FI87202B - Method for production of therapeutically active quinoline and quinoxalinedione derivatives - Google Patents

Description

1 87202

This invention relates to a process for the preparation of novel organic compounds. These novel compounds are quinolinedione or quinoxalinedione derivatives of the formula o 10 fif (R) (R) or R (III) or R (III) 20 are C 2-4 alkoxycarbonyl, C 1-4 alkanoyl, benzyl, phenyl, m-trifluoromethylphenyl, 2-benzoxazolyl or 2-benzothiazolyl or their pharmacologically acceptable acid addition salts.

The organic bases of formula I, II or III prepared in accordance with this invention form non-toxic acid addition salts with a variety of pharmacologically acceptable organic and inorganic salt-forming reagents. Thus, acid addition salts formed by mixing an organic free base with one or more acid equivalents, suitably in a neutral solvent, are formed from acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, sulfamic, maleic, lactic, malic, with succinic, tartaric, acetic, fumaric, gluconic and ascorbic acid and the like. For purposes of this invention, the free bases are equivalent to their non-toxic acid addition salts. The acid addition salts of the organic bases prepared according to the invention are generally crystalline solids, relatively soluble in water, methanol and ethanol, but relatively insoluble in non-polar organic solvents such as diethyl ether, benzene, toluene and the like.

The quinoxaline dione derivatives of formula III as defined above are prepared according to the invention as shown in the following reaction scheme: "rvs λλ. ^ Yvp- ·

UstfJ * 'vj1 * £ „Xjr w (D 0 (2)' J (3) 20 where R is as defined above.

According to the above reaction scheme, 5,8-quinoxalinedione (1) is reacted with an appropriately substituted piperazine (2) in an inert solvent such as dioxane, dimethylformamide or tetrahydrofuran at ambient temperatures for 2-5 hours to give the final product (3).

The quinoline dione derivatives of formula I or II as defined above are prepared according to the invention as shown in the following reaction scheme:

^ N N-R

5 o ΤΓ N_ /

Il o (5)

r ^ V ^ i / - \ J

I + HN N-R-H

^ N ^> f w Λ ~ \

10 (4) O ^ | P \ ___ / "R

^ N y (6) wherein R is as defined above.

According to the above reaction scheme, 5,8-quinolinedione (4) is reacted with an appropriately substituted piperazine (2) in an inert solvent such as 1,2-dimethoxyethane, dioxane or tetrahydrofuran at ambient temperatures for about 4-48 hours to give 7 a mixture of isomer (6) and isomer (6).

The novel compounds according to the invention are very effective as anti-asthmatic and anti-allergic agents, as shown below.

The compounds prepared according to the invention differ substantially in structure from the compounds known, for example, from FI patent application 865 182 and from EP patents 107 365 and 107 367. For example, FI patent application 865 182 relates to naphthalenediones to which a substituted amino group is attached. The compounds prepared according to the invention instead have a different ring structure, i. quinoline or quinoxaline, and is substituted with a substituted piperazino group. Due to this structural difference between the compounds, the valuable properties of the compounds according to the invention cannot be considered as expected on the basis of the prior art mentioned.

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Bronchospasm in allergic asthma is the result of the release of mediators such as histamine and the slow-reacting substances of mast cells. The role of mediator release in the induction of an asthma attack has been extensively described and documented, cf. Kaliner, M. and Austen, K.F., Bronchial Asthma Mechanisms and Therapeutics, ed. E. B. Weiss, Little, Brown and Company, Boston (1976), p.163, Lichtenstein, L.M., Asthmaphysiology, Immunopharmacology and Treatment, Second International Symposium, 10 eds. L.M. Lichtenstein and K.F. Austen, Academic Press, New York (1979), p. 51 and Bell, S.C. et al., Annual Reports in Medicinal Chemistry, ed. H.J. Hess, Academic Press, New York, 14 (1979), p. 51.

The novel compounds 15 prepared according to the invention have been tested against L.M. Lichtenstein and A.G. Oslerin, J. Exp. Med. 120 (1964) 507-530, a method for evaluating the ability of compounds to inhibit the release of a mediator (histamine) from immunologically stimulated human basal cells. Reagents 20 IPX Concentrated Tris Buffer

Dissolve 140.3 g of sodium chloride, 7.45 g of potassium chloride and 74.5 g of Trizma-Tris Pre-Set, reagent grade, pH 7.6 at 25 ° C (Sigma Chemical Co.), in sufficient water to give a final the volume becomes 2 liters.

Human Alfumin (Sigma Chemical Co.) (30 mg / ml)

Calcium and magnesium stock solutions Prepared to be 0.75 and 0.5 molar, respectively, of calcium chloride dihydrate and magnesium chloride hexahydrate.

Three-A buffer. . Dilute 10 ml of 10X Tris buffer and 1.0 ml of human albumin to 100 ml with water.

Tris-ACM buffer 35 Dilute 10 ml of 10X Tris buffer, 1.0 ml of human albumin, 0.8 ml of calcium stock solution and 0.2 ml of magnesium stock solution to 100 ml with water.

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Rabbit anti-human IgE

Behring Diagnostics (usually used at a final concentration of 10 pg protein / ml).

House dust mite extract (Dermatophagoides Farinae) 5 Sensitizing extract, strength 1: 100 (w / v),

Hollister-Stier Labs. Generally, this is diluted 1: 1,000 to 1: 10,000 (keeping the ampoule as a stock solution).

Other sensitisers

Intradermal solutions for intramuscular preparations for use in sensitization, Hollister-Stier Labs. The final concentration used is of the order of 1 PNU / ml.

Separation of leukocytes from human blood and stimulus 80 ml of blood is taken from individuals known to react with histamine releasing anti-IgE, ragweed-15 antigen or other specific sensitizer using four heparinized tubes. This 80 ml of blood is mixed with 20 ml of saline containing 0.6 g of dextrose and 1.2 g of dextran. The blood is allowed to sediment at room temperature in two 50 ml polycarbonate-20 centrifuge tubes until a clear interface (60-90 minutes) develops between the red blood cells and the plasma. The plasma layer (top) of each tube is removed with a pipette and transferred to the corresponding polycarbonate tubes. The plasma is centrifuged for eight minutes at 110 g at 25 ° C. The supernatant is carefully discarded as completely as possible and the cell pellet is resuspended in 2-3 ml of Tris-A buffer using a siliconized Pasteus pipette. Resuspension is accomplished by gently withdrawing the liquid in the pipette back and forth, keeping the tip of the pipette below the liquid surface until a uniform cell suspension is obtained. Sufficient Tris-A buffer is then added to bring the volume of liquid in the tube to about 45 ml and the tube is centrifuged at 110 g for eight minutes at 4 ° C. The supernatant is discarded and the cell pellet is resuspended and centrifuged as described above. The supernatant is discarded and the 6 87202 cell pellet is suspended in 2-3 ml of Tris-ACM buffer to make the final volume sufficient to be added to the reaction tubes.

Reaction tubes containing anti-IgE or antigens, either alone or with the test compound, in a total volume of 0.2 ml are prepared and placed in a 37 ° C water bath. The cells are warmed to 37 ° C and the tubes are often shaken to ensure uniform suspension while adding a 1.0 ml volume of liquid to each reaction tube. The tubes are then incubated for 60 minutes at 37 ° C with gentle rotation every 15 minutes to keep the cells evenly suspended. When the reaction is complete, the tubes are centrifuged for 10 minutes at 1,500 rpm at 15 ° C to sediment the cells. Aliquots of one ml of supernatant are transferred to 12 x 75 mm polyethylene tubes and 0.2 ml of 8% perchloric acid is added to each tube. Blind tests and total determinations are included in each test. Blind experiments contain cells and all reagents except antigen or anti-IgE. Total assays contain 0.24 ml of 8% perchloric acid, one ml of cells and 0.2 ml of buffer. All samples are then centrifuged to remove precipitated protein.

Determination of released histamine by an automated fluorometric method This automated method is described by R.P. Siraganian, Anal. Biochem. 57 (1974) and J. Immunol. Methods 7 (1975) 283 and is based on P.A. Shoren et al., J. Pharmacol. Exp. Ther. 217 (1959) 182, to the manual method.

The automated system consists of the following parts of the Techni-con Autoanalyzer II: Sampling IV, Dual Speed Dosing Pump III, Fluoronephelometer with Narrow Slit Primary Filter 7 to 60 and Secondary Filter 35 3 to 74, Recorder, and Digital Printer. The running program used is described by Siraganian (see above) with the following modifications: the dialysis machine is not used, all pumping pipes pass through a single high-capacity dosing pump and twice the volume of the sample is taken for analysis.

5 The automated test procedure consists of the following steps: extraction from basic brine to butanol, extraction back into dilute hydrochloric acid with the addition of heptane, reaction of histamine and o-phthalaldehyde (OPT) at high pH and conversion of the OPT adduct to a stable phosphoric acid phosphoric acid. The reaction product is then passed through a fluorometer. The full scale response is adjusted to correspond to 50 ng of histamine with a threshold sensitivity of about 0.5 ng.

Calculation of Histamine Release Test Results 15 The amount of histamine expressed as ng of each sample is subtracted from the instrument blank (rinse). The amount of histamine, expressed in ng, for each sample is then divided by the average of three total assays (cells lysed with perchloric acid) to obtain the amount released as 20%.

Control samples contain antigen but do not contain test compound. Blind (or spontaneous release) experiments do not contain antigen or test compound. The mean of the blank experiments (three replicates) 25 is subtracted from the percentage of control samples and test compounds released.

Calculate the means of the control and test compound groups and the test compound results as a percentage of the control using the formula: 30% released histamine with test compound% released histamine for controls

Values obtained with different concentrations of test compound are used to calculate the ED50 (concentration in pM that provides 50% inhibition of histamine release) by linear regression. A compound is considered to have an effect if the ED50 is $ 48 μΜ.

The results of this test for typical compounds of the invention are shown in Table 5 I.

Table I

Inhibition of Histamine Release from Immunologically Irritated Human Basal Cells Compound ED50 μΜ 10 4- (5,8-Dihydro-5,8-dioxo-6-quinoxalinyl) -1-piperazinecarboxylic acid ethyl ester 3,7 6- [4- [3- (trifluoromethyl) phenyl] ] -1-Piperazinyl] -5,8-quinoxalinedione 6,6 6- [4- (2-benzothiazolyl) -1-piperazinyl] -5,8-quinoxalinedione 1,2 4- (5,8 -dihydro-5,8-dioxo-6-quinolinyl) -1-piperazinecarboxylic acid ethyl ester 17.4 6- [4- (phenylmethyl) -1-piperazinyl] -5,8-quinolinedione 12.1 20 The ability of these compounds to inhibit lipoxygenase density expressed as the release of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) and the suppression of biosynthesis were measured as follows.

In this experiment, 3 x 107 guinea pig peritoneal neutrophils were incubated in Dulbeccos buffer containing 50 mM Tris buffer (pH 7.4). Control solvent or test compounds were added to neutrocells at a concentration of 10 pg / ml five minutes before the addition of 100 μΜ: η arachidonic acid and 20 μΜ: η calcium ionophore (A23187).

Three minutes after the addition of arachidonic acid and calcium ionophore, the total lipid was separated into chloroform after adjusting the pH to three with citric acid and adding equal amounts of methanol and chloroform.

35 5-HETE and LTB4 were separated by HPLC using a 5 μΜ, 4 x 25 cm octadecyl silica column (IBM instruments) running 87202 in a solution of 70-80% methanol in water adjusted to pH three with acetic acid. When pumping the mobile phase at 1.0 ml / min, LTB4 and 5-HETE absorbances of 270 and 236 nm, respectively, were observed.

5 LTB4 and 5-HETE were quantified by comparison to control and results were expressed as a percentage of control. The lower the percentage, the more active the compound.

The results of this test for representative compounds prepared according to the invention are shown in Table II. 10 Table II

Inhibition of neutrophil lipoxygenase by immunologically irritated guinea pig neutrocytes Compound% of control

LTB4 5-WEEK

6- [4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] -5,8-quinoxalinedione 0,6 6- [4- (phenylmethyl) -1-piperazinyl] -5,8-quinoxalinedione 8 53 .9 6- [4- (2-Benzothiazolyl) -1-piperazinyl-20-yl] -5,8-quinoxalinedione 8 67,2 6- [4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] -5 , 8-quinolinedione 5.7 11.9 6- [4- (2-benzoxazolyl) -1-piperazinyl] -5,8-quinolinedione 8 36.9 25 7- [4- (2-benzoxazolyl) -1 -piperazinyl] -5,8-quinolinedione 35.8 22.7

The novel compounds of the invention are effective anti-asthmatic agents in infants in amounts ranging from about 0.1 to about 100 mg / kg body weight per day. For optimal results, the preferred method of administration would be from about 1 to about 25 mg / kg body weight per day using dosage units such that the total amount of active compound administered to a subject weighing about 70 kg is from about 7 mg to about 1.8 g in 35 hours. This method of administration can be adjusted to produce an optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. An undeniable practical advantage is that these active compounds can be administered by any suitable route, such as orally, by aerosol, intravenously, intramuscularly or subcutaneously.

The active compounds may be administered orally, for example, with an inert diluent or an assimilable edible carrier, or may be encapsulated in hard or soft shell gelatin capsules or compressed into tablets or incorporated directly into dietary foods. For the purpose of oral therapeutic administration, the active compounds can be incorporated with inert drug carriers and used in the form of ingestible tablets, lozenges, lozenges, capsules, elixirs, suspensions, syrups, cachets, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The pronon contents of the compositions and preparations may, of course, be exchanged and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions and preparations are prepared in an oral dosage unit form of between about 5 to 200 mg of active compound.

Tablets, cachets, capsules, and the like may also contain: a binder such as tragacanth or acacia, corn starch or gelatin, indifferent drug carriers such as dicalcium phosphate, a disintegrant such as corn or potato starch, or other starch; , such as magnesium stearate, a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, winter oil li 87202 or cherry flavor. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a coloring agent and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds can be incorporated into sustained release preparations and formulations.

Compositions having the desired clarity, stability and suitability for parenteral use are obtained by dissolving 0.10 to 10.0% by weight of the active compound in a solvent consisting of a polyhydric aliphatic alcohol or mixtures thereof. Particularly satisfactory are glycerin, propylene glycol and polyethylene glycols. Polyethylene glycols consist of a mixture of non-volatile, normally liquid polyethylene-25 glycols which are soluble in both water and organic liquids and have molecular weights of about 200 to 1,500. Although the amount of active compound dissolved in the above solvent may vary from 0.10 to 10.0% by weight. , it is preferred that the amount of active compound used be from about 3% to about 9% by weight. Although the above-mentioned polyethylene glycols can be used in various mixtures, it is preferred to use a mixture having an average molecular weight of about 200 to about 400.

In addition to the active compound, parenteral solutions may contain various preservatives that can be used to prevent bacterial and fungal contamination. Such preservatives include, for example, myristyl-gamma-picoline chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerol ether, methyl and propyl parabens, and time-5 rosal. As a practical aspect, it is also convenient to use anti-oxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite and sodium formaldehyde sulfoxylate. Generally, antioxidants are used in concentrations of about 0.05 to about 0.2%. These compounds can also be administered by inhalation using conventional Aerosol (R) formulations.

The invention is illustrated in more detail by the following specific examples.

Example 1 5,8-Quinoxalinedione 9.2 g of 5,8-dihydroxyquinoxaline in 300 ml of p-dioxane were heated under reflux with 16.2 g of silver oxide for 6 hours. The mixture was cooled, then filtered and the filtrate was concentrated in vacuo. The residue was slurried in 75 mL of acetone, cooled and a solid collected, washed with acetone and dried to give 8.0 g of the desired product, m.p. 172 - 173 9C.

Example 2 4- (5,8-Dihydro-5,8-dioxo-6-quinoxalinyl) -1-piperazinecarboxylic acid ethyl ester 160 mg of 5,8-quinoxalinedione and 316 g of 1-piperazinecarboxylic acid ethyl ester in 10 ml of dioxane stirred for three hours. The resulting solid was collected, washed with ether and dried to give 150 mg of the desired product as a red solid, m.p. 180-195 ° C (dec.).

Example 3 6- [4- [3- (Trifluoromethyl) phenyl] -1-piperazinyl-5-yl] -5,8-quinoxalinedione 160 mg of 5,8-quinoxalinedione and 460 mg of 4- [3- (trifluoromethyl) phenyl] -1-Piperazine in 10 ml of dioxane was stirred for 3 hours and then diluted with 20 ml of ether and stirred for a further hour. The solid was collected to give 110 mg of the desired product as crystals, m.p. 165-190 ° C (dec.).

Example 4 6- [4- (Phenylmethyl) -1-piperazinyl] -5,8-quinoxalinedione 160 mg of 5,8-quinoxalinedione and 352 mg of 1-benzylpiperazine in 10 ml of dioxane were stirred for three to 10 hours. The solvent was then removed and the residue triturated with ether. This solid was collected, washed with ether and dried to give 110 mg of the desired product, m.p. 165-168 ° C (dec.). Example 5 6- [4- (2-Benzothiazolyl) -1-piperazinyl] -5,8-quinoxalinedione 640 mg of 5,8-quinoxalinedione and 876 mg of 4- (2-benzothiazolyl) -1-piperazine in 40 ml of dioxane were stirred for 24 hours. for an hour. The solid was collected to give 650 mg of the desired product, m.p. 104-105 ° C. Example 6 5,8-Quinolinedione Dissolved in 23.2 g of 5-hydroxyquinoline in 1,600 ml of methanol in an ice bath, a total of 36 g .25 of potassium dihydrogen phosphate and 96 g of potassium nitrosodisulfonate in 8.8 liters of water were added in five portions over five hours. The mixture was then stirred overnight at room temperature, followed by extraction with four 1,500 ml portions of chloroform. The extracts were combined, dried, filtered through alumina and evaporated to dryness to give 12.0 g of crude product. An analytical sample was prepared by crystallization from petroleum ether, m.p. 110 ° C.

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Example 7 6- [4- [3- (Trifluoromethyl) phenyl] -1-piperazinyl] -5,8-quinolinediones A 1.1 g portion of 5,8-quinolinedione was dissolved in 100 5 ml of 1,2- dimethoxyethane. A solution of 3.45 g of 4- [3- (trifluoromethyl) phenyl] -1-piperazine in 25 ml of 1,2-dimethoxyethane was added dropwise with stirring over 10 minutes. Stirring was continued for 30 minutes, then 1 g of silver oxide was added and stirring was continued for 48 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated with ethyl acetate and the solid was collected. This solid was boiled in ethyl acetate, then the mixture was cooled and an orange solid was collected to give 1.45 g of the desired product, m.p. 186-188 ° C.

Example 8 4- (5,8-Dihydro-5,8-dioxo-6-quinolyl) -1-piperazinecarboxylic acid ethyl ester 1.1 g of 5,8-quinolinedione in 100 ml of 1,2-dimethoxyethane were added dropwise to a solution of 2.37 g of ethyl 1-piperazinecarboxylic acid in 25 ml of 1,2-dimethoxyethane with stirring. Stirring was continued for 30 minutes, then 1 g of ho-25 pea oxide was added and this mixture was stirred overnight. The mixture was filtered and the solid was washed with dichloromethane. The filtrate and washings were combined, evaporated, triturated with ethyl acetate and the solid collected. This solid was chromatographed eluting with dichloromethane and then ethyl acetate. The active fractions were combined and evaporated to give 817 mg of the desired product, m.p. 192-194 ° C (dec.).

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Example 9 6- [4- (Phenylmethyl) -1-piperazinyl] -5,8-quinolinedione

To a solution of 1.1 g of 5,8-quinolinedione in 100 ml of 1,2-5 dimethoxyethane was added dropwise a solution of 2.64 g of 4- (phenylmethyl) -1-piperazine in 25 ml of 1,2-dimethoxyethane with stirring. minutes. Stirring was continued for 30 minutes, then 1 g of silver oxide was added and the mixture was stirred overnight and filtered. The filtrate was evaporated. The residue was triturated with ethyl acetate to give an orange solid. This solid was chromatographed on silica gel packed in dichloromethane eluting with ethyl acetate. The smaller component was isolated and recovered (see Example 10). The major component was isolated and dried to give 295 mg of the desired product, m.p. 167-169 ° C (dec.).

Example 10 7- [4- (Phenylmethyl) -1-piperazinyl] -5,8-quinolinedione

The smaller component isolated in Example 9 gave 83 mg of the desired product identified by proton nuclear magnetic resonance.

Example 11 6- [4- (2-Benzoxazolyl) -1-piperazinyl] -5,8-quinolinedione To 1.1 g of 5,8-quinolinedione in 100 ml of 1,2-dimethoxyethane was added dropwise a solution of 1.7 g of 4- (2-benzoxazolyl) -1-piperazine in 25 ml of 1,2-dimethoxyethane with stirring for 10 minutes. Stirring was continued for 18.5 hours and the solid was collected and collected. The filtrate was evaporated and the residue was triturated with ethyl acetate. This solid was collected, combined with the solid obtained above and chromatographed on silica gel eluting with 87202 dichloromethane, then ethyl acetate and finally chloroform-methanol (20: 1). The desired fractions were combined and evaporated to give 1.35 g of the desired product, m.p. 200 ° C (dec.).

The less polar component was treated as described in Example 12.

Example 12 7- [4- (2-Benzoxazolyl) -1-piperazinyl] -5,8-quinolinedione The less polar component isolated in Example 11 was dried to give 80 mg of the desired product, m.p. 235-240 ° C (dec.).

♦ * ^

Claims (9)

A process for the preparation of therapeutically active quinoline or quinoxalin dione derivatives of the formula: (M) R (II) or Γ T i w st 'n-R (III) for I Wherein R is C2-4 alkoxycarbonyl, C1-3 alkanoyl, benzyl, phenyl, m-trifluoromethylphenyl, 2-benzoxazolyl or 2-benzothiazolyl, and pharmacologically acceptable salts thereof, wherein 5,8-quinoline indione or 5,8-quinoxalinidone is reacted with a monosubstituted piperazine of the formula 30 R H wherein R is as defined above, in an inert solvent at ambient temperature for a time sufficient to the condensation must take place substantially. 2. A process according to claim 1, characterized in that the ethyl ester of 4- (5,8-dihydro-5,8-dioxo-6-quinoxalinyl) -1-piperazine carboxylic acid is prepared. 3. A process according to claim 1, characterized in that 6- [4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] -5,8-quinoxalinedione is prepared. 10 4. A process according to claim 1, characterized in that 6- [4- (phenylmethyl) -1-piperazinyl] -5,8-quinoxalinedione is prepared. 5. A process according to claim 1, characterized in that 6- [4- (2-benzothiazolyl) -1-piperazinyl] -5,8-quinoxalinedione is prepared. 6. A process according to claim 1, characterized in that 6- [4- [3- (trifluoromethyl) phenyl] -1-piperazinyl] -5,8-quinoline indione is prepared. Process according to Claim 1, characterized in that the ethyl ester of 4- (5,8-dihydro-5,8-dioxo-6-quinolyl) -1-piperazine carboxylic acid is prepared. 8. A process according to claim 1, characterized in that 6- [4- (phenylmethyl) -1-piperazinyl] -5,8-quinoline dione is prepared. 25 Process according to claim 1, characterized in that 7- [4- (phenylmethyl) -1-piperazinyl] -5,8-quinoline indione is prepared.