New derivatives of the pyrrole, their preparation and the compositions pharmaceutical which contain them.

ΐ

The present invention provides novel pyrrole derivatives of general formula:

in which A forms with the pyrrole ring an isoindoline ring, 3 dihydro 6.7 BH-pyrrolo [3.4 b] pyrazin, tetrahydro-2, 3, 6, 7 fl. 5h-to-oxathiinno, 4] [2, 3 - c] pyrrole or tetrahydro-2, 3, 6, 7 [1.4] 5h-to-dithiinno [2.3 c] pyrrole and HET represents a radical naphthyridinyl, quinolyl or pyridyl unsubstituted or substituted by a halogen atom or an alkyl radical (1 to 4 C.), alkyloxy (1 to 4 C.), 10 alkylthio (1 to 4 C.) or trifluoronéthyle and R is an alkenyl radical containing 3 I to 10 carbon atoms in straight or branched chain alkyl or unsubstituted or substituted by a radical of alkyloxy, alkylthio, cycloalkyl having 3 to 6 carbon atoms, an amino, alkylamino, dialcoylamlno, alcoylcarbonylamino (whose 13 amino can be optionally substituted by an alkyl radical), piperazinyl-1 or 2, piperidyl, piperidino, piperidinyl, pyrrolidinyl, azetidinyl and 1, carbamoyl, alcoylcarbamoyle, dialcoyl - carbamoyl, (piperazinyl-1) carbonyl, piperidinocarbonyl, (pyrrolidinyl 1) carbonyl, phenyl, pyridyl, imidazolyl-1, or R 20 represents pyrrolidinyl-2 or 3, piperidyl-2.3 or 4, it being understood that the alkyl radicals are straight-chain or branched and contain, except special endorsement, 1 to 10 atoms' carbon and that the radical piperazinyl, piperidino, piperidyl, pyrrolidinyl and azetidinyl can be a-unsubstituted or substi-to-23 killed in any position by an alkyl radical, alkylcarbonyl, benzyl or hydroxy alkyl or form together with the nitrogen atom of the lactam ring function, as well as, where they exist, their pharmaceutically acceptable salts and optical isomers of the products of formula (I in).

Living room 1 'a, ' the LOS géraéraloforoulo products (9.ï} wherein Hat is defined horn précédônnent to 1' oxeoption OD represent a radical naphthyridine-a 1.8 yl-2 at position 7 is substituted by a radical alcoylosy alkylthio or TDC SAL other syabolosprôcôdQïa are defined as " have, capable willwill ôtra prepared by action of an acid of general formula:

R-COOH(III)

or an alkaline salt is acid, wherein R is defined as above on a product of general formula;

wherein Met ' has the meanings given above for hat in confectioneries except L-naphthyridin® - represent a radical, concerns yl-2 7 substituted by a radical of alkyloxy or alkylthio and hr is as defined hereinbefore.

Reaction is carried out usually in the presence of a condensing agent such as diaaa-a 1 and 8, a bicycle (5.4.0] undêeème-to-7 or the diâsa above 1.5 bi-cycle [s. 3.0] nonene and 5 or a quaternary ammonium hydroxide such as 1' triéthylbenaylaiieniui hydroxide, in an organic solvent such as dimethylformamide at a temperature between 20 and iôOe^O had simply, when employing the alkali salt of the acid, the temperature of 20 diséthylforttâmidô confectioneries^than1 d..

The products of general formula (iii) can be prepared by chlorination of a product of general formula;

wherein A and Het are defined coasseprécêdsajaent.

Reaction is carried out usually in the presence of a chlorinating agent such as sulfinyl chloride or phosphorus oxychloride in the presence of catalytic amounts of àiméthylformamide at a temperature between 20 °c and the reflux temperature of the reaction eélange or other agent known to the hotuae the loom for converting a hydroxyl radical in chloro without touching the rest of the molecule.

The products of general formula (VI) may be prepared by applying or adapting methods described in the patents or Belgian 815,019 835,325.

According to the invention, the products of general formula (I-) can also be prepared by the action of a derivative of general formula:

RCOS X (V.)

wherein R is as defined hereinbefore and X represents unatone halogen such as chlorine, or represents a remains activated such as imidazolyl-1 radical or a radical R "c0-to-0-in which R" represents alkyl, with a compound of general formula (VI) as defined hereinbefore.

Generally it is carried out in an organic solvent such as chloroform or methylene chloride or an ether such as tetrahydrofuran or dioxane or dimethylformamide, at a temperature between 0 °c to the reflux temperature of the reaction mixture in the presence of a base such as sodium hydride or an acid acceptor such as triethylamine or pyridine.

According to the invention, the products of general forsule ©. (!) can also be prepared by the action of an alkali salt of an acid of formula - (it) on a general® product d © fornulo general %

(VI)

wherein represents a radical containing aleoyle9.ï to 4 carbon atoms in straight or branched chain or a radical phényie and I and Het are defined comae previously..

Generally it is carried out in an organic solvent such as diméthylfornaaide at a temperature of from. between 0 and 25° g "

The products of general formula (IV) may be prepared by action of a product of general formula;

(VIII) for Cl

in which R represents a radical alkyl® ^ containing I to 4 carbon atoms in straight or branched chain or a radical ' phenyl,, on a product of general formula (VI) wherein SfetotThe EL are as defined above.

Generally it is carried out in an organic solvent such as dimethylformamide in the presence of a base such as an alkali metal as hydrur® 1' hydrur® sodium at a temperature between -5 et + 25 °c.

It need not be isolated CD 1 © product of general formula (IV) for carrying out the method according to the invention®. It is sufficient to carry out the condensation of compounds of general formula (VIII) and (VI) comae it just said, then adding 1®acid alkali salt of general formula (III) in Lo reaction mixture.

As those skilled in the reporting system could, some radicals entering web defining the symbol R are incompatible with reagents described in covers the course of TDC must be protected prior to the implementation of the methods or d © certain phases processes described previously. It is noted the case when the radical R contains primary or secondary amino function or functions of hydroxylated likely to give rise to side reactions. In this case said functions should be protected by any method known to the skilled person and then decremented after reaction.

The novel products of general formula (I-) can be purified by the usual known methods, by exenple by crystallization, chromatography or successive extractions in the acidic and basic.

The novel products of general formula (I-) can be converted into acid addition salt by action of an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent. The salt formed precipitates, optionally after concentration of its solution; it is separated by filtration or decantation.

The products of general formula (I-) have particularly interesting pharmacological properties indicative of activity anxiolytique,-hypnotic, anticonvulsant, antiepileptic and myorelaxant. Thus they have a good affinity in vitro receptor sites to benzodiazepine concentrations whose values are between 0.4 and 200 nm according to the technique described by J.C. Blanchard and L JULOU, J d'Neurochemistry, 40, 601 (1983) inspired works BRAESTRUP Squires and, in nature, 266, 732 (1977).

The animal (mouse) microsympatric they s® are nontrés active A. back proportioned generally ranging between 0.3 and 200 nanograms/mmHg © spoken of substrates® against convulsions induced pentétrasol technology close to that Unique and BïGMSDS, J. Pbanaacel._I §1, 402 (1944).

The novel products of general foraule (s) and their salts also show low toxicity. Their is generally between 300 and 900 of Ag/kg body weight, orally microsympatric mouse.

For ii ' medicinal use, it may be makes use of novel products of general formula (I-) as such or as a pharmaceutically acceptable salt thereof, it is to say non-toxic doses of use.

Examples of pharmaceutically acceptable salts - pharmaceutiqueiaent include addition salts with mineral acids such as hydrochlorides -, sulfate, nitrate, phosphate or organic such as acetates, propionates is, succinate, benzoate, funaratss, naléates, aêthanesulfonates, isethionates, theophylline-acetates, salicylate, phénolphtalinates, aethylene bis P-oxynaphtoates or substitution derivatives of these compounds.

particularly interesting are the products of general formula (I-) wherein confectioneries forms with the pyrrole ring an isoindoline ring, dihydro 6.7 5h pyrrolo [3.4 b] pyrazine derivatives, and HET represents a naphthyridine-a 1.8 yl 2 substituted by a halogen atom or a radical alkyloxy (1 to 4 grams) and s represents an alkyl radical containing 1 to 6 carbon atoms in a straight or branched chain gun® © unsubstituted or substituted by a radical of alkyloxy, dialkylamino, alcoylcarbonylamino, pipérasinyle-to-ii, piperidino, piperidinocarbonyl, phenyl or S represents pyrrolidinyl-2, piperidyl-3 or 4, it being understood that the alkyl radicals are straight-chain or branched and contain, except special endorsement, 1 to 10 carbon atoms and the radicals pipérasinyle, piperidino, piperidyl, pyrrolidinyl may be unsubstituted or substituted in any position by one or more alkyl radicals, alkylcarbonyl or form with the atom asote cycle function lactam.

Are of particular interest, the following occurred:

Acétanido and 4 - butyrate (chlor-7 naphthyridine-a 1.8 yl 2) -2 oxo 3 - isoindolinyl L (R)

- (Propionyl 1 piperidyl-4) carboxylata SD (chlor-7 naphthyridine-a 1.8 yl 2) -2 oxo 3 - isoindolinyl-a 1 (SRV)

Methyl 5 - hsxanoat® of (néthoxy-to-7 naphthyridine-a 1.8 yl 2) -2 oxo 3 - isoindolinyl-a 1 (SRV).

Diisopropylanino-a 3 - propionate (ehloro-to-7 naphthyridine-a 1.8 y1 and 2) -2 oxo 3 - isoindolinyl-a 1 (SRV)

The following examples, non-limiting exemplary, shows how the invention can be put into practice,

EXAMPLE 1

To a solution of 16.5 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in 100 cm3 of diméthylforaamid® anhydrous, maintained under argon atmosphere, is added, at a temperature close to 20 °c, 9.2 g of hydrochloride acid diaéthyl-amino 3 propionic and 16.7 g of diaza 1.8 [5.4.0] bicyclô undecene and 7 and the resulting suspension stirred during 24 hours at a temperature of around 20 °c th. Then added 200 cm3 distilled water © 200 cm3 T-dichloromethane. The aqueous phase is separated by settling and then reextracted by 3 times 50 cm3 d-® dichloromethane. The organic phases are combined, washed with 2 times 50 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated th bag under reduced pressure (2.7 kPa gauge) to 80 °c. The residue obtained is dissolved in 100 cm3 dichloromethane and the solution is extracted with 2 times 100 cm3 of an aqueous solution of hydrochloric acid in vivo. The aqueous phases are combined, washed by 50 cm3 of dichloromethane, alkalized with a solution of soda ion to a pH around it and extracted by 2 times 150 cm3 of dichloromethane. The organic phases are combined, raised by 2 times 30 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa gauge) to 60 °c. After two successive recrystallizations in ethanol the product thus obtained, 2.9 g of obtained dimethylamino-3 propionate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 150®C. melting.

&© © 1 e hydrochloride⁹ the PR=® Large d25aéthylaEai⧩] I-I-|<3!" içp © gjnl&LQTS be obtained by the mâiheûsdéerite by. such!®: hr<Æo ©&SSSQSSfsslisliïfeü * I * OJ ÆE © SoSSe! @ O-] lïG33ô sec @ GBthe n -55the n 4571 (jîlîSîJo ^

&has chler<has "*® (® m-I © © ." ^ $7 aaplîfcfsiüsis ρ ≈ 1 2 L-le of £© ΐ·=¾ "g3m" ηοη℮ ≈ 1 has limited analytical STRs © prepared © Da and the manner in © & & ' 15 * 5 φ 4 * Êg8S|OS sw°=3 (méthes3y-to-7 naphtyxidino L * s-yl 2}<" 2 ls © iffiâ © Û=!! 2 © 1j aq values₅ © © @® T-ai has dripped to drop® wherein s stirring 2s © SST ls TDs&erurssuiSinyi © © - - D.* reaction is heated to be sélangereflus; KBES stirring peaisSiavs * -

1! hr® URs © then is added TMs 10 * 3 &3><3q dfxaéthyM © ffias © ifcb © T-heated to new to reflûæ during 3! hours * P®-îorsfe @ £ hr. revenue® temperature neighbor®'d © €0®c and concentrate hr. © © e - _ is U-© pressed ©®reduced (2 * 7 6 © °co kSaî the Li end * residue obtained is 10®®b3 additions ûq © diéhleresé® ethan 1 © concentrate and dry blending sounds the PR © DPC © has recited (2 * 7! $&} to €0 °C " thatit soli © * calculated residual is added. 109... this® OD âieMôrsséthosfâstored characteristics 1®concentrate mixture under pressure reduces ΣeE © (2 * 7 Μ ¾} to SS^{the O} 0 © year residual solid obtained is adding © 1 * @ 9 eæ3 © © dichlorealthas of TM.

agitated churning 10. O-minute 3ks insoluble product is separated by code filter "" thine and washed by 15 cm3 of diefoloreméthan © followed by 2 2s fèio @ e 00 ii D.⁹ © © diisopropyl CD ryd® has dried l°airo hereby 12 * 4 grams. Its the Chl © R. © "3 (chlor-7 naphtyrid of £n-©=>1 *® ^ 1 ≈ 2) ≈ 2 ls © iDadsiiia © has®" 1!* infecifela Ο ≈ Ο β 0 to 3

&⁰ h5fdro2tv^W. 3 (méthoxy°7 NAPs&tyridine * "1 * s yl=2)"=e lioiaisli " hone-in 1 can be prepared by the method described in Belgian Patent © 1 © © 19 © to SIS

Bîtesæss grams

By operating the d⁰ a manner analogous to that described to ^ ℮ π ℮ξ ≈ IP © 1 * but to. from a fixed © 8 * 25§of chlorous (HLB © R. © " ^ 0 * I-aaphfefridisîG 7. 3 fl * 2 * ieoindoXInonoMI "2j" 4 * 25 grams of d-© hydrochlorides 4s 1 "Large diEsSthy" lamino==4 * 7 * 6 g of butanoïqua and DA diasa®'!* 3 bieyoî © / Τΐο ΐξΡ®üé 46"=℮℮ β ℮· ≈ 7 Q. 4 * 1 grams of d obtained © diméthyiansinofefetangats ^ d-OD(© aaphtyridin οΜ θ ξο ≈ 7 """ 2î "=1 * 8 y3l isomers © ISSR-PCR=3 ©=igoiâdolinyl^, 1 * - 14§melting^Q ©■cautious

&^has cyclopentan&diméthylamina ^ butanoïqus confectioneries can be prepared by the method described by co hsj8riüsbü OF ** Mefoigsânn&B-yen_QChoHo * (* 54 ISISJ-to-410_&

EXAMPLE 3

To a solution of 6.6 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2} - 2 templateless-a 1 in 60 cm3 of diméthy1formamide anhydrous maintained under an argon atmosphere, is added at a temperature close to 20 °c, 2.4 g acid mêthyl and 4 and 3.05 g of pentanoic diaza 1.8 the bicyclo [5.4.0] undecene and 7 and stirred during 24 hours the obtained suspension at a temperature close to 20 °c. Then added 150 cm3 500 cm3 of distilled water and dichloromethane. The aqueous phase is separated by settling and then reextracted by 2 times 150 cm3 of dichloromethane. The organic phases are combined, washed by 3 times 50 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa gauge) to 60 °c. The oily residue is purified by chromatography on 150 g of silica gel contained in a 3.5 cm diameter column [eluent: dichloromethane-methanol (98 - 2 by volume)]. By eluting first with 200 cm3 solvent: the eluate corresponding is eliminated; one then elutes with 900 cm3 solvent:

the eluate corresponding is concentrated dry under reduced pressure (2.7 kPa gauge) to 40 °c. After recrystallization from ethanol, obtained 4 g of methyl-4 pentanoate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1, melts at 147 °c.

EXAMPLE 4

By operating as to the example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in 100 cm3 of anhydrous dimethylformamide, of 5.4 g of hydrochloride acid methyl-1 piperidine-3 carboxylic and 10.7 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7, is obtained, after precipitation in water 1000 cm3, filtration and air drying, 11.3 g of a product flux to 70 °c. The solid obtained is dissolved in 40 cm3 of ethanol. Has the hot solution obtained, is added a solution of 3 g of acid in ethanol 30 cm3 furaaric. The crystallized product obtained is separated by filtration, washed with ethanol and 15 cm3 dried under reduced pressure (0.07 kPa gauge) to 45 °c. The result is 9.8 g of hydrogen fumarate methyl-1 piperidine-3 carboxylate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 211 °c.

The hydrochloride (raéthyl-to-ii pp.ipêridine and 3) earbexylic can be prepared as follows: 17.1 grams of (raéthyl-to-1 piperidine-3) carboxylate are dissolved in an aqueous solution of 67 cm3 hydrochloric acid 6n. After 6 hours at reflux, the solution is concentrated to dry and the residue recrystallized from acetone. This provides 15.7 g of hydrochloride acid derivatives® (methyl-1 piperidine-3) carboxylic melts at 186 °c.

. EXAMPLE 5

By operating as to the example 1 but from 9.9 grams trochlear platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in 100 cm3 of diméthylfarraamide anhydrous, of 5.4 g of hydrochloride acid methyl-1 piperidine-4 carboxylic acid and 10.7 g of diasa-a 1.8 the bicyclo [5.4.0] undecene above 7, and after two successive recrystallizations of the residue obtained in 1 'ethanol and then in 1' acetonitrile derivative, 5.6 g of obtained methyl 1 piperidinecarboxylate and 4 of (chloro 7 naphthyridine-a 1.8 yi in-2j and 2 oxo 3 melts at 136 °c isoindolinyl-a 1 and 157 °c.

Hydrochloride acid methyl-1 piperidine-4 carboxylic acid can be prepared according to the method described in example 4 for the preparation of the hydrochloride acid derivatives® methyl-1 piperidine-3 carboxylic but from 8.6 g of methyl-1 piperidine-4 carboxylate and 33 cm3 of a 6n aqueous hydrochloric acid solution. After recrystallization from acetone, 6.5 g of hydrochloride is obtained acid methyl-1 carboxylic piperidine-4 231° g melts.

Methyl 1 piperidine-4 carboxylic acid ethyl ester can be prepared as follows: to a solution of 15.7 g of piperidine-4 carboxylate 8 cm3 in water, maintained at a temperature close to 5 °c, added 15 minutes at the same temperature to a solution of 37% 20.3 cm3 {in volume/weight) of formaldehyde and then a new and in 15 min 11.5 g of formic acid. Is heated to reflux during 4 hours and is then cooled and causes the mixture to pH

close to 10 using ion in an aqueous sodium hydroxide solution. After extraction by 3 times 150 cm3 of methylene chloride, washing th water of organic extracts, drying and concentrating to dryness under reduced polyethylenes (2.7 kPa gauge) to 70 °c, obtained 13.5 grams OD aèthyl-to-1 carboxylate piperidine-4 state-crude oil used in subsequent syntheses.

EXAMPLE 6

By operating as to the example 1 but from 6.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in 70 cm3 of anhydrous dimethylformamide, of 4.4 g of hydrochloride acid diisopropylaminophenylpropyl 3 propionic and 7.45 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7 and after successive recrystallizations of the residue obtained first in acetonitrile and then in ethanol, 2.7 g of obtained diisopropylaminophenylpropyl 3 propionate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 flux th 135 °c.

Hydrochloride diisopropylaminophenylpropyl 3 propionic acid can be obtained by operating according to the method described in 1' example 4 for the preparation of methyl-1 carboxylic pipêridine thereof 3. but from 5 g of diisopropylaminophenylpropyl 3 ethyl propionate At of 35 cm3 of an aqueous solution of hydrochloric acid 6n * of the product obtained after recrystallization from acetone, 2.3 g is obtained. hydrochloride diisopropylaminophenylpropyl 3 propionic melts î70 °C.

The diisopropylaminophenylpropyl 3 ethyl propionate can be obtained as follows e is introduced, drop by drop, in 30 min, 18.1 g of bromo 3 ethyl propionate in a solution of 28.5 cm3 diisopropylamine ethanol 40 cm3 and held at a temperature of 25 °c. The suspension obtained is heated under reflux for 4 hours confectioneries. After cooling, the reaction mixture is taken up by 100 cm3 of water and 70 cm3 of aqueous solution of hydrochloric acid is also © 4n.

after washing by 100 cm3 ethyl ether, is alcalinissto a pH around 9 by a 4m aqueous soda solution. The oil is extracted by 3 times formed 150 cm3 of methylene chloride. After washing by 2 times 100 cm3 of water and drying, the solution obtained is concentrated to dry chloromithylsnic under pressure reduces® (2.7 kPs) th 40®C. and 11.6 g of ethyl propionate diisopropylaminophenylpropyl 3 state-crude oil used in subsequent syntheses.

EXAMPLE 7

to a solution of 12.3 g of (eéthoxy-to-7 naphtyridiné-a 1.8 yl 2) hydroxy 3 -2 templateless-to-ii in 200 cm3 methylene chloride maintained at a temperature close to 20 °c, 27 cm3 of triethylamine is added. Then inserted, drip drip confectioneries, in 20 min, 10.8 g of methyl chloride 4 pentanoyl and 50 mg of dimethylamino-4 pyridine derivatives and then the reaction mixture is heated under reflux for 19 hours. The resulting slurry is poured into 800 cm3 of water and the solid obtained is filtered out and removed. The organic phase is decanted, washed with water, dried and concentrated to dry under reduced pressure (2.7 kPa gauge). The oily residue obtained is purified by chromatography on 150 g of silica gel (0,063 - 0,2 mm) contained in a 2.7 cm diameter column (eluent; methylene chloride) in êluant fractions of 50 cm3. Fractions 6 to 18 are pooled and concentrated to dry under reduced pressure (2.7 kPa gauge) to 40 °c. After recrystallization from 1' acetonitrile derivative of the solid obtained, 4.9 g of obtained aéthyl-to-4 pentanoate (methoxy-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 133 °c.

The methyl chloride 4 can be prepared according to F. pentanoyl k0gl SALEMINK and AC, ECR. Su. Chem, 71, 779 - 97 (1952).

bxbbpie has .

In operating as to 1' example 1 be born from OD 9.9 s of chïoro and 3 (ehloro-to-7 nephiyridine-a 1.8 γ 1 - 2) -2 templateless-a 1 in 100 cm3 of anhydrous dimethylformamide, of 5.1 g of cyclopentan © acetyl 1 pipêràdi-to-do-4 carboxylic® T of 4.6 grams dede.diaza-a 1.8 bi-cycle [5.4.03 undécSne and 7 and after successively in a aélange recrystallizations of acetone and water (2 - 1 by volume) and then in ethanol, obtained 7, e grams of acétyl-to-1 piperidyl-4) cerboxylate'd® (chlor-7 naphthyridine-a 1.8 yl 2j and 2 oxo 3 isoindolinyl-to-1 melts at 101 °c.

EXAMPLE 9

By operating as WITH the example 1 but WITH from 9.9 g of ehloro and 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-I in 100 cm3 of anhydrous dimethylformamide, D. © 3, 9 grams of methyl 5 4.6 g of hexahoic and diaza 1.8 the bicyclo [5.4. 0j undecene and 7 and ' after recrystallization from ethanol, 8 g of obtained methyl 5 hexanoate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 lsoindolinylè-to-1 melts at 132 °c.

EXAMPLE 10

It is performed as th the example 7 but from a fixed confectioneries © 6, 8 g of (methoxy-7 naphthyridine-a 1.8 yl 2) hydroxy 3 -2 templateless-I in 100 cm3 of methylene chloride, of 10.1 g of triêthylaminô, imposition 6.4 g of methyl chloride 5 hexanoyl and 50 mg of pyridine derivatives diaéthylamino thereof 4. The residue obtained after processing, is purified by chromatography on 100 g of silica gel (0,063 - 0,2 mm) contained in a column of 2.8 cm diameter'd © (eluent: methylene chloride) to collect fractions of 30 cm3. 19 94 Fractions are pooled and concentrated to dry under reduced pressure th (2.7 kPa gauge).

After recrystallization of the residue obtained in 75 cm3 heptane, obtained methyl 5 5.6 g of d-ethylhexanoate © (methoxy-7 naphthyridine-a 1.8-yl "2)" 2 oxo 3 isoindolinyl-a 1 105®C. melting.

EXAMPLE 11

By operating as to the example 1 but from 9.9 g of ' chlor-3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 isoindoîinone-I in 100 cm3 of dimêthylformamide anhydrous, of b, b. grams acid propiônyl I-piperidine-4 carboxylic acid and 4.6 grams - diaza-1.8 a-bi - i5.4 .0j. undeeene and 7 and by recrystallization from ethanol, 4.9 g of obtained (propionyl 1 piperidyl-4) earfooxylate of (chloro 7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 189 °c.

Acid propionyl 1 piperidine-4 carboxylic acid can be prepared as follows: a mixture of 25.8 g acid piperidine-4 carboxylic acid and 100 cm3 of propionic anhydride is heated for 2 hours and 30 minutes at a temperature in the region of 135°ç. The reaction mixture is concentrated under reduced pressure® dry confectioneries (2.7 kPa gauge) and the oily residue is taken up by 200 cm3 of methylene chloride. The solution obtained is washed by chloromethylenic 4 times 80 cm3 of water, dried and concentrated to dry under reduced pressure (2.7 kPa gauge). The oil obtained is crystallized by stirring with 50 cm3 of ethyl ether. The result is 5.8 g acid propionyl 1 piperidin-to-4 carboxylic melts at 91 - 94⁹ C..

EXAMPLE 12

By operating as to the example 1 but from 29.7 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 isoindoiinone-I in 300 cm3 of anhydrous dimethylformamide, of 13.1 g acid benzylamide 4 butyric and 13.7 grams dediaza-a 1.8 the bicyclo [5.4.0] undecene and 7, is obtained, after recrystallization from 1' acetonitrile derivative, 18 grams of acéta-to-aido-to-4 butyrate (chlor-7 naphthyridine-a 1.8 yl 2) 2 oxo 3 - isoindolinyl-to-1 melts at 186 °c.

EXAMPLE 13

Operation is carried out as in example 1 but confectioneries production from®4.95 g of platinic 3 (chlor-7 naphtyrldine-a 1.8 yl 2) -2 isoindollnonô-a 1 in 60 cm3 of diraéthylformamid® anhydrous, phenylacetic acid of 2.05 g of 2.25 g of AT diasa-a 1.8 the bicyclo [5.4.0] undecene and 7. After recrystallization from ethyl acetate, 4.4 g of obtained phenylacetate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-a 1 222 and 224° melts.

EXAMPLE 14

Operation is carried out as in example 1 but confectioneries from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 γ 1 - 2) -2 isoimdolinone-a 1 in anhydrous dimethylformamide 100 cm3, of 3.9 g of DL-pyroglutamic and 4.6 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7. After recrystallization from dimethylformamide, obtained 8.8 grams of oxo-to-5 pyrrolidinecarboxylate and 2 of (chloro 7 naphthyridine-a 1.8 yl 2) oxo 3 isoindolinyl-to-1 melts at 255 °c (decomposition).

EXAMPLE 15

Operation is carried out as in example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 lsoindolinone-a 1 in anhydrous dimethylformamide 100 cm3, of 5.55 g of n, n-pentamethylene succinamic 4.6 grams of d® and diasa-a 1.8 the bicyclo [5.4.0] undecene and 7. After recrystallization in acetonitrile and then successively in 1' ethanol, obtained 7.5 g of N, m pentaraethylene succinamate of (chloro 7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 flux th 199 °c.

N, n-pentamethylene succinamic can be prepared according to the D. Pitre, J. M. Gustafson, L Pauling ionic, dermatitis. Chetn. Soc., 70, 1352 (1948).

EXAMPLE 16

By operating coma 1' 1 instance be born to advantage? of 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 letlet us isoiradolinons-I in 100 cm3'd® dlaéthylforaamid® anhydrous, 5.7 g of hydrochloride of the d © acid (dimethyl-2.6 piperidino) propionic and d®10.7 -3 diaza 1.8 Schengen on® the bicyclo [5.4.0] undecene and 7, is obtained, after recrystallization from ethanol, 6g of (diiaéthyl-to-2.6 piperidino) -3 propionate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-a 1 159 °c melts.

Hydrochloride acid {diaéthyl-to-2.6 piperidino) -3 APOR ion may be obtained by operating the net ' node bs described in example 4 for the preparation hydrochloride aêthyl-to-ii piperidine-3 carboxylic but from 12.5 g of hydrochloride (dimethyl-2.6 piperidino) -3 ethyl propionate and 35 cm3 of an aqueous solution of acid is® hydrochloric 6m " this gives the hydrochloride (diraéthyl-to-2.6 piperidino} - propionic 3 melts at 215 °c.

Hydrochloride (diaéthyl-to-2.6] piperidino-a 3 ethyl propionate may be obtained by operating according to the method described in example 6 for the preparation of the diisopropylaminophenylpropyl 3 ethyl propionate but from 18.1 g of ethyl propionate broao and 3, 27 cm3 of dimethyl-2.6 piperidine © T 30 cm3 of ethanol. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa gauge) © T-the residue obtained is taken up by 50 cm3 © T-water solution 30 cm3 aqueusè 4n hydrochloric acid. The aqueous phase is washed with 2 times 80 cm3 ethyl ether, and neutralized with an aqueous solution of d 40 cm3 © 4m soda. Oil soluble is extracted 3 times 120 cm3 © by ethyl ether J organic extracts are then washed by water and 2 times 80 cm3 concentrates to dry under reduced pressure (2.7 kPa gauge) to 40 °c. The residue is dissolved in ethyl ether 10q cm3, hr the resulting solution, is added a solution of 13.4 cm3 4, 5n gaseous hydrochloric acid in ethyl ether. The product precipitates. ir is separated by filtration, washed and air dried. This provides 14.4 g of hydrochloride (dimethyl-2.6 piperidino) ethyl propionate melts at -3 î46 °C. '

EXAMPLE 17

In-operating as illustrated. 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in anhydrous dimethylformamide 100 cm3, 6.2 grams of d-© hydrochloride piperidino-4 butyric and 10.7 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7, is obtained, after the R © crystallization in ethanol, 9.4 g of piperidino-4 butyrate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 flux th 166 °c.

The hydrochloride of the piperidino-4 butyric acid may be obtained by operating according to the method described in example 4 for the preparation hydrochloride methyl I-piperidine-3 carboxylic, but to from piperidino-4 19.9 g of ethyl butyrate and 66.5 cm3 of a 6n aqueous hydrochloric acid solution and refluxed 24 hours en heating. This provides 16.3 g of hydrochloride acid piperidino-4 melts at 190 °c butyric.

The piperidino-4 ethyl butyrate may be prepared by working according to the method described in example 6 for the preparation of the diisopropylaminophenylpropyl 3 ethyl propionate, but from 48.8 g of bromo 4 ethyl butyrate, of 42.5 g of piperidine and 75 cm3 of ethanol. The reaction mixture is taken up by 200 cm3 120 cm3 of water and an aqueous solution of 4n hydrochloric acid. After washing by 150 cm3 ethyl ether, the aqueous phase is alkalized at a pH around 9 by a 4n aqueous sodium hydroxide solution. The oil is extracted by 3 times formed 150 cm3 of methylene chloride. The organic extracts are combined, washed with water, dried and concentrated to dry under reduced pressure (2.7 kPa gauge) © to 70 °c. This provides 47 g of piperidino-4 ethyl butyrate th state of oil used crude in subsequent syntheses.

EXAMPLE 18

Operation is carried out as in the example 1 from a fixed jaais confectioneries © 4, 3 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 isoindolinehe-l 40 cm3 of diméthylformarnide anhydrous, of 2.2 § acid (oxo 2 pipêridino) -3 2 g of propionic acid and diaga-a 1.8 bi-cycle [g. 4 .01 undeeene above 7. After recovery of the reaction mixture th water, methylene chloride extraction and evaporation of the solvent, the residue obtained is recrystallized in acetonitrile. The product thus obtained is purified by chromatography on 100 g of silica (0,063 - 0,2 mm) cohtenus in a column diameter of 2.3 cm (eluent: methylene chloride) by collecting fractions 50 - cb3. The fractions 56 to 64 are pooled and concentrated to dry under reduced pressure (2.7 kPa gauge) th 20 °c. The residue obtained is recrystallized in acetonitrile. This gives 2.0 g of (oxo 2 piperidino) -3 propionate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 175° g.

The acid (oxo 2 piperidino) propionic -3 die can be prepared as follows: adding a solution of 3.8 g of potassium hydroxide in 15 cm3 & water solution of 9.2 g of (oxo 2 piperidino) methyl propionate -3 40 cm3 in ethanol. The reaction mixture is stirred for 20 hours at a temperature of around 20 °c th and evaporated th dry under reduced pressure (2.7 is proposed). The residue is taken up by 100 cm3 of water. The solution obtained is washed by ethyl ether then acidified 50 cm3 th a pH around 1 by an® aqueous solution of hydrochloric acid and extracted® 3 times by 4n 100 cm3 of methylene chloride. After washing th water and drying, the. the solution is concentrated to dry eblorométhyléniquè under reduced pressure (2.7 is proposed). This gives 2.3 g acid (oxo 2 piperidino) propionic -3 105 and 110 degrees Celsius melts.

The (oxo 2 piperidino) methyl propionate -3 can be prepared according to the method described by H. T.&KAKATA et, mal. Apotex. Miniature bull. -, 28 (12), 3632 - 8 (1980).

EXAMPLE 19

By operating in a manner analogous to that described in example 1, but from 9.9 g of platinic 5 (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] acid pyrazin®, of 9, e g of diaza 1.8 bieyclo [5.4. 0j undecene and 7 and 4.8 g of hydrochloride acid dimethylamino-3 propionic, is obtained, after recrystallization in acetonitrile, 2.2 g of dimethylamino-3 propionate (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazinyl and 5 melts at 200 °c.

The chloroacetamide 5 (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazine can be prepared the following manner: 23.2 grams of hydroxy-a 5 has (methoxy-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazine derivatives, is added, dropwise, with stirring, 300 cm3 sulfinyl chloride. The reaction mixture is heated at reflux with stirring for 1 hour and then added with 1 cm3 of diméthylfornamide and heated at reflux for 3 again th hours, and then cooled at a temperature close to 60 °c and concentrated to dry under reduced pressure (2.7 kPâ). At residue obtained, is added 100 cm3 dichloromethane and dry th concentrating the mixture under reduced pressure (2.7 kPa gauge). At residual solid obtained, dichloromethane is added and stirred for 100 cm3 10 min. The insoluble product is separated by filtration and washed by 15 cm3 dichloromethane followed by 2 times 25 cm3 diisopropyl oxide and air-dried. This gives 21 g of platinic 5 (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyràzlne, melts at 264 °c.

The hydroxy-a 5 (methoxy-7 naphthyridine-a 1.8 yl 2) -6 086 - 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazine can be prepared by the method described in the Belgian Patent 815,019.

The dihydrochloride of the propionic acid dimethylamino-3 can be prepared by the method of Clarke Τ. hr ., © T-al, dermatitis. Mal. Soc., 55, 4571 (1933).

EXAMPLE 20

hr a solution of 6.6 g of platinic 3 (ehlero-to-7 naphtyri-to-do-1.8 yl 2) -2 templateless-a 1 in 60 cm3 of diséthylfonaaraide anhydrous maintained at a® temperature close to 20 °c, adding the n © © 4, 2 g of (aeétyl-to-4 pipérasinyl I) sodium acetate and © hmaintientDélange reaction during the 15 hours at a temperature of 20 °c been neighbourly th. Then adding at least® 3 g of diasa-a 1.8 the bicyclo [5.4.0] undeeene-to-7 then acts again during 24 hours © at a temperature close to 20 °c. Le reaction mixture is resumed by 250 cm3 of water and 3 times 150 cm3 © extensive research by methylene chloride, tough water washing and concentrating to dryness under reduced pressure (2.7 kPa gauge) of the organic phase, the residue obtained-is recrystallized in ethanol. This gives 3.7 g of (acetyl-4 pipérasinyl L) acetate (ehloro-to-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 192 °c.

The (acetyl-4 pipéraainyl L) sodium acetate may be prepared as follows; added 4.3 g of (acetyl-4 pipérasi-to-nyl-to-1) ethyl acetate to a mixture of 20 cm3 of ethanol and 20 cm3 of 1w an aqueous sodium hydroxide solution. The reaction mixture is stirred for 20 hours at a temperature close to 20 °c eoncentré is then dry under reduced pressure (2.7 kPa gauge) 80 °c confectioneries. The solid obtained is suspended in 80 cm3 © isopropyl oxide and stirred, then separated by filtration and dried. This gives 4.3 g of (acetyl-4 pipérasinyl L) sodium acetate melting between 100 and 105 °c.

The (acetyl-4 pipérasinyl L) ethyl acetate can be prepared according to the method described by D. Tuesday and e. MâSSftRMî, J the MED. Mal. 14 (7), 635 (1971).

EXAMPLE 21

By operating as to the example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in

100 cm3 of anhydrous dimethylformamide, of 4.8 g acid conjugate thereof 4 butanoic acid and 4.6 g of diaza 1.8 the bicyclo [5.4.0] undéeêne and 7, is obtained, after recrystallization from 1' acetonitrile derivative, 6.6 g of protein conjugate-to-4 butyrate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 flux th i79 °C.

The ACID-® protein conjugate-to-4 butanoic acid can be prepared as follows: added, in 15 min, 10.3 g of butyric acid aaino and 4 10 cm3 of propionic anhydride at a temperature close to 20 °c, then 5 drops of concentrated sulfuric acid (d=l, 83) and is heated to a temperature of® around 100 °c during 2 hours. After cooling, the crystalline solid is separated by filtration, washed by ethyl ether 5 times 100 cm3 © T-dried. The result is 9.8 g acid conjugate thereof 4 butanoic acid melts at 85 and 90°.

EXAMPLE 22

To a solution of 9.2 g of (aéthoxy-to-7 naphthyridine-a 1.8 yl 2) -2 hydroxy 3 isoindolinone derivatives thereof 1 and 20 cm3 of triethylamine in 150 cm3 of dichloro-1.2 ethane maintained at a temperature close to 20 °c, is added, in 20 min, a® solution of 9 g of methyl chloride 2 propoxyacétyle in 20 cm3 of dichloro-3.2 ethane and then 50 mg of dimethylamino-4 pyridine and heated under reflux for 16 hours th. The reaction mixture is poured into water and then extracted by 250 cm3 100 cm3 of methylene chloride. After washing with water, drying and concentration th dry under reduced pressure (3 kPa gauge), the residue obtained is purified by two successive recrystallizations in ethanol. This gives 7.9 g of methyl-2 propoxyacêtate of (methoxy-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 114 °c.

The methyl chloride 2 propoxyacétyle can be obtained as follows: added, in 15 min, 5 cm3 of thionyl chloride to a solution of 8.3 g acid methyl-2 propoxyacetic 50 cm3 in chloroform. The mixture is heated to reflux during 5 heurps and evaporated to dry under reduced pressure (2.7 kPa gauge). This provides 7.5 g of methyl chloride 2 propoxyacétyle state oil used crude in subsequent syntheses.

The cyclopentan © propoxyacetic séthyl and 2 can be obtained as follows; has 200 cm3 of isobutyl alcohol saintenu confectioneries each at around 100 °c, added 12.7 g sodium and heats up to disappearance thereof - is then added, in the I hour, 23.6 g acid ehlorscetic CD continues the heating for 2 hours. After cooling, the reaction mixture is poured into. 250 ea3 of water, the aqueous phase is washed by ethyl ether 200 cm3, concentrated confectioneries half volume under reduced pressure (3 kPà) acidified® to a pH close to the fillet EIT 1 with an aqueous solution of hydrochloric acid in vivo. Oil formed is extracted by ethyl ether 3 times 150 cm3, the organic phase ' is washed with water, dried and concentrated to dry under reduced pressure (3 kPa gauge). After distillation under reduced pressure® the residue obtained, 21.8 g acid obtained néthyl-to-2 propoxyacetic boiling at 92 and 96 °C under 0.93 kilopascals.

EXAMPLE 23

Operation is carried out as in example ii confectioneries be born from 6.6 g of platinic 3 (chlor-7 naphthyridine-a 1.8 - 2 γ. 1) -2 templateless-I in anhydrous dimethylformamide 60 cm3, of 4.3 g of hydrochloride acid isopropyl 1 piperidine-4 carboxylic acid and 7.1 g of diasa-a 1.8 the bicyclo [5.4, 0] undécèn®-7. Is obtained, after recrystallization from 1' acetonitrile derivative, 4.1 g of a solid is dissolved in refluxing ethanol confectioneries 120 cm3; adding at least © 1, 03 g acid 20 cm3 funaric in solution in ethanol. After crystallization in 1' acetonitrile derivative, obtained 4.9 g of fumaric acid-cyclopentan® (isopropyl 1 piperidyl groups and 4) esrboxylat® of (chloro 7 naphthyridine-a 1.8 γ 1 - 2) oxo 3 -2 isoindolinyl-to-1 melts at 184^I C..

L®-hydrochloride 1 'acid isopropyl 1 the carboxyl anhydride piperidine-4' can be prepared according to the method described in example 4 for the preparation hydrochloride methyl a-1 piperidine-3 carboxylic but from 6.5 g of hydrochloride of isopropyl-to-1 pipêridine-to-4 carboxylate and 18.6 cm3 of a 6m aqueous hydrochloric acid solution. The OH obtained 4.5 g of hydrochloride acid isopropyl 1 piperidine-4 carboxylic melts at 260 and 265 degrees Celsius.•

The hydrochloride of isopropyl-a 1=4 pipéridîâeearboxylate ethyl can be prepared how®5 has a® solution of 6.15 g of bromo 2 propane in 50 cm3 propanol, is adding®, in 10 min, 15.7 g of piperidine-4 carboxylate ethyl® at a temperature of 25 © neighbor^I C. the reaction is heated churning nélang © 48 hours under reflux and then concentrated to dry under reduced pressure (2.7 kPa gauge).

The residue is taken up by 150 cm3 an aqueous hydrochloric acid solution 1.5 n and the resulting solution is washed with 2 times 100 cm3 ethyl ether. The aqueous phase is Qlcallnisi® at pH■close to 9 by a 4m aqueous soda solution, extracted with 3 times 100 cm3 - © d-methylene chloride. The organic phase is washed with water, dried and concentrated to dry under reduced pressure (2.7 kPa gauge) to 40 °c. The residue obtained is carried © n-solution in ethanol 30 cm3, hr the resulting solution, is added a solution 4, 5m 12 cm3 gaseous hydrochloric acid in ethyl ether. The formed precipitate is separated by filtration, washed and dried. In this way, 6.9 g of hydrochloride of isopropyl-I-carboxylate plpéridyl-to-4 melts at 195 and 200 degrees Celsius.

EXAMPLE 24

To a solution of 3.9 g of n-acetyl-P-alanine in 66 cm3 of diméthylforoamide, 6.6 g of added chloro 3 (chlor-7 naphtyri -. Dines and 1.8 yl 2) -2 isoindolinone derivatives thereof 1. & the suspension tan obtained®, is added, dropwise, 3.8 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7 and stirred, at a temperature close to® the d®20 °c, during 18 hours. Again added 1 g of n-acetyl-P-alanine then I-g of diaza 1.8 the bicyclo [5.4.0] undecene and 7 and in acting®, confectioneries and a® temperature close to 20 °c, 24 hours during. The reaction mixture is then poured into 130 cm3 of water, the resulting solid is separated by filtration, washed with 3 times 25 cm3 of water and purified by pressurized chromatographi® (50 kilopascals) on 500 g of silica contained in a 5 cm diameter column [eluent: dichloromethane-raéthanol (95 - 5 by volume)] by collecting fractions 75 cm3. The fractions 7 to ' 9 are pooled and concentrated to dry under reduced pressure (2.7 is proposed) ©.

After reoristallisation of the solid obtained in 1' acetonitrile derivative, obtained 3.9 grams of acétamido-to-3 propanoate (chlor-7 naphtyrldine-to-l, e γ 1 - 2) oxo 3 -2 isoindollnyle-a 1 melts at 220 °c.

H-acetyl-p-alanlne © can be prepared according to the example 21 nêthode described for preparing acid derivatives® the PR © piônâmid © a-4 butanôïque usages from 8.9 g of P-alanine derivatives, of 9.6 g of acetic anhydride. The result is 12.9 grams de n-acetyl Pi-alanine state, oil used crude in subsequent syntheses.

EXAMPLE 25

operation is carried out as to the example 24 but confectioneries from 5 g of pentanoic acid benzylamide 5 66 in AC diaéthylioraaside, of 6.6 g of ehloro and 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 and 4.7 cm3 diaza-1.8 the bicyclo [5.4.0] undecene and 7. After reeristallisation in acetonitrile, obtained 3.3 grams of acétamido-to-5 pentanoate (chlor-7 naphthyridine-a 1.8 yl 2) -2 isoindolinyl-I-oxo 3 melts at 185 °c.

Pentanoic acid benzylamide 5 may be prepared according to the method described in the example 21 for the preparation of conjugate-to-4 butanoic but from 11.7 g acid amino 5 pentanoic and 12.6 g of acetic anhydride. The reaction mixture is concentrated to dryness under reduced pressure (0.05 kilopascals), this gives 6 g of pentanoic acid benzylamide 5 oil used as a raw in the syntheses subsequent.

EXAMPLE 26

operation is carried out as in example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in anhydrous dimethylformamide 100 cm3, of 5.2 g acid isobutyrylamino-to-4 butyric and 4.6 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7. The residue obtained is recrystallized in 1' acetonitrile derivative and then purified by chromatography on 130 g of silica (0,063 - 0,2 K. ") contained in each column of 3 cm in diameter [êluant 5 mixture of methylene chloride-methanol (98 - 2 by volume)] by collecting fractions of 25 cm3. The moieties are joined © 79 to 85 T-concentrated to dry under reduced pressure (2.7 kPa gauge). The residue obtained is crystallized by stirring it in isopropyl oxide. This provides 5.5 grams of isobu-to-tyrylaœino-to-4 butyrate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 208 °c.

isobutyrylamino-to-4 butyric acid may be prepared by the method described in the example 21 for the preparation of conjugate-to-4 butanoïgue but from 10.3 g acid amino 4 butyric and 15.8 g of isobutyric anhydride. This gives 15.5 g of butyric acid isobutyrylamino-a 4 state-crude oil used in subsequent syntheses.

EXAMPLE 27

Operation is carried out as in example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in anhydrous dimethylformamide 100 cm3, of 6 g acid butyryl 1 pipérl-to-Dines and 4 carboxylic acid and 4.6 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7. The residue obtained is purified by chromatography on 250 g of silica (0,063 - 0,2 mm) contained in a column 4.2 cm diameter, [eluent: mixture of methylene chloride and methanol (99 - 1 by volume)] by collecting fractions 70 cm3. The fractions 82 to 110 are pooled and concentrated to dry under reduced pressure (2.7 kPa gauge)•. The solid obtained is resumed under stirring with isopropyl oxide then separated by filtration and dried. 6 G of obtained aipsi (butyryl 1 piperidine-4) carboxylate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts î65 °C.

The acid (butyryl 1 piperidyl-4) carboxylic acid can be prepared according to the method described in the example 21 for the preparation of conjugate-to-4 butanoic but production from®12.9 g acid piperidyl-4 carboxylic and 15.8 g of butyric anhydride. This provides 16 g acid (butyryl-- ^ 1 piperidyl-4) carboxylic state oil used crude in subsequent syntheses.

EXAMPLE 28

With a suspension of 9.9 g of platinic 3 {chloro 7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 and 6.7 g of hydrochloride acid diisopropylqmino and 4 100 cm3 diraèthÿMormamide of butyric, is added, dropwise, 10.7 g of dia2a L, the bicyclo [5.4.0] 8 undecene and 7 and stirred, at a temperature close to 20° d, during 20 hours. Then the reaction mixture is poured into water 130 cm3. The resulting solid is separated by filtration and then dissolved in 200 cm3 of methylene chloride. The organic extracts are lifted with 2 times 35 cm3 of an aqueous solution of hydrochloric acid 0, 1m, 35 cm3 of 0, 5n aqueous solution of hydrochloric acid and then with 2 times 35 cm3 of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa gauge). the residue obtained is taken up by 200 cm3 of methylene chloride. The organic layer is washed 2 times with 50 cm3 of a saturated aqueous solution of sodium hydrogencarbonate. The organic phase is dried over magnesium sulfate ©, filtered and concentrated to dryness under reduced pressure (2.7 kPa gauge). the residue is recrystallized in ether isoprolylic. This provides 7.1 g of diisopropylaminophenylpropyl greatly accelerated butyrate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-a 1 melts at 118 °c.

Hydrochloride diisopropylaaino-to-4 butyric acid may be obtained by operating according to the method described in example 4 for the preparation hydrochloride (methyl-1 piperidine-3) carboxylic but from 9.2 g of diisopropylaminophenylpropyl 4 ethyl butyrate and 28.5 cm3 of a 6n aqueous hydrochloric acid solution and by heating for 6 hours at reflux. This gives 8 g of the hydrochloride melts at butyric diisopropylaminophenylpropyl 4 136 °c.

The diisopropylaminophenylpropyl 4 ethyl butyrate can be obtained as follows: to a solution of 39 g of ethyl butyrate broao and 4 80 cm3 in ethanol, is added, dropwise, 40.4 g of isopropylamine. The resulting solution is heated at reflux for 6 hours. After filtration of the insoluble formed, the filtrate is concentrated to dryness under reduced pressure (2.7 kPa gauge). The residue is taken up by 15 cm3 of distilled water and 100 cm3 of a 4n aqueous hydrochloric acid solution. The aqueous phase is washed by 3 times 75 cm3 ethyl ether then alkalized by ion in an aqueous sodium hydroxide solution. Oil formed is extracted by ethyl ether 3 times 75 cm3. The organic phase obtained is concentrated to dryness under reduced pressure (2.7 kPa gauge). This gives 9.2 g of ethyl butyrate diisopropylaminophenylpropyl 4 state-crude oil used in subsequent syntheses.

EXAMPLE 29 '

With a suspension of 12.5 g of (chloro 7 naphthyridine-a 1.8 yl 2) -2 hydroxy 3 isoindolinone derivatives and 1 600 cm3 in methylene chloride, 12.2 g of triethylamine is added, 90 cm3 9.7 g of pyridine and methyl chloride 3 butyryl by maintaining the temperature at about 25 °c. After 4 hours of stirring at a temperature of around 25 °c, added 9.7 g of th new methyl chloride 3 butyryl and stirred for a further 16 hours is confectioneries this temperature.

The reaction mixture is then concentrated to dryness under reduced pressure (3 kPa gauge) and the residue is taken up by 500 cm3 of water. The insoluble product formed is separated by filtration, washed, dried and then recristallisê in a mixture of isopropyl and ethyl acetate (50 - 50 by volume). This gives 7.9 g of. methyl 3 butyrate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 154 °c.

EXAMPLE 30

Λ a solution of 3.2 g of (chloro 7 naphthyridine-a 1.8 yl 2) -2 hydroxy 3 160 cm3 templateless-a 1 in methylene chloride, successively adding 24 cm3 pyridine followed, in 30 min, 5.5 g of propionyl chloride by maintaining the temperature in the vicinity of 25 °c. The mixture is stirred for 3 hours at this temperature and then added with 100 cm3 of water. The organic phase is decanted, washed with water, dried and concentrated to dry under reduced pressure (2.7 kPa gauge). The residue obtained is crystallized from isopropyl oxide then recrystallized in a mixture of isopropyl and ethyl acetate (25 - 75 by volume). This gives 1 g of propionate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 160 °c.

EXAMPLE 31

Operation is carried out as in example 30 but from 6.4 g of (chloro 7 naphthyridine-a 1.8 yl 2) -2 hydroxy 3 320 cm3 templateless-a 1 in methylene chloride, pyridine and 48 cm3 of 12.8 g of butyryl chloride. After recrystallization from isopropyl oxide and then two recrystallizations in 1' acetonitrile derivative, 3.4 g of obtained butyrate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-1 melts at 140 °c.

EXAMPLE 32

Operation is carried out as in example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in 100 cm3 of diraéthylformamide anhydrous, of 4.25 g acid cyclohsxanone-to-4 carboxylic acid and 4.6 g of diaza 1.8 the bicyclo [5.4.0] undecene and 7. After recrystallization from acetonitrile, obtained 8.5 grams of oxo-to-4 cyclohexanecarboxylate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-a 1 203 °c melts.

EXAMPLE 33

Operation is carried out as in example 7 but th from 8.55 g (bromine-7 naphthyridine-a 1.8 yl 2) hydroxy 3 -2 templateless-a 1 110 cm3 in methylene chloride, 11.1 g of triethylamine of, of 7 g of methyl chloride 5 hexanoyl and 50®g of dimethylamino-4 pyridine derivatives. After crystallization in 1' hexane and then recrystallization of the residue obtained in ethanol, 7.5 g of obtained aéthyl-to-5 hexanoate (bromine-7 naphthyridine-a 1.8 yl 2) -2 oxo 3 melts at 136 °c isoindolinyl-a 1.

The (bromine-7 naphthyridine-a 1.8 yl 2) -2 hydroxy 3 isoindolinone derivatives and 1 may be prepared as described in Belgian Patent 815,019.

EXAMPLE 34

Operation is carried out as in example 7 but from 6.3 grams of hydroxy-a 5 (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazine in 80 cm3 of methylene chloride, 5.05 g of triethylamine of, of 3.14 g of chloride and 50 mg of aéthacryloyle dimethylamino-4 pyridine derivatives. The residue obtained is purified by recrystallization in acetonitrile followed by chromatography on 50 g of neutral alumina contained in a 1.5 cm diameter column by eluting with methylene chloride and collecting fractions 15 cm3. Fractions 12 to 34 are pooled and concentrated to dry under reduced pressure (2.7 kPa gauge) to 40 °c. This gives 1.4 g of methacrylate (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazinyl and 5 melts at 255 °c.

The hydroxy-a 5 (chlor-7 naphthyridine I, 8 γ 1 - 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazine can be prepared as described in Belgian Patent 1®815,019.

EXAMPLE 35

Operation is carried out as in example 7 but from 6.3 grams of hydroxy-a 5 (chlor-7 naphthyridine-a 1.8 γ 1 - 2) - δ oxo 7 dihydro e, 7 5h pyrrolo [3.4 b] pyrasine d-® methylene chloride in 80 cm3, 5.05 g of triethylamine of, of 4.25 g of isobutyryl® chloride and 50 mg of dimethylamino-4 pyridine derivatives. The solid obtained is washed with tetrahydrofuran. This gives 2.3 g of isobutyrat'd® (chlor-7 naphthyridine-a 1.8 γ 1 - 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazinyl-a 5 260 and 262° melts.

The hydroxy-a 5 (chlor-7 naphthyridine-a 1.8 yl 2) -6 oxo 7 dihydro 6.7 5h pyrrolo [3.4 b] pyrazine can be prepared as described in Belgian Patent 815,019.

EXAMPLE 36

confectioneries 6.15 g of a suspension of hydroxy-a 3 (métboxy-to-7 naphthyridine-a 1.8 yl 2) -2 templateless-a 1 in 50 C.®3 of anhydrous dimethylformamide, is added, in 15 min, 0.96 g of an oily suspension (50% by weight) sodium hydride by maintaining the temperature at about 0 °c followed by stirring during 30 minutes to again 0 °c. Then added, dropwise, in 30 min, diethyl cblorophosphate of 2.9 cm3 by maintaining the temperature at about 0 °c. hr the resulting solution, is added at a temperature close to 0 °c, a solution of acétylamino-to-4 butanoate prepared from 2.9 g of butyric acid benzylamide 4 30 cm3 of anhydrous dimethylformamide and 0.96 g of an oily suspension (50% by weight) of sodium hydride. The mixture is stirred for 1 hour at 0 °c then 20 hours at a temperature close to 20 °c and finally 4 hours to 80 °c. The reaction mixture is poured into water and extracted by 400 cm3 3 times 200 cm3 of methylene chloride.

The combined organic extracts are washed at T-©, © T-dried dry concentrated under reduced pressure (2.7 kPa gauge)®. The residue obtained is purified by chromatography on 350 g of silica (0,063 - 0,2 no.) contained in a 5 cm diameter column [eluent: methylene chloride-methanol (99 - 1 by volume)]® n-collecting moieties 100 cm3. The fractions 23 to 39 are joined © T-concentrated to dry under reduced pressure (2.7 kPa gauge) to 40 °c; the residue is recrystallized in acetonitrile. This provides 2 grams of acétylaraino-to-4 butyrate (methoxy-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-L-melts at 190 °c.

EXAMPLE 37

Operation is carried out as in example 7 but confectioneries confectioneries from 3.7 g of (methyl-7 naphthyridine-a 1.8 yl 2) -2 hydroxy 3 isoindolinone derivatives and 1, of 7.8 g of methyl chloride 5 hexanoyl, of 12 cm3 of triâthylamine and 50 mg of pyridine derivatives diaéthylamino thereof 4. After recrystallization from methylcyclohexane the solid obtained after processing, 3.8 g of obtained methyl 5 hexanoate (aéthyl-to-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-L-melts at 144 °c.

The hydroxy-a 3 (methyl-7 naphthyridine-a 1.8 yl 2) -2 templateless and 1 may be prepared by the method described in German patent 2,423 650.

The methyl chloride 5 hexanoyl can be prepared by the method described by GOERNER G.L. and al, J 92. Chem., 24, 1561 (1959).

EXAMPLE 38

Operation is carried out as in example 1 but from 9.9 g of platinic 3 (chlor-7 naphthyridine-a 1.8 yl 2) isoindolinone derivatives thereof 1~2 in anhydrous dimethylformamide 100 cm3, of 4.8 g acid (n-methyl-acetamido) -4 butanoic and diaza 1.8 4.6 g of the bicyclo [5 · 4 · 0] undecene and 7. The oily residue obtained is purified by chromatography on 150 g of silica (0,063 - 0.2 mm) contained in a column 3 cm in diameter [eluent: methylene chloride - methanol (99 - 1 by volume)] and collecting fractions of 30 cm3. The fractions 76 175 confectioneries are concentrated to dry under reduced pressure (2.7 kPa gauge) to 60 °c and after crystallization in ethyl ether, 3.1 g of obtained (n-methyl-acêtamido) -4 butyrate (chlor-7 naphthyridine-a 1.8 γ 1 - 2) oxo 3 -2 isoindolinyl-L-melts at 170 °c.

The acid (n méthy1-acetamido) -4 butanoic acid may be prepared from there as follows: to a solution of 15.4 g of hydrochloride acid (N-methyl-amino) butanoic acid in 200 C. -4®3 of one 2, 5n aqueous soda solution, maintained at a temperature close to 5⁶ C., is added, in 1 hour, 11.8 g of acetyl chloride. The mixture is stirred 30 min during a new and 5 secs^I C.: then acidified to a pH around 1 using a 12n aqueous hydrochloric acid solution. The mixture is concentrated to dry to 80 °c under reduced pressure (2.7 kPa gauge) and 1®residue obtained is resumed by 150 cm3 of ethanol. A solid is separated by filtration and the filtrate is concentrated to dry at 60 °c under reduced pressure, then the residue is taken up by 150 cm3 of methylene chloride. The organic phase is dried over magnesium sulfate and concentrated to dry at 60 °c under reduced pressure (2.7 kPa gauge). This provides 19 g acid (ω-methyl-acétaraido) butanoic -4 state-crude oil used in subsequent syntheses.

EXAMPLE 39

Operation is carried out as in example 7 but from 5g of (fluoro 7 naphthyridine-a 1.8 yl 2) hydroxy 3 -2 isoiodolinone-to-ii in 60 cm3 methylene chloride die, of 6.5 g of triéthyXamine, of 3.66 g of methyl chloride 4 pentanoyl and 10 Ag diiaéthylàmino-to-4 pyridine derivatives. Is obtained, after recrystallization in-ethanol, 1.2 g of methyl-4 pentanoate (GBP fluoro-to-7 naphthyridine-a 1.8 yl 2) oxo 3 -2 isoindolinyl-to-ii melts at 154 °c.

The (fluoro 7 naphthyridine-a 1.8 yl 2) hydroxy 3 -2 templateless-I can be prepared in the following manner: with a suspension of 16.6 g of (fluoro 7 naphthyridine-a 1.8 yl 2) -2 isoindolinedione and 1.3 in a mixture of anhydrous methanol and 90 cm3 90 cm3 of dioxane, is added, at a temperature close to 20 °c, by small portions, 2.3 g of potassium tétrahydruroborate, and agitates the suspension obtained during 3 hours at a temperature close to 20 °c the DS. The oélang® réactionnai © CD then poured into a mixture of ice and 240 cm3 120 g of water. The insoluble product CD © separated by filtration, washed by 3 times 50 cm3 of water, air dried and recrystallized in acetonitrile. This gives 10.3 g of (fluoro 7 naphthyridine-a 1.8 γ 1 - 2) hydroxy 3 -2 templateless-a 1 246 °c melts.

The (fluoro 7 naphthyridine-a 1.8 yl 2) -2 isoindolinedione and 1.3 may be prepared in the following manner: with a suspension of 20.6 g of (chloro 7 naphthyridine-a 1.8 yl 2) -2 isoindolinedione and 1.3 in 270 cm3 anhydrous nitrobenzene, maintained under argon atmosphere, is added 15 g of potassium fluoride and heats the reaction mixture refluxed under stirring, during 22 hours. After cooling th at around 80 °c, the reaction mixture is concentrated under reduced pressure dry confectioneries (0.13 kPa gauge) to 80 °c. The residue obtained is taken up by 170 cm3 of ethyl acetate. The insoluble product is separated by filtration, washed sequentially by 30 cm3 ethyl acetate, 6 times 30 cm3 of water and air dried. This provides 16.9 g of (fluoro 7 naphthyridine-a 1.8 yl 2) -2 isoindolinedione-to-1.3 melts at 264 °c.

The (chlor-7 naphthyridine-a 1.8 yl 2) -2 isoindolinedione and 1.3 may be prepared by the method described in the Belgian Patent 835,325.

The present invention also relates to medicaments containing the products of formula (I-) th in the pure state or as compositions in which they are associated with an adjuvant, diluent and/or a coating compatible and pharmaceutically acceptable. These drugs can be used orally, rectally, parenterally or percutaneously.

As solid compositions for oral administration can be used tablets, pills, powders (generally in gelatin capsules) or granules. In these compositions, the active product according to the invention is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions may also comprise substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, emulsions may be used. pharmaceutically acceptable, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil. These cempositions may also comprise substances other than diluents, for example wetting products, sweeteners or flavorings.

The compositions for parenteral administration may be sterile solutions aqueous or non aqueous, suspensions or emulsions. As solvent or vehicle, propylene glycol can be employed, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate. The compositions may also contain adjuvants, in particular wetting agents, emulsifying and dispersing agents.. The sterilization can be in a number of ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be formulated as a sterile solid compositions which can be dissolved at the time of use in sterile water or other sterile injectable medium.

The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter or the base for support-to-eire.

The compositions for percutaneous administration are creams, ointments, lotions and liniment, in which the active is associated with excipients liquid or pasty, preferably in combination with a pro-migration percutaneous.

The medicaments and compositions according to the invention are particularly useful in human therapeutics for their action anxiolytic, hypnotic, ânticonvulsivante, antiepileptic and myorelaxant.

In human therapy, the doses depend on the desired effect and the duration of the treatment; they are generally between 10 and 500 mg per day orally for an adult.

A® so general®, 1®physician will determine the dosage it deems most appropriate based on the age, weight and all the other factors specific to the subject to be treated.

The following examples, exemplary non-limiting, illustrate a composition of the invention.

Is prepared in the usual way of tablets to 10 mg of active product having the following composition:

diméthylamlno-a 3 - propionate (chlor-7 naphthyridine-a 1.8 yl 2) oxo 1 -2 isoindolinyl-L-0,010 grams

- starch 0,200 grams

- precipitated silica 0,036 grams

- magnesium stearate................................... 0,004 grams

By operating the same way, can be prepared tablets that have an active © converter consists of the following products:

Acétamldo and 4 - butyrate (chlor-7 naphtyridins-a 1.8 yl 2) oxo 3 -2 isoindolinyl L " (R)

- (Propionyl 1 piperidyl-4) carboxylate (chlor-7 naphthyridine-a 1.8 yl 2) -2 isoindolinyl-L-oxo 3" (the HS)

Methyl 5 - hexanoate (methoxy-7 naphthyridine-a 1.8 yl 2) -2 oxo 3 - isoindolinyl-I agonist (R)

- Diisopropylaminophenylpropyl 3 propionate (chlor-7 naphthyridine-a 1.8 yl 2) -2 oxo 3 - isoindolinyl L (R).