo[5.4»0]|undec-7-ene (4.6 g), 2-(7»chloro~ 1,8-naphthyridin-2-y 1)-3-oxo-l-isoindolinyl 4-propion-amidobutyrate (6.5 g), m.p. 179®C, is obtained after recrystallization is acetonitrile. 15 4-Propionamidobutanoic acid may be prepared in the following manners 4-aminobutyric acid (10.3 g) is added in th® course of 15 minutes to propionic anhydride (10 cc) at a temperature in the region of 20°Cfollowed by 5 drops of concentrated sulphuric acid (d=l„83)t and 20 the mixture is heated to a temperature in the region of 100°C for 2 hours. After the mixture is cooled, the crystallized solid is separated off by filtration, washed with ethyl ether (5 x 100 cc) and dried. 4-Propionamido-butanoic acid (9.8 g), m.p.. 85~90#C, is thereby obtained. 25 EXAMPLE 15 To a solution, maintained at a temperature in the region of 20"Cl of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydbcoxy-l-isoindolinone (9.2 g) and triethylamine (20 cc) in 1f2-dichloroethane (150 cc), there is added, 30 in the course of 20 minutes, a solution of 2-methy 1-propoxyacetyl chloride (9 g) in 1„2-dichloroethane (20 cc) followed by 4-dimethylaminopyridine (50 mg), and the mixture is heated to reflux for 16 hours. The reaction mixture is poured into water (250 cc) and then 35 extracted with methylene chloride (100 cc). After the extract is washed with water, dried and concentrated to dryness under reduced pressure (3 kPa), the residue obtained is purified by two successive recrystallizations in ethanol. 2-(7-Methoxy-1,8-naphthyridin-2-yl)- 1 7 3-oxo-l-isoindolinyl 2~methylpropoxyacetate (7.9 g), m.p. 114°C, is thereby obtained. 2»Methylpropoxyacetyl chloride may be obtained in the following manner: thionyl chloride (5 cc) is added in 5 the course of 15 minutes to a solution of 2-methyl~ propoxyacetic acid (8.3 g) in chloroform (50 cc). The mixture is heated for 5 hours under reflux and then evaporated to dryness -un.der reduced pressure (2.7 kPa) . S-Methylpropoxyacetyl chloride (7.5 g) is thereby ob-10 tained in the form of an oil, which is employed in the crude state in the subsequent syntheses. 2~Methylpropoxyacetic acid may be obtained in the following manners sodium (12.7 g) is added to isobutyl alcohol (200 cc) maintained at a temperature in the 15 region of 100°C, and the mixture is heated until the sodium has disappeared. Chloroacetic acid (23.S g) is then added in the course of 1 hour - and heating is continued for 2 hours. After being cooled;, the reaction mixture is poured into water (250 cc). The aqueous phase 20 is washed with ethyl ether (200 cc) l? concentrated to half the volume under reduced pressure (3 kPa) and then acidified to a pH in the region of 1 with 1 N aqueous hydrochloric acid solution. The oil formed is extracted with ethyl ether (3 x 150 cc). The organic phase is 25 washed with water, dried and concentrated to dryness under reduced pressure (3 kPa)« After the residue obtained has been distilled under reduced pressure, 2~methylpropoxyacetic acid (21.8 g) b.p. 92-96°C (0-93 kPa), is obtained. 30 EXAHPLE 16 The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-l,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) in anhydrous dimethylformamide (SO cc). 1-isopropy1-4-piperidinecarboxy1ic acid hydro-35 chloride (4.3 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (7.1 g). After recrystallization in acetonitrile, a solid (4.1 g) is obtained, which is dissolved in ethanol (120 cc) under reflux; fmft&ric acid (1.03 g) dissolved in ethanol (20 cc) is added. After crystallisation in 1 8 acatonitrile t 2-(7-chloro-l {. 8-naphthyridin-2~yl) -3»oxo~ 1-isoindolinyl l-isopropyl-4-piperidinecarboxylate acid fumarate (4,9 g), m.p. 184"C, is obtained. 1-1sopropy1-4-piperidinec arboxy1ic acid hydro-5 chloride may be prepared according to the method described in Example 4 for the preparation of 1-methyl-3» piperidinecarboxylie acid hydrochloride g but starting with ethyl l-isopropyl-4-piperidinecarboxylate hydrochloride (S.5 g) and S N aqueous hydrochloric acid 10 solution (18.6 cc). 1-1sopropy1- 4 ~piperidinecarboxy1ic acid hydrochloride (4.5 g), m.p. 260-265°C(. is thereby obtained.
Ethyl l-isopropyl-4~piperidinecarboxylate hydrochloride may be prepared in the following manners ethyl 15 4~piperidinecarboxylate (15.7 g) is added in the course of 10 minutes at a temperature in the region of 25"C to a solution of 2-bromopropane (6.15 g) in propanol (50 cc). The reaction mixture is heated for 48 hours under reflux and then concentrated to dryness under 20 reduced pressure (2.7 kPa). The residue is taken up with 1.5 N aqueous hydrochloric acid solution (150 cc) and the solution obtained is washed with ethyl ether (2 x 100 cc). The aqueous phase is alkalinized to a pH in the region of 9 with 4 JS aqueous sodium hydroxide 25 solutione and extracted with methylene chloride (3 x 100 cc). The organic phase is washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. The residue obtained is dissolved in ethanol (30 cc). A 4.5 N solution (12 cc) of gaseous 30 hydrochloric acid in ethyl ether is added to the solution obtained. The precipitate formed is separated by filtration, washed and dried. Ethyl l~isopropyl~4-piperi-dinecarboxylate hydrochloride (6-9 g), m.p. 195-200*C„ is thereby obtained. 35 EXAMPLE 17 3-Chloro~2-(7-chloro-l,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) is added to a solution of N-acetyl-jS-alanine (3.9 g) in dimethyl formamide (66 cc). 1,8-Diazabicyclo[5.4.0]undec-7-ene (3.8 g) is added dropwise to the beige suspension, obtained, and the mixture is stirred at a temperature in the region of 20°C for 18 hours. i>I-acetyl~/3-alanine (1 g) is added again, followed by 1,8-diasabicyclo[5.4.0]undec-7~ene (1 g) , and 5 the mixture is stirred at a temperature in th® region of 20°C for 24 hours. The reaction mixture is then poured into water (130 cc). The solid obtained is separated by filtration, washed with water (3 x 25 cc) and purified by chromatography under pressure (50 kPa) on silica (500 g) 10 contained in a column 5 cm in diameter [eluants dichloro-methans/methanol (95s5 by volume)]„ collecting 75-cc fractions. Fractions 7 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa), After the solid obtained has bean recrystallized in acatonitrile, 15 2- (7-chloro-l, 8-naphthyrid.in-2~yl) -3-oxo-l-isoindolinyl 3-aeetamidopropanoate (3.9 g), m.p. 220°C, is obtained.
N-Acetyl-^-alanine may be prepared according to the method described in Example 14 for the preparation of 4-propionamidobutanoic acid, but starting with ^-alanine 20 (8.9 g) and acetic anhydride (9.6 g). N~Acetyl-£-alanine (12.9 g) is thereby obtained in the form of an oil, with is employed in the crude state in the subsequent syntheses.
EXAMPLE 18 25 The procedure is as in Example 17, but starting with 5-acetamidopentanoic acid (5 g) in dimethyl formamide (66 cc), 3-chloro-2»(7-chloro-l,8-naph-thyridin-2-yl)-l~isoindolinone (6,6 g) and 1,8-diazabi-cyclo[5.4.0]undec-7-ene (4.7 cc). After recrystallization 30 in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3~ oxo-1-isoindolinyl 5-acetoaiaidopentanoate (3.3 g), m.p. 185°C, is obtained. 5-Acetaiaidopentanoic acid may be prepared according to the method described in Example 14 for the pre-35 paration of 4-propionamidobutanoic acid, but starting with 5~aiainopeirtanaic acid (11.7 g) and acetic anhydride (12.6 g). The reaction mixture is concentrated to dryness under reduced pressure (0.05 kPa) and 5-acetamido-pentanoic acid (6 g) is thereby obtained in the fom of 2 0 an oil* which is employed in the crude state in the subsequent syntheses.
EXAMPLE 19 The procedure is as in Example 1, but starting 5 with 3-chloro-2-(7-chloro-l,8-naphthyridin-2~yl)-1- isoindolinone (9,9 g) in anhydrous dimethyl formaraide (100 cc), 4-isobutyry 1 aminobutyric acid (5*2 g) and l,8-diasabicyclo[5.4.0Jundec~7-ene (4.6 g) . The residue obtained is recrystallized in acetonitrile and then 10 purified by chromatography on silica (0.063-0.2 mm;? 130 g) contained in a column 3 cm in diameter [eluants methylene chloride/methanol (98s2 by volume) mixture] collecting 25-cc fractions™ Fractions 79 to 85 are combined and concentrated to dryness under reduced 15 pressure (2.7 kPa). The residue obtained is crystallised by stirring in isopropyl ether. 2-(7-Chloro-1,8-naphthyr idin- 2 -yl )-3-oxo-l-isoindolinyl 4-isobutyrylamino-butyrate (5.5 g), m.p. 208"0, is thereby obtained. 4-Isobutyrylaminobutyric acid may be prepared 20 according to the method described in Example 14 for the preparation of 4~propionamidobutanoic acid, but starting with 4-asainobutyric acid (10.3 g) and isobutyric anhydride (15.8 g) - 4-1sobutyry1aminobutyric acid (15.5 g) is thereby obtained in the form of an oil, which 25 is employed in the crude state in the subsequent syntheses.
EXAMPLE 20 lf8-Diazabicyclo[5.4.0]undec-7-ene (10-7 g) is added dropwise to a suspension of 3-chIoro~2~(?-chloro-30 1,8-naphthyridin~2-yl)-1-isoindolinone (9.9 g) and 4-diisopropylaminobutyric acid hydrochloride (6.7 g) in dimethyl formamide (100 cc)f> and the mixture is stirred at a temperature in the region of 20°C for 20 hours- The reaction mixture is then poured into water (130 cc). The 35 solid obtained is separated by filtration and then dissolved in methylene chloride (200 cc). The organic extracts are washed with 0.1 H aqueous hydrochloric acid solution (2 x 35 cc), 0.5 N aqueous hydrochloric acid solution (35 cc) t» and then with water (2 x 35 cc). The 2 1 organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with methylene chloride (200 cc). The organic phase is washed with 5 saturated aqueous sodium hydrogen carbonate solution (2 x 50 cc). The organic phase is dried over magnesium sulphate £, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallised in isopropyl ether. 2-(7~Chloro~l,S~naphthyridin~2-yl)~ 10 3-oxo-l-isoindolinyl 4-diisopropylaminobutyrate (7.1 g), m.p. H8eC, is thereby obtained. 4-Diisopropylaminobutyric acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of l-methyl-3-piperi-15 dinecarboasylic acid hydrochloride,, but starting with ethyl 4-diisopropylaminobutyrate (9.2 g) and 6 N aqueous hydrochloric acid solution (28.5 cc) and by heating for 6 hours under reflux. 4-Diisopropylaminobutyric acid hydrochloride (8 g), m.p. 136°C(, is thereby obtained. 20 Ethyl 4-diisopropylaminobutyrat© may be obtained in the following manners diisopropylamine (40.4 g) is added dropwise to a solution of ethyl 4-bromobutyrate (39 g) in ethanol (80 cc). The solution obtained is heated to reflux for 6 hours. After the insoluble 25 material formed has been filtered off the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up with distilled water (15 cc) and 4 M aqueous hydrochloric acid solution (100 cc). The aqueous phase is washed with ethyl ether (3 x 75 cc) and 30 then alk&llnized with 10 1 aqueous sodium hydroxide solution. The oil formed is extracted with ethyl ather (3 x 75 cc). The organic phase obtained is concentrated to dryness under reduced pressure (2.7 kPa). Ethyl 4-diisopropylaxainobutyrate (9.2 g) is thereby obtained in 35 the form of an oil,, which is employed in the crude state in the subsequent syntheses.
EXAMPLE 21 Triethylamine (12.2 g), pyridine (90 cc) and then 3~me t hy Ibutyry 1 chloride (9.7 g) is added to a suspension 2 2 of 2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-l-iso-indolinone (12.5 g) in methylene chloride (600 cc), while the temperature is maintained in the region of 25 °C. After 4 hours' stirring at a temperature in the region of 5 25°C, 3-methylbutyryl chloride (9.7 g) is added again and the mixture is stirred for a further 16 hours at this temperature. The reaction mixture is then concentrated to dryness under reduced pressure (3 kPa) and the residue is taken up with water (500 cc). The insoluble product 10 formed is separated by filtration, washed, dried and then recrystallized in a mixture of isopropyl ether and ethyl acetate (50s50 by volume). 2-(7-Chloro-l,8-naphthyridin~ 2»yl)-3-oxo-l-isoindolinyl 3-methylbutyrate (7.9 g), m.p. 154"C, is thereby obtained. 15 EXAMPLE 22 Pyridine (24 cc) followed, in the course of 30 minutes, by propionyl chloride (5.5 g) are added successively to a solution of 2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-l-isoindolinone (3.2 g) in 20 methylene chloride (160 cc)while the temperature is maintained in the region of 25 °C. The Miixture is stirred for 3 hours at this temperature and then treated with water (100 cc) . The organic phase is separated after settling has occurred., washed with water, dried and 25 concentrated to dryness under reduced pressure (2.7 kPa).
The residue obtained is crystallised in isopropyl ether and then recrystallized in a 'mixture of isopropyl ether and ethyl acetate (25s75 by volume). 2-(7-Chloro-l,8-naphthyridin-2-y 1)-3-oxo-l-isoindolinyl propionate (1 g), 30 m.p. 160°C, is thereby obtained.
EXAMPLE 23 The procedure is as in Example 22, but starting with 2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (6.4 g) in methylene chloride (320 cc), 35 pyridine (48 cc) and butyryl chloride (12.8 g). After one recrystallization in isopropyl ether followed by two recrystallizations in acetonitrile, 2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl butyrate (3.4g), m.p. 140°C, is obtained.
EXAMPLE 24 The procedure is as in Example 7, but starting with 2- (7-bromo-l, 8 -naphthyr idin-2 -y 1) - 3-hydroxy-1 -isoindo1inone (8.55 g) in methylene chloride (110 cc), 5 triethylamine (11.1 g)t, 5-methylhexanoyl chloride (7 g) and 4-dimethy 1 erai n a pv r i d i ne (50 mg). After the residue obtained has been crystallised in hexane and then recrystallized in ethanol, 2~(7~brorao-lt,8-naphthyridin-2~yl)-3-oxo-l-isoindolinyl 5-methylhexanoate (7.5 g) t m.p. 10 135°C, is obtained. 2-(7-Bromo-l,8-naphthyridin-2-yl)~3-hydroxy-1-isoindolinone may be prepared as described in Belgian Patent 815,019.
EXAMPLE 25 15 Mn oily suspension (50% by weight? 0.9S g) of sodium hydride is added in the course of 15 minutes to a suspension of 3-hydroxy-2-(7-methoxy-l,8-naphthyridin-2-yl)-l~isoindolinone (6.15 g) of anhydrous dimethyl-formamide (50 cc) while the temperature is maintained in 20 the region of 0°C, the mixture then being stirred again for 30 minutes at 0°C. Diethyl chlorophosphat® (2.9 cc) is then added dropwise in the course of 30 minutes while the temperature is maintained in the region of 0°C. A solution of sodium 4-acetylaminobutanoate# prepared from 25 4-acetamidobutyric acid (2.9 g) in anhydrous dimethy1-formamide (30 cc) and an oily suspension (50% by weight; 0.96 g) of sodium hydride, is added at a temperature in the region of 0"C to the solution obtained. Th® mixture is stirred for 1 hour at 0°C, then 20 hours at a tempera-30 ture in the region of 20*C, and finally 4 hours at 80#C.
The reaction mixture is poured into water (400 cc) and extracted with methylene chloride (3 x 200 cc). The organic extracts are combined and washed with water,? dried and concentrated to dryness under reduced pressure 35 (2.7 kPa). The residue obtained is purified by chroma tography on silica (0.063-0-2 mm; 350 g) contained in a column 5 cm in diameter [eluant: methylene chloride/-methanol (99si by volume) ] - collecting 100-cc fractions. Fractions 23 to 39 are combined and concentrated to 2 4 dryness under reduced pressure (2.7 kPa) at 40°C? the residue is recrystallized in acetonitrile. 2-(7-Methoxy-1e8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl 4-acetyl-aminobutyrate (2 g) f m.p. 190°C, is thereby obtained. 5 EXAMPLE 26 The procedure is as in Example 7, but starting with 2-(7-methyl-1,8-naphthyridin-2-yl)-3-hydroxy-1-i s o i n.do 1 i no ne (3.7 g), 5-methylhexanoyl chloride (7.8 g), triethylamine (12 cc) and 4«dimethylaminopyridine 10 (50 nig) . After the solid obtained after treatment has been recrystallized in methylcyclohexane, 2-(7-msthyl-1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl 5-methylhexanoate (3.8 g), m.p. 144°c, is obtained. 3 -Hydroxy- 2 - (7 -methyl -1 , 8 -naphthyr idin- 2 -y 1) -1-15 isoindo1inone may be prepared by the method described in German Patent 2,423,650. 5-Methylhexanoyl chloride may be prepared by the method described by GOERNER G.L. et al., J. Org. Chem., 24., 1551 (1959). 20 EXAMPLE 27 The procedure is as in Example 1, but starting with 3-ehloro-2~(7-chloro-l,8-naphthyridin-2-yl)-1-is oindo1inone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-(N-methylacetamido)butanoic acid (4.8 g) and 25 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g) . The oily residue obtained is purified by chromatography on silica (0.063-0.2 mm; 150 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (99:1 by volume)] and collecting 30-ce fractions., Fractions 76 to 30 175 are concentrated to dryness under reduced pressure (2.7 kPa) at 60°C and, after recrystallization in ethyl ether, 2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxo-l-iso-indolinyl 4-( N-methylacetamido)butyrate (3.1 g), m.p. 170°C, is obtained. 35 4- (N-Methylacetamido)butanoic acid iaay be pre pared in the following manner: acetyl chloride (11.8 g) is added in the course of 1 hour to a solution, maintained at a temperature in the region of 5 °C of 4-(N-methylamino)butanoic acid hydrochloride (15.4 g) in 2 5 2.5 N aqueous sodium hydroxide solution (200 cc) . The mixture is stirred again for 30 minutes at approximately 5°C and then acidified to a pH in the region of 1 using 12 N aqueous hydrochloric acid solution. The mixture is 5 concentrated to dryness at 80°C under reduced pressure (2.7 kPa) and the residue obtained is taken up with ethanol (150 cc). A solid, is separated by filtration, the filtrate is concentrated to dryness at SO eC under reduced pressure and the residue is then taken up with methylene 10 chloride (150 cc) . The organic phase is dried over magnesium sulphate and concentrated to dryness at 60 °C under reduced pressure (2.7 kPa). 4-(N-Methylacetamido)-butanoic acid (19 g) is thereby obtained in the form of an oil ^ which is employed in the crude state in the 15 subsequent syntheses.
EXAMPLE 28 The procedure is as in Example 7, but starting with 2-(7-fluoro-l,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (5 g) in methylene chloride (60 cc), 20 triethylamine (6.5 g) f 4-methylpentanoyl chloride (3.66 g) and 4-dimethylaminopyridine (10 mg). After recrystallization in ethanol, 2-(7-fluoro-l#8-naph-thyridin-2-yl)-3-oxo-l-isoindolinyl 4-methylpentanoate (1.2 g), m.p. 154°C, is obtained. 25 2- (7-Fluoro-l, 8-naphthyridin-2-yl) - 3 -hydroxy-1 - isoindolinone may be prepared in the following manner: potassium boroliydride (2.3 g) is added in small portions at a temperature in the region of 20°C to a suspension of 2- (7-f luoro-1,8-naphthyridin-2-yl) -1 # 3-isoindolinedione 30 (16.6 g) in a mixture of anhydrous methanol (90 cc) and dioxane (90 cc), and the suspension obtained is stirred for 3 hours at a temperature in the region of 20"C. The reaction mixture is then poured into a mixture of ice (120 g) and water (240 cc). The insoluble product is 35 separated by filtration, washed with water (3 x 50 cc), dried in the air and recrystallized in acetonitrile. 2-(7-Fluoro-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (10.3 g), m.p. 246°C, is thereby obtained. 2 -(7-Fluoro-l,8-naphthyridin-2-yl)- 2^*) o 1,3-isoindolinedione may be prepared in the following manner; potassium fluoride (15 g) is added to a suspension, maintained under an argon atmosphere, of 2- (7-chloro-1,8-naphthyridin~2-yl) -1,3»isoindolinedione (20.6 g) in anhydrous nitrobenzene (270 cc), and the reaction mixture is heated to reflux with stirring for 22 hours. After being cooled to a temperature in the region of 80"C, the reaction mixture is concentrated to dryness under reduced pressure (0.13 kPa) at 80°C. The residue obtained is taken up with ethyl acetate (170 cc). The insoluble product is separated by filtration, washed successively with ethyl acetate (30 cc) and water (6 x 30 cc) and dried in the air. 2~(7~Fluoro~l,8-naphthyr idin-2-yl ) -1,3-isoindolinedione (IS.9 g), m.p. 264°C, is thereby obtained. 2-(7-Chloro-l,8-naphthyridin~2-yl)-1,3-isoindolinedione may be prepared by the method described in Belgian Patent 835,325.
The present invention also relates to the medicinal products which contain the products of formula (I) in th® pure state or in the form of compositions in which they are combined with an adjuvant,,, a diluent and/or a coating which is compatible and pharsnaceutically acceptable. These medicinal products may be used orally, rectally, parenterally or percutaneously. hB solid compositions for oral administration, tablets, pills, powders (generally in gelatin capsules) or granules may be used. In these compositions, the active product according to the invention is mixed with one or mors inert diluents such as sucrose, lactose or starch. These compositions can also contain substances other than diluents, e.g. a lubricant such as magnesium stearate.
As liquid compositions for oral administration, emulsions that are pharmaceutically acceptable, solutions,, suspensions, syrups and elixirs containing inert diluents, such as water or liquid paraffin, may be used. These compositions can also contain substances other than diluents, e.g. wetting, sweetening or flavouring products.
The compos it ion.£ according to the invention for parenteral administration can be suspensions t emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, it is possible to use propylene glycol, a polyethylene glycol,, vegetable oils,, especially olive oil, or injectable organic esters, e.g. ethyl oleate. These compositions can also contain adjuvants, especially wetting agents , emulsifiers and dispersants. The sterilisation may be carried out in several ways, e.g. using a bacteriological filter,, by incorporating sterilising agents in the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.
The compositions for rectal administration are suppositories which can contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.
The compositions for percutaneous administration are creams, ointments, lotions and liniments, in which the active product is combined with liquid or pasty excipients, preferably in combination with a vehicle which promotes percutaneous migration.
The medicinal products and compositions according to the invention are especially useful in human therapy on account of their anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant action.
In human therapy, the doses depend on the effect sought and th© period of treatment; they are generally between 10 and 500 mg per day orally for an adult.
In general, the doctor will determine the dosage which he considers most suitable in relation to the age and weight and all other factors particular to the subject to be treated.
The examples which follow illustrate a composition according to the invention.
Example A Tablets containing 10-mg doses of active product 2 8 and having the following composition are prepared accord-ing to the usual technique; 2-(7-chloro-l,8-naphthyridin-2~yl)-1-oxo-1-isoindolinyl 3-dimethylaminopropionate ... 0.010 g 5 starch 0.200 g precipitated silica 0.036 g magnesium stearata ......................... 0.004 g Working in the same manner, tablets may be prepared in which the active principle consists of the 10 following products: (RS)-2~(7-Chloro-l,8-naphthyridin~2-yl)-3-oxo-l-isoindolinyl 4-acetamidobutyrate (RS)-2-(7-Chloro-lf8-naphthyridin-2~yl)-3-oxo-l-isoindolinyl l-propionyl-4-piperidinecarboxylate 15 (HS)-2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-l- isoindo1inyl 5-methvlhexanoate (HS)-2-(7-Chloro-l„8-naphthyridin~2-yl)-3-oxo-l-isoindolinyl 3-diisopropylaminopropionate.
Claims (9)
1. A new pyrrole derivative which is of the general formula: o 1 OCO-H in which A forms with the pyrrole ring an isoindoline ring-system, Het denotes a naphthvridinyl radical substituted with a halogen atom or a (1 to 4 C) alkyl or (1 to 4 C) alkyloxy radical and R denotes an alkyl radical which is unsubstituted or substituted with an alkyloxy or dialkvlamino radical, with an alkylcarbony1amino radical (in which the amino portion can optionally be substituted with an alkyl radical), or with a piperidyl or piperidino radical, or alternatively R denotes a 4-piperidyl radical, on the understanding that the alkyl radicals are straight- or branched-chain radicals and contain, except where specifically stated, 1 to 10 carbon atoms, and that the piperidino and piperidyl radicals can be unsubstituted or substituted at any position with an alkyl radical, as well as, where they exist, its pharmaceutically acceptable salts and the optical isomers of the products of formula (I).
2. A process for preparing a product according to claim 1, in which Het is defined as in claim 1 with the exception of denoting a 1,8-naphthyridin-2-yl radical substituted at the /-position with an alkyloxy radical wherein an acid of general formula: R-COOH (ID or an alkali metal salt of this acid, in which R is defined as in claim 1, is reacted with a product of general formula: in which Het1 is defined as Het in claim 1, with the exception of denoting a 1,8-naphthyridin-2-yl radical substituted at the 7-position Mith an alkyloxy radical and A is as defined as in claim 1, and the product obtained is then isolated and optionally converted, where appropriate, to a pharmaceutically acceptable salt.
3. A process for preparing a product according to claim 1, wherein a product of general formula: 1 (mi R-CO-X (V) in which R is defined as in claim 1 and X halogen atom or a reactive ester residue, with a product of general formula: denotes a is reacted OH in which A and Het are defined as in claim 1, and the product obtained is then isolated and optionally converted, where appropriate, to a pharmaceutically acceptable salt.
4. A process for preparing a product according to claim 1, wherein an alkali metal salt of an acid of general formula: R-COOH (II) in which R is defined as in claim 1, is reacted with a product of general formula: o 0^(C©U)2 59 * * in which R4 denotes a straight- or branched-chain alkyl radical containing 1 to 4 carbon atoms or a phenyl radical and A and Het are defined as in claim 1, and the product obtained is then isolated and converted, if so desired and where appropriate, to a pharmaceutically acceptable salt. U w
5. A pharmaceutical composition which contains at least one product according to claim 1, in combination with one or more diluents which are compatible and pharmaceutically acceptable.
6. A compound according to claim 1, substantially as hereinbefore described and exemplified.
7. A process for preparing a compound according to claim 1, substantially as hereinbefore described and exemplified.
8. A compound according to claim 1, whenever prepared by a process claimed in a preceding claim.
9. - A pharmaceutical composition according to claim 5, substantially as hereinbefore described and exemplified. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8616796A FR2607504B1 (en) | 1986-12-02 | 1986-12-02 | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE873252L true IE873252L (en) | 1988-06-02 |
| IE61089B1 IE61089B1 (en) | 1994-09-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE325287A IE61089B1 (en) | 1986-12-02 | 1987-11-30 | New pyrrole derivatives, their preparation and pharmaceutical compositions which contain them |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0271404B1 (en) |
| JP (1) | JPS63154682A (en) |
| KR (1) | KR880007517A (en) |
| AT (1) | ATE66219T1 (en) |
| AU (1) | AU594215B2 (en) |
| CA (1) | CA1298295C (en) |
| DE (1) | DE3772172D1 (en) |
| DK (1) | DK169969B1 (en) |
| ES (1) | ES2038687T3 (en) |
| FI (1) | FI84723C (en) |
| FR (1) | FR2607504B1 (en) |
| GR (1) | GR3002490T3 (en) |
| HU (1) | HU197573B (en) |
| IE (1) | IE61089B1 (en) |
| IL (1) | IL84658A (en) |
| MA (1) | MA21118A1 (en) |
| MX (1) | MX9558A (en) |
| NO (1) | NO166037C (en) |
| NZ (1) | NZ222752A (en) |
| OA (1) | OA08696A (en) |
| PT (1) | PT86261B (en) |
| SU (3) | SU1616515A3 (en) |
| ZA (1) | ZA879001B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2607506B1 (en) * | 1986-12-02 | 1989-01-06 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2607503B1 (en) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| CZ309617B6 (en) * | 2019-04-05 | 2023-05-24 | Ústav organické chemie a biochemie AV ČR, v. v. i | 3α5ß-Neuroactive steroids for the treatment of epilepsy and seizure disorders |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2101081B1 (en) * | 1970-08-19 | 1974-01-11 | Rhone Poulenc Sa | |
| OA04285A (en) * | 1972-01-07 | 1979-12-31 | Rhone Poulenc Sa | New derivatives of pyrrolo (3,4-b) pyrazine and their preparation. |
| AR207555A1 (en) * | 1972-12-04 | 1976-10-15 | PROCEDURE TO PREPARE ARIL-6-PIPERAZINOCARBONYLOXY-5 OXO-7-TETRAHYDRO-2,3,6,7 DITIINE (1,4) (2,3-C) PYRROLES | |
| ZA756953B (en) * | 1974-11-07 | 1976-10-27 | Rhone Poulenc Ind | 1,4-oxathiino(2,3-c)pyrrole derivatives |
| AR208414A1 (en) * | 1974-11-07 | 1976-12-27 | Rhone Poulenc Ind | PROCEDURE TO OBTAIN NEW DERIVATIVES OF ((ACIL-4PIPERAZINIL-1) CARBONYLOXI-5 PYRROLINONE-2) |
| ATE39483T1 (en) * | 1982-04-02 | 1989-01-15 | Takeda Chemical Industries Ltd | CONDENSED PYRROLINONE DERIVATIVES AND THEIR PREPARATION. |
| FR2559484B2 (en) * | 1983-07-06 | 1986-09-26 | Provesan Sa | NEW DERIVATIVE 7- (PYRROL-1-YL) OF 1-ETHYL-1,4-DIHYDRO-4-OXO- (1,8-NAPHTYRIDIN) -3-CARBOXYLIC ACID, ITS PREPARATION AND ITS APPLICATION AS A MEDICAMENT |
| CS274601B2 (en) * | 1983-07-27 | 1991-09-15 | Dainippon Pharmaceutical Co | Method of 1,8-naphthyridine derivative production |
| JPS6169773A (en) * | 1984-09-14 | 1986-04-10 | Takeda Chem Ind Ltd | Isoindolinone derivative |
| US4657913A (en) * | 1985-04-18 | 1987-04-14 | Warner-Lambert Company | Trifluoro- quinoline -3- carboxylic acids and their use as anti-bacterial agents |
| FR2607506B1 (en) * | 1986-12-02 | 1989-01-06 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2607503B1 (en) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1986
- 1986-12-02 FR FR8616796A patent/FR2607504B1/en not_active Expired
-
1987
- 1987-11-27 MA MA21359A patent/MA21118A1/en unknown
- 1987-11-29 IL IL84658A patent/IL84658A/en unknown
- 1987-11-30 ZA ZA879001A patent/ZA879001B/en unknown
- 1987-11-30 NZ NZ222752A patent/NZ222752A/en unknown
- 1987-11-30 AU AU81936/87A patent/AU594215B2/en not_active Ceased
- 1987-11-30 IE IE325287A patent/IE61089B1/en not_active IP Right Cessation
- 1987-12-01 FI FI875299A patent/FI84723C/en not_active IP Right Cessation
- 1987-12-01 CA CA000553252A patent/CA1298295C/en not_active Expired - Lifetime
- 1987-12-01 SU SU874203799A patent/SU1616515A3/en active
- 1987-12-01 KR KR870013649A patent/KR880007517A/en not_active Application Discontinuation
- 1987-12-01 DK DK630487A patent/DK169969B1/en not_active IP Right Cessation
- 1987-12-01 DE DE8787402708T patent/DE3772172D1/en not_active Expired - Fee Related
- 1987-12-01 AT AT87402708T patent/ATE66219T1/en not_active IP Right Cessation
- 1987-12-01 HU HU875398A patent/HU197573B/en not_active IP Right Cessation
- 1987-12-01 ES ES198787402708T patent/ES2038687T3/en not_active Expired - Lifetime
- 1987-12-01 EP EP87402708A patent/EP0271404B1/en not_active Expired - Lifetime
- 1987-12-01 MX MX955887A patent/MX9558A/en unknown
- 1987-12-01 NO NO875012A patent/NO166037C/en unknown
- 1987-12-02 JP JP62305512A patent/JPS63154682A/en active Pending
- 1987-12-02 OA OA59236A patent/OA08696A/en unknown
- 1987-12-02 PT PT86261A patent/PT86261B/en not_active IP Right Cessation
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1988
- 1988-11-04 SU SU884356873A patent/SU1685264A3/en active
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1991
- 1991-08-16 GR GR91400274T patent/GR3002490T3/en unknown
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