FI63589C - FORM OF THERAPEUTIC ACTIVATION OF 6- (7-CHLORO-1,8-NAPHTHYRIDIN-2-YL) -5-CARBAMOYLOXY-7-OXO-6,7-DIHYDRO-5H-PYRROLO (3,4-B) PYRAZINER - Google Patents

Description

1 63589

Process for the preparation of therapeutically active 6- (7-chloro-1,8-naphthyridin-2-yl) -5-carbamoyloxy-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazines Application 760937 (Patent 60012)

The invention relates to a process for the preparation of therapeutically active 6- (7-chloronaphthyridin-2-yl) -5- (carbamoyloxy) -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazines of the formula is

O

III (ι) 15'N''O-CO-NR. ^ 20 in which represents an alkyl group having 1 to 4 carbon atoms and R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

According to the invention, the general formula I can be renewed

1) When R 1 and R 2 are as defined above, new compounds of general formula I can be obtained by reacting an amine of the general formula hnr 1 r 2 (II) 2 wherein R 1 and R 2 are as defined above. , reacting with 63589 2 2- (2-phenylcarbonyloxy-5-oxopyrrolin-1-yl) -7-chloro-1,8-naphthyridine of the general formula

O

(III) ^ -cl 10 O-CO-OAr wherein Ar represents a phenyl radical (optionally substituted with an alkyl radical containing 1 to 4 carbon atoms or a nitro radical),

The reaction is usually carried out in an anhydrous organic solvent such as acetonitrile or dimethylformamide at a temperature in the range of 20 to 100 ° C.

A compound of general formula III can be obtained by administering a chloroformate of general formula IV

Cl — CO-O-Ar (IV) 25 wherein Ar is as defined above, affects a derivative of the general formula 0 30 (v)

OH

3 63589

The reaction is usually carried out in a basic organic solvent such as pyridine, most preferably at a temperature in the range of 0 to 60 ° C.

The compound of general formula V can be obtained by partial reduction of an imide of general formula 0 nn <vi>. 1 —ci o 15

The reaction is usually carried out with alkali borohydride and working in an organic or aqueous-organic solution, for example a mixture of dioxane-water, dioxane-methanol, methanol-water, ethanol-water or tetrahydrofuran-methanol.

An imide of general formula VI can be obtained by administering 25 [mu] H of N-N-Cl (VII) of 2-amino-7-chloronaphthyridine of general formula VII.

Λ NN

30 affects the anhydride of general formula

O

(VIII) ζ.γ o _ - 1. - - 4 63589 wherein the intermediate is optionally a compound of the general formula OC CO- “»

N 2 COOH

10 15

The reaction of a 2-aminonaphthyridine of general formula VII and an anhydride of general formula VIII is usually carried out by heating in an organic solvent such as ethanol, acetic acid, dimethylform-20Q amide, acetonitrile, phenyl ether or dimethylformamide with N-cyclodexyl imidecarboxylate. hydroxy-succinimide.

The cyclization of a compound of general formula IX to a compound of general formula VI can usually be carried out either by heating with acetyl chloride in acetic acid or acetic anhydride, or by reacting a condensing agent such as dicyclohexylcarbodiimide in dimethylformamide at a temperature between 20 ° C and 20 ° C. C, or by administering thionyl chloride or phosphorus oxychloride optionally in an organic solvent such as methylene chloride or chloroform.

2,3-Pyrazinedicarboxylic anhydride can be prepared according to the method described in S. Gabriel et A. Son, Chem. Ber., 40, 4850 (1907).

OD

2 63589 2) When both symbols and R 2 represent alkyl having 1 to 4 carbon atoms, the novel compounds of general formula I can be obtained by administering carbamyl chloride / having the general formula: ___ 5 c 1 -C 10 -NR 1 (XI) wherein R 1 and R 2 represent same as above, affects a compound of general formula V.

Typically, a compound of general formula XI is reacted with an alkali salt of a compound of general formula V, optionally prepared in situ, and worked up in an anhydrous organic solvent such as dimethylformamide or tetrahydrofuran at a temperature below 60 ° C.

The reaction can also take place by reacting a compound of general formula XI with a compound of general formula V and working in pyridine and optionally containing a tertiary amine such as triethylamine.

3) When in the general formula IR 1 represents an alkyl radical containing 1 to 4 carbon atoms and R 2 represents a hydrogen atom, the novel compounds of the general formula I can be obtained by giving an isocyanate of the general formula XII O = C = N - R 1 (XII) in which R ^ represents an alkyl containing 1 to 4 carbon atoms, acts on a compound of general formula V.

The reaction is usually carried out in an organic solvent such as acetonitrile at a temperature in the range of 20 to 100 ° C and optionally a tertiary amine such as triethylamine is present in the solution.

k 6 63589

The compounds of general formula I may optionally be purified by physical methods (such as crystallization or chromatography) or by chemical methods (such as salt formation, crystallization and then decomposition in an alkaline medium).

The novel compounds of the invention have advantageous pharmacological properties. They have proven to be particularly effective tranquilizers, anticonvulsants and relaxants.

10 Orally administered to animals (mice) at doses ranging from 0.1 to 10 mg / kg, the new compounds have proven to be particularly effective in the following experiments: - Electric shock, according to a technique approximately identical to that described in Tedeschi et coll. J. Pharmacol. 125, 28 (1959).

- Pentetrazole-induced convulsion, according to a technique approximately identical to that described in Everett et Richards, J. Pharmacacol., 81, 402 (1944).

20 - Supramaximal electric shock, according to a technique identical to that described in Swinyard et al., J. Pharmacol. 106 319 (1952).

- Mortality by strychnine, according to a technique approximately identical to that described in F. Barzaghi 25 et al., Arzneimittel Forschung, 23, 683 (1973), and - locomotor activity, according to the technique described in Courvoisier, CongrSs des Mödecins Aliönsies et Neurologistes, Tours, 8-13 June 1959, and 30 Julou, Bulletin de la SociStS de Pharmacie de Lille, No. 2, Jänvier 1967, page 7.

In addition, they have only very low toxicity: their 50% lethal dose (LD 2) is usually above 300 mg / kg po. mice.

63589 7

Pharmacological comparative tests

The therapeutic activity of the compounds according to the invention was compared with 2- (7-chloro-5,8-naphthyridin-2-yl-3- (4-methylpiperazin-1-yl) carbonyloxyisoindoline-1, a compound known from Example 1 of FI Patent 55659). -on to the corresponding activity.

Methodology 1. Dependence test (mice)

Mice were placed in a horizontal position on 10 tensioned metal wires. It was considered that any animal that failed to hang after three attempts or that fell in 5 or less seconds was subjected to a neuromuscular depressive effect. All control animals hung easily on the wire, remained hanging, and even rose in 5 or less 5 seconds so that at least one of the hind legs touched the wire. 5 or 6 mice per dose and 3-5 doses per test substance were used. DE ^ q is the dose of test substance that, at the culmination of the effect, induces neuro-20 muscular depressive activity in 50% of animals.

2. Aggression caused by electric shock (in mice)

Male mice, placed in pairs on a metal plate and given an electric shock at regular intervals, rise to their hind legs and begin to fight after 20-60 seconds. A dose of test substance (DA ^ q) was determined which, 1 1/2 hours after oral administration of the substance, inhibited this aggressive behavior in 50% of the experimental animals. 5 pairs of mice per dose and 3-4 doses per test substance were used.

3. Pentetrazole chemically induced convulsion

Mice weighing 18-22 g were used as experimental animals. All mice were administered subcutaneously 150 mg / kg Pente-35 trazole (25 ml of a unit dose per kg body weight of 8,63589 mice). The test substances were administered orally 1 1/2 hours before the administration of pentetrazole and the unit dose per kg of mouse weight was contained in 25 ml of solution. 5 mice per dose and 3 doses per 5 test substances were used. Following pentetrazole injection, mice were placed in a box divided into 13 cm wide compartments so that each mouse was isolated throughout the observation period. The box was covered with a transparent plate. All control animals that received subcutaneously 150 mg / kg pentetrazole developed more or less severe seizures after at least 15 minutes, leading to rapid death. Mice were observed for 30 minutes after pentetrazole injection. Mice that were not protected at all during this 30 min were considered to be protected against convulsions. DA ^ q is the dose of test substance that inhibits pentetrazole-induced seizures in 50% of experimental animals.

4. Toxicity 11 Sep 20 The dose of test substance (DLjjq) that caused death in 50% of the experimental animals was determined.

The results are shown in the following table.

9 63589

S

. <u in

H -P rH CO <N VO

Hl C - - «· * · CP S« ΛΓ'ττ ro vo h · (0 Dj H A 1—1 0 o 'm in

W ö D Q

• +3 vo m O. U «· * 5j.p ld n o m m vo

• H C (N rH r-l H

Ti K, ^ ^

o o m m ö W Q Q

Λ 8 ^ 6 <n 4-i Q: iö * σι> H m ftf -H t — I Qj * · n-

U M rH TT O O ro O IN

ϊη e $ IJgfl__ 3 h m M ^ m r ~ m 1 -H · - *> *

• H> -. o m o <n o o rH

2 -H afl · Γ "O rH i — I H

2 -H rH O, m> 8 a h Cp Λ § g * o <

Isa pj "! En to —- a - 'e · o o

S3 9 S S

13 »ss si”

Dj JÄ -P g -P g OI 00 rH in ti3a I Isis____ M - _>, · o o o o o o o o o o o o · o oi en. oi oi on

rH * h cp A l§ 8 l§ 8 S 8: j3 8 S

fiä ^ t II ii ii li II

Sg "" · ill? 3LL? IIII

a anj-H H III Bj H H aiB-HH

w __ (1) 0.4-1¾ ω Dj-p h o Δ-p fa 10 63589

The absolute value of the activity of the compounds according to the invention is often lower than the corresponding value of the reference compounds. However, the compounds according to the invention have a specific effect which the reference compounds do not have.

In Zbinden, G & Randall, L.O. Advances in Pharmacology 5, 213-291 (1967), which relates to sedatives belonging to the group of benzodiazepines, has shown by comparing the results of laboratory and clinical trials in mice that an experiment the methodology of which is described in Everett & Richards, J. Pharmac., 81, 402 (1944).

15 The other experiments used, in particular the aggression caused by electric shock (Tedeschi et al.) And the dependence test, are less specific, but they can to some extent specify the activity spectrum of the product. For example, mild sedatives used in clinics such as chlorothiazepoxide and diazepam have activity at a dose only slightly higher than the dose of psychotropic products, whereas neuroleptic products / Julou, L & ai. Excerpta Media International Congress Series, No. 129, pp. 293-303 (1967) /, or products which, when used therapeutically, have a secondary sedative effect, for example antihistamines / Boissier, J.R. & ai., Ann.

Pharm. Franc., 26, 277-285 (1968) / are very active, especially Tedeschi & al. in an aggression test caused by electric shock.

The specificity of the action of the compounds according to the invention is apparent from the relationship between the active dose obtained in the pentetrazole-induced convulsion test and the active dose obtained in the electroshock aggression test: U 63589 DE50 aggr.

DE ^ q pentetr.

or the relationship between the active dose obtained in the dependence test and the active dose obtained in the 5 pentetrazole-induced test: DE50 riiPP * 10 DE50 Pentetr *

The higher the ratios presented above, the greater the specificity of the effect. It can be seen from the above table that the compounds prepared according to the present invention have a mild sedative effect 3a with a very weak secondary sedative effect.

2-Heterocyclyl-3- (1-piperazinyl) carbonyloxypyrrole derivatives having similar activity to the compounds prepared according to the invention are already known. Known compounds are described in F1 patents 54712, 55659 and 60707. Compared to the known compounds, the effect of the compounds according to the invention is more selective, which is manifested as a very weak secondary sedative activity.

The following examples show how the invention can be practiced.

Example 1 6- (7-Chloro-1,8-naphthyridin-2-yl) -7-oxo-5-piperidinecarbonyloxy-6,7-dihydro-5H-pyrrolo [S, 4-b] pyrazine

To a suspension of 5.2 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -7-oko-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo / 3,4- b7pyrazine 21 in anhydrous dimethylformamide, a solution of 3.06 g of piperidine in 5 cm 3 of anhydrous dimethylformamide is added. The reaction mixture is then stirred for 12 minutes at a temperature in the region of 25 [deg.] C., after which 75 cm3 of isopropyloxide are added. The insoluble product is isolated by filtration, washed 4 times with 10 ml of isopropyl oxide and then treated with 100 cm of methylene chloride. The weak insoluble matter is filtered off, after which the organic solution obtained is washed by decantation 2 times successively with 25 cm @ 1 of soda and 25 cm <3> of water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. After recrystallization from 130 cm of acetonitrile, 2.25 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-5-piperidinecarbonyloxy-6,7-dihydro -5H-pyrrolo [3,4-b] pyrazine, melting at 249 ° C.

By working in the same way, but replacing the piperidine with dimethylamine, N-methylbutylamine and n-butylamine, the following are obtained, respectively:

6- (7-chloro-1H-8-naphthyridin-2-yl-5-dimethylaminocarbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine, mp 270 ° C

5- (N-butylmethylaminocarbonyloxy) -6- (7-chloro-1,8-naphthyloxy)

thyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine, m.p. 234 ° C

5-n-butylaminocarbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine, m.p.

25 264 ° C.

6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-5-phenoxy-carbonyloxy-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine can be prepared by adding with constant stirring and maintaining the temperature at about 5 ° C, 9.4 g of phenyl chloroformate to a suspension of 6.3 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7 -oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine in 63 g of anhydrous pyridine. When the addition is complete, the reaction mixture is gradually heated to 60 ° C and maintained at this temperature for 1 h. The reaction mixture is cooled and then poured onto 350 cm of distilled water 13 63589 and the temperature is maintained at about 10 ° C. The insoluble product 3 is filtered off, washed successively with 120 cm3 of water, 40 cm3 of acetonitrile and 40 cm3 of isopropyl oxide. After drying, 7.2 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine are obtained, melting at 270 ° C.

6- (7-Chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine can be prepared by adding with constant stirring and maintaining the temperature At about 3 ° C, 0.97 g of potassium borohydride to a suspension of 7.45 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5,7-hydroxy-6,7-dihydro -5H-pyrrolo / 3,4-t7py, racine in 288 cm 3 of a mixture of dioxane and methanol (50:50 by volume) - Stir for 2 h at about 3 ° C and then separate the insoluble product by filtration, wash successively 24 cm 3 of a mixture of dioxane-methanol (volumes 50:50), 24 cm 3 of water, 24 cm 3 of a mixture of dioxane-methanol (volumes 50:50) and 12 cm 3 of isopropyl oxide. After drying, 5.3 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7-oxo-6,7-di-20-hydro-5H-pyrrolo / 3,4- ^ 7pyrazine, which melts at 270 ° C with decomposition.

6- (7-Chloro-1,8-naphthyridin-2-yl) -5,7-hydroxy-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine can be prepared by the slightest addition of about 15 ° C, 32 g of 6- (7-25 hydroxy-1,8-naphthyridin-2-yl) -5,7-dioxo-6,7-dihydro-4H-pyrrolo [3,4-b] pyrazine in a solution of 3 , 8 cm of dimethylformamide in 128 cm of phosphorus oxychloride. When the addition is complete, the reaction mixture is heated under reflux conditions for 1/2 h, cooled and poured onto 1.3 kg of crushed ice in 1.3 kg portions. The insoluble product is filtered off and washed with water until the pH of the washings is 5. After drying, 21.3 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5,7-hydroxy-6,7-dihydro -5H-pyrrolo [3,4-b] pyrazine, melting at 340 ° C with decomposition. 35 6- (7-Hydroxy-1,8-naphthyridin-2-yl) -5,7-dioxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine can be prepared by cooling to 16,63589. a suspension of 22.4 g of 2-amino-7-hydroxy-1,8-naphthyridine and 23 g of 2,3-3-pyrazinedicarboxylic anhydride in 280 cm of acetic acid. After heating the reaction mixture with a reflux condenser for 1 h, the mixture is cooled to about 30 ° C and 280 cm of acetic anhydride is added. The reaction mixture is reheated with a condenser for 10 minutes then cooled to about 20 ° C. The insoluble product 3 is filtered off, washed with 40 cm of acetic acid 3a 3 and 10 200 cm of isopropyl oxide. After drying, 32.1 g of 6- (7-hydroxy-1,8-naphthyridin-2-yl) -5,7-hydroxy-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine are obtained, which melts at 373 ° C.

2-Amino-7-hydroxy-1,8-naphthyridine can be prepared according to the method described in S. Carbone et al. Gazz. Chim. Ital. 95, 1498 (1965).

Example 2 6- (7-Chloro-1,8-naphthyridin-2-yl) -5-dimethylaminocarbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo-20,3,4-b / pyrazine

To a suspension of 4.7 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo / 3,4- b / -pyrazine in a mixture of 47 cm 3 of anhydrous methylene chloride and 16 cm 3 of anhydrous pyridine is added successively 4.85 g of dimethylcarbamyl chloride, then 4.55 g of triethylamine. The reaction mixture is then heated with a condenser for 2 h, cooled and then poured onto 180 cm3 of water. The light insoluble matter is filtered off, the aqueous layer is separated by decantation and washed 3 times with successive decantations 2 times for 50 cm; methylene chloride. The combined organic layers are washed successively by decantation twice with 30 cm of 1N soda, then twice with 30 cm of water, dried over anhydrous sodium sulphate to which decolorizing carbon has been added, filtered and evaporated to dryness under reduced pressure.

15 63589 3

The residue obtained is taken up in 20 cm of acetonitrile and the insoluble matter is filtered off and washed 3 times with 3 cm2 of acetonitrile. This material is recrystallized from 3 to 14 cm of dimethylformamide to give 4.1 g of solvated material. It is dissolved in about 70 cm of dimethylformamide, which is 100 cm. The solution thus obtained is poured onto 3 1200 cm of water and the insoluble matter is filtered off and washed 5 times with 20 cm of water. 3.6 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-dimethyl-10-aminocarbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo [1,4-b] pyrrole are dried. -razine melting at 270 ° C.

Example 3 5- (N-Butyl-N-methyl) aminocarbonyloxy-6- (7-chloro-1,3-naphthyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [ 3,4-b7pyratsiini

Work as in Example 2, but starting from 4.7 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo / 3,4 -b7pyrazine and 6.23 g of N-butyl-N-methylcarbamyl chloride in a mixture of 3 3 20 47 cm of methylene chloride and 16 cm of pyridine and 4.55 g of triethylamine, and, after recrystallization, 3.9 g of 3 65 cm of acetonitrile are obtained 5- (N-Butyl-N-methyl) aminocarbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrazine melting at 234 ° C. Example 4 5-n-Butylaminocarbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyrrata- toxin

To a suspension of 7.8 g of 6- (7-chloro-1,8-naphthyridin-2-yl) -5-hydroxy-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyridine -razine 156 in anhydrous acetonitrile, 5 g of n-butyl isocyanate are added and the mixture is heated with a reflux condenser for 7 h. The insoluble product is filtered off and washed twice with 10 cm of anhydrous acetone. The product obtained is dissolved in 430 cm of methylene chloride, ie 63589, and the resulting solution is washed by successive decantation with 3 to 85 cm of 0.1 N soda and 85 cm of water. Dry and then concentrate the organic phase under reduced pressure (20 mm Hg). The residue obtained is recrystallized from 230 cm3 of acetonitrile 3a to give 5.2 g of 5-n-butylaminocarbonyloxy-6- (7-chloro-1,8-naphthyridin-2-yl) -7-oxo-o- -dihydro-SH-pyrrolo (S) -b / pyrazine, melting at 264 ° C.

Claims (4)

63589 Claim. Process for the preparation of therapeutically active 6- (7-chloro-1,8-naphthyridin-2-yl) -5- (carbamoyloxy) -7-oxo-6,7-dihydro-5H-pyrrolo / 3,4- b7 for the preparation of pyrazines of the formula O 10 -CO-NR 15 wherein R 1 represents an alkyl group having 1 to 4 carbon atoms and R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, characterized in that 1: an amine of the formula hnr 1 r 2 (II) wherein R 1 and R 2 are as defined above, are reacted with 6- (7-chloro-1,8-naphthyridin-2-yl) -5-oxo-pyrrolo-D 4 -b7pyrazine of formula 0 i <; | f "| 0-CO-Ar 35 63589 wherein Ar is a phenyl group which may be substituted by an alkyl group or a nitro group having 1 to 4 carbon atoms, the compound obtained is isolated and, if desired, converted into an acid addition salt, or when R 1 and R 2, which may be the same or different, denoting an alkyl group having 1 to 4 carbon atoms, a carbamyl chloride of the formula C1-CO-NR1R2 (XI) 10 is reacted with 2- (5-oxo-7-hydroxy-pyrrolo [3,4-b] pyrazole); -6-yl) -7-chloro-1,8-naphthyridine of the formula O Γλί ^ v I (V) II Cl OH 20 and the compound obtained is isolated or 3: when R 1 represents an alkyl group having 1 to 4 carbon atoms, and R 2 is a hydrogen atom, an isocyanate of the formula O = C = N - R x (XII) is reacted with 2- (2-hydroxy-5-oxo-pyrrolo [5,4-b] pyrazin-6-yl) of the formula (V) With -7-chloro-1,8-naphthyridine and the compound obtained is isolated. 63589 For the preparation of therapeutically active 6- (7-chloro-1,8-naphthyridin-2-yl) -5-carbamoyloxy-7-oxo-5,6,7-dihydro-5H-pyrrolo [3,4-b] 4- b7pyraziner with formula 0 f 1 N 10. IN_L L f) -Cl (I) o-co-nr1r2 15 color R1 is an alkyl group having 1-4 cholaters and R2 is a hydrogen atom with an alkyl group having 1-4 cholaters, 20 turns are shown in Figure 1: The amine with the formula hnr1r2 (II) 25 color R1 and R2 is an angidic acid, which is 6- (7-chloro-1,8-naphthyridin-2-yl) -5-oxo-pyrrolo / 3,4- b / pyrazine with formula O / V \ uii) IIN --C1 35 O-CO-OAr i