HU183172B - Process for producing indolo/2,'3':3,4/pyrido/2,1-b/quinazoline-5-ones - Google Patents

Abstract

The present invention relates to a process for the preparation of the indolo [2 ', 3': 3,4] pyrido [2,1-b] quinazolin-5-ones of formula I wherein R is hydrogen or C 1 -C 4 alkyl; is hydrogen, R2 is hydrogen or, optionally, R1 and R2 are taken together to form - (CH = CH) 2 - which are attached to two adjacent carbon atoms of the benzene ring, R3 is hydrogen, halogen, C1-4alkyl, cyano, phenyloxy or phenyl; C 1 -C 4 alkoxy, such that 6-hydrazono-6,7,8,9-tetrahydro-1 H -pyrido [2,1b] quinazolin-1-one or an acid addition salt thereof is used. Wherein R, R1, R2 and R3 are as defined above, in the presence of an acid. The compounds of formula (I) can be used in medicine for their valuable circulatory pharmacology, in particular their diuretic effect. -1-

Description

The present invention relates to a process for the preparation of new indolo [2 ^{, 3f} : 3.4] pyrido [2,1b] quinazolin-5-ones of formula (I).

Compounds of formula (1) are novel substituted derivatives of Rutecarpin III (J. Pharm. Soc. Japan 1915, 405, 1293), known from the flora. R Rutecarpine III is a diuretic that is beneficial in folk medicine. with circulatory effects and a respiratory agent [Yao Hsuch Hsueli Pao 1966.13, 265; Comp. Order 220, 792 (1945); 255, 1152 (192) J. R ec (III) similar to The outstanding representatives of the compounds of the formula I can be used as medicaments for their above-mentioned effect.

The most commonly used process for the preparation of Rutecarpin of Formula III, i.e., for the construction of the backbone of indo10 (2- [3,4] pyrido [2,1b] quinazolin-5-one), is 1,2,3,4-tetrahydro-norharman-1. -one or 3,4-dihydrobeta-carboline is reacted with an anthranilic acid derivative (J. Pharm. Soc. Japan 543, 51 (1927); 60 311 (1940); J. Chem. Soc. 1927, 1710; Angew. Chem. 50, 779 (1937); Acta Chim. Hung. 72, 221 (1972); Heterocycles 4, 23 (1976); 4, 1487 (1976); J. Am. Chem. Soc. 98, 6186 (1976); 99, 2306 (1977)].

According to our invention it is. Indolo [2 ', 3, 3 ^, 4, 3, 3, 4 ^, 3] pyrido [2,1b] quinazolin-5-one of the formula:

R is hydrogen or (1-4C) alkyl;

R ¹ is hydrogen,

R ² is hydrogen, or optionally R 'and

R ^{2 taken} together form a - (CH-CH) ₂ - group attached to two adjacent carbon atoms of the benzene ring,

R ³ is hydrogen, halo, C 1 -C 4 alkyl, cyano, phenyloxy or C 1 -C 4 alkoxy - can be prepared in good yield from 6-phenyl-lidrazono-6,7,8,8,9-tetrahydro- (II). 1 H-pyrido [2,1b] quinazolin-11-one or their acid addition salts - in which R, R ¹ ,

R ² cs R ^{3 is} as given above in the Fischcrole indole synthesis [Chem. Port. 63: 373 (1963); 69, 230 (1969): Tetrahedron 36, 161 (1980)].

In a preferred embodiment of the process, the pyridoquinazoline derivatives of formula (H) are heated in the presence of a mineral acid or a Lewis acid.

The mineral acid is preferably polyphosphoric acid, the Lewis acid is preferably metal halide, preferably zinc chloride. The reaction is carried out at a temperature dependent on the catalyst used.

In a particularly preferred embodiment of the process, the pyridoquinazoline H or its acid addition salt thereof is heated at a temperature between 160 ° C and 220 ° C, preferably five to twenty parts by weight of polyphosphoric acid per compound of formula II. The reaction is preferably carried out for 5 minutes to 120 minutes.

The resulting indolo [2 ', 3': 3,4] pyrido [2,1b] quinazolin-5-ones of general formula (I) are prepared by diluting the reaction mixture with water in a conventional manner and then crystallizing the product. removal (e.g., filtration, centrifugation).

The present invention relates to the optically active isomers of the compounds of formula (I) The optical isomerism of the compounds of formula (I) may occur when R is a (1-4C) alkyl group.

The starting pyridoquinazolines of formula (II) are generally 6,7,8,9-tetrahydro-11,11-pyrido (2,1-b] quinazolin-11-one of formula (IV) in general formula (V). The diazo coupling is carried out in a manner known in the art, preferably in an aqueous acetic acid medium: 6,7,8,9-tetrahydro-1H-pyrido [2,1-a] -b] quinazo) in-lones are compounds known in the literature and may be prepared, for example, from the 2-piperidone derivative and the corresponding anthranilic acid derivative [J. Chem. Soc. 99, 2306 (1977)].

Outstanding representatives of the compounds of formula (I) may be used as medicaments because of their favorable biological activity. Some derivatives can be developed into drugs by virtue of their beneficial cardiovascular, for example, diuretic effects.

An example of the diuretic activity of the compounds of formula I is shown in Table 1. The experiment was carried out for 16 hours on oral fasting (1% methylcellulose suspension) rats of both sexes in CFY. Each group consisted of 3 to 3 homogeneous animals.

Compound A: methylcellosolve

Compound B: 6-Chloro-3,4-dilutro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide (Hypothiazide)

Compound C: 10-Methyl-7,8-dihydro-5H, 13H-indol-2 ', 3': 3,4] pyrido [2,1-b] quinazolin-5-one (Example 1)

The compositions may be formulated for oral or parenteral administration in the form of, for example, tablets, dragees, capsules, powders, aerosol sprays, aqueous suspensions or solutions, or injectable solutions or syrups. The compositions may contain suitable solid diluents or carriers, sterile aqueous diluents or non-toxic organic solvents. The oral

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I. devotees table

Material sign Rat sex Dose Collectors of urine / ml (10000) 0-5 h 5-24 h 0-24 h THE female 1.24 3.81 5.05 THE male 5 mg 1.73 4.35 6.08 n female 2.70 7.96 10.66 SHE male 5 mg 2.81 5.61 8.42 p female 3.51 10.05 13.56 male 5 mg 3.75 10.42 14.17

sweetening or flavoring agents may be added to the compositions for administration.

Tablets for oral administration may contain, for example, lactose, sodium citrate, calcium carbonate, and disintegrating agents (for example starch, alginic acid) as lubricants (for example, talc, sodium lauryl sulfate, magnesium stearate). The carrier for the capsules may be lactose and polyethylene glycol. Aqueous suspensions may contain emulsifying or suspending agents. The organic solvent suspension diluent may be ethanol, glycerol, chloroform.

Formulations for parenteral administration and inhalation are solutions or suspensions of the active ingredient in a suitable vehicle (e. G., Peanut oil, sesame oil, polypropylene glycol or water). Injectable compositions may be administered intramuscularly, intravenously or subcutaneously. Injectable solutions are preferably formulated in an aqueous medium and the pH is adjusted to 35. The solutions may be prepared in isotonic saline or glucose solution if necessary.

The daily dose of active ingredient may vary within wide limits and will depend upon the severity, age, weight, form of the condition and activity of the particular patient. For oral administration, the daily dose is generally 0.05 to 15 mg / kg, while for intravenous administration, it is usually 0.001 to 5 mg / kg in single or multiple daily doses. The above information is for guidance purposes only and may vary both upwards and downwards depending on the requirements of the individual case and the physician's prescriptions.

The following examples further illustrate the process without limiting the invention to the examples.

EXAMPLES

EXAMPLE 1 6 g of 6 - [(4-Methyl-phenyl) -hydrazono] -6,7,8,9-tetrahydro-1H-pyrido [2,1-b] quinazolin-11-one in 10 g of polyphosphoric acid heated to 180 ° C is added in small portions over 5 minutes. After the addition, the reaction mixture was stirred at 180 ° C for another 30 minutes. After cooling, it is diluted with 40 ml of water and, with cooling, adjusted to pH 5 with 25% (w / v) ammonium hydroxide solution. The precipitated crystals are filtered off and washed with water. After drying, the product is dissolved in dimethylformamide and the carbon is clarified at 100 ° C. The dimethylformamide solution was diluted with water to give yellow-white crystals, which were filtered and washed with water. After drying, 0.6 g (63%) of 10-methyl) -7,8-dihydro-5H-13H-indolo [2 ', 3': 3,4] pyrido [2,1b] quinazoline m.p. -5-ont we get.

Analysis for C H _{I9] S} O N ₃ O:

Found: C, 75.72%; H, 5.01%; N, 13.94%; Found: C, 75.43; H, 4.99%; N, 14.05%.

Example 2 g 6 - [(4-Chloro-phenyl) -hydrazono] -6,7,8,9-tetrahydro-11H-pyrido [2,1-quinazolin-11-one] 10 g was heated to 180 ° C. added to polyphosphoric acid and stirred for 20 minutes at this temperature. After cooling, it is diluted with 40 ml of water and the precipitate is filtered off and washed with water. After drying, it is recrystallized from a solvent mixture of dimethylformainide-ethyl acetate. 0.77 g (81%) of 10-chloro-7,8-dihydro-5H, 13H-indolo [2 ', 3': 3,4] pyrido [2,1b] quinazolin-5-one is obtained. 312 ° C.

Analysis using the formula C ₁₈ H ₁₂ N ₃ OCl:

Found: C, 67.19; H, 3.76%, N, 13.05%, Cl, 11.01%; Found: C, 67.11; H, 3.74; N, 13.13; Cl, 10.97.

Example 3 • g of 6 - [(4-fluorophenyl) hydrazono] -5,6,7,8-tetralidro1111pyrido [2,1b] quinazolin-11-one, as described in Example 2. and worked up, 0.75 g (79%) of 10-fluor7,8-dihydro-5H, 13H-indolo [2 ^', 3': 3,4] pyrido [2, lb] quinazolin-5-one, exhibiting a 290 ° They are C's.

Calcd _C₁₁-j2 N ₃ OF formula:

Found: C, 70.81%; H, 3.96%; N, 13.76%; Tahit: C, 70.70%; H, 3.94%; N, 13.91%.

Example 4 6 - [(4-Bromophenyl) hydrazono] -5,6,7,8-tetrahydro-1H-pyrido [2,1b] quinazolin-11-one was converted and processed as in Example 2. 0.85 g of product is obtained, which is dissolved in 10 ml of dimethylformamide, decolorized with carbon and applied to a 15 g column of silica gel, 0.1-0.2 mm, eluting with ethyl acetate.

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0.64 g (67%) of yellowish-white crystals of yellow bromo-7,8-dihydro-5H, 13H-indolo [2 ', 3': 3,4] pyrido [2,1-b] quinazolin-5-one are obtained. 284 ° C.

Analysis using the formula C ₁₈ H ₁₂ N ₃ OBr:

Found: C, 59.03%; H, 3.30%; N, 11.47%; Found: C, 59.09; H, 3.22%; N, 11.28%.

Example 5 g 6 - [(4-Cyanophenyl) hydrazono] -6,7,8,9-tetrahydropyrido [2,1-b] quinazoline! 1-one is heated in 10 g of polyphosphoric acid at 180 ° C for 30 minutes. After cooling, the reaction mixture was diluted with water (40 mL) and adjusted to pH 5 with 25% aqueous ammonium hydroxide. The precipitated product is filtered off, washed with water and dried. 0.88 g (92%) of 10-thio-7,8-dibidro-5H, 13H-indolo [2 *, 3 ': 3,4] pyrido [2,1-b] quinazolin-5-one is obtained, m.p. recrystallized from dimethylformamyl melting at 255 ° C.

Analysis for C ₁₉ N ₄ O II _{I 2} O:

Found: C, 73.06%; H, 3.87%; N, 17.93%; Found: C, 72.95; H, 3.86%, N, 17.90%.

EXAMPLE 6 6- (2-Naphthylhydrazono) -6,7,8,9-tetrahydropyrido [2,1-b] quinazolin-11-one g converted to Example 5 by 0.85 g (89%) 7, 8-Dihydro-5H, 13H-benzo (1) indolo [2 ', 3': 3.4] pyrido [2,1b] quinazolin-5-one is obtained, m.p. 298 ° C.

Analysis for C ₂₂ H | According to the formula ₅ N ₃ O:

Found: C, 78.32%; H, 4.48%; N, 12.45%; Found: C, 78.51; H, 4.60%; N, 12.21%.

Example 7 6 - [(4-Phenyloxyphenyl) -imidazono] -6,7,8,9-tetrahydropyrido [2,1-b] quinazolin-11-one was added to 15 g of polyphosphoric acid heated to 180 ° C and keep at this temperature for minutes. After cooling, the reaction mixture was diluted with water (50 mL) and the pH adjusted to 5 with 25% aqueous ammonium hydroxide solution while cooling. The precipitated product is filtered off and washed with water. After drying, 15 g of a 0.1 cm diameter Kieselgel column with a diameter of 0.1 to 0.2 mm was loaded with 5 ml of dimethylformamide and eluted with ethyl acetate. 0.4e (41%) 10-phenyl.xi7.8-dihydro-5-oxo-5H, 13H-indolo [2,3 ': 3,4] pyrido [2,1-b] quinazolin-5-one M.p. 276-278 ° C.

Analysis for the C H ₂₄ N ₃ O ₂ Formula _I7:

Calculated: C, 75.97; H4,51%; N, 11.07%; Found: C, 76.09; H, 4.55%; N, 11.02%.

Example 8 6 - [(4-Methylphenyl) hydrazono] -6,7,8,9-tetrahydropyrido [2,1-b] quinazolin-11-one 5 g of anhydrous zinc chloride. and stirred at 200 ° C for 30 minutes. After cooling, the reaction mixture was diluted with water (50 mL) and the greenish-brown precipitate that precipitated was filtered and washed with water. The filtered product was dissolved in 40 ml of chloroform, clarified with activated carbon and the chloroform was evaporated. The residual solid was crystallized from ethyl acetate. 0.58 g (62%) of 10-methyl-7,8-dihydro-5H, 13H-indolo [2 ', 3': 3,4] pyrido [2,1b] quinazolin-5-one is obtained, m.p. melt, and when mixed with the product of Example 1, gives no melting point reduction.

Example 9 6-Phenylhydrazono-9-methyl-o, 7,8,9-tetrahydro-pyrido [2,1-b] quinazolin-11-one was added to 10 g of polyphosphoric acid preheated to 180 ° C and stirred at this temperature for 30 minutes. After cooling, it is diluted with 50 ml of water and made basic with 25% aqueous ammonium hydroxide solution to pH = 5. The precipitate was filtered off and washed with water. It is then dissolved in 40 ml of chloroform and extracted with 2 x 10 ml of 5% w / v sodium hydroxide solution and water and the chloroform phase is extracted. After drying over anhydrous sodium sulfate, the chloroform solution is clarified with activated carbon and evaporated. The residual solid was crystallized from isopropanol. 0.45 g (48%) of 7-methyl-7, 5-dihydro-5H, 13H-in <RTIgt; Jo-{2 ', 3': </RTI> 3,4-pyrido [2,1-b] quinazolin-5-one is obtained. -8 ° C.

Calcd CigH _l5 N ₃ O O:

calculated. C 75.72%; H, 5.01%; N, 13.94%; Found: C, 75.86%; H, 5.12%; N, 13.78%.

Example 10 6-Phenylidene-Thazono-9-methyl-6,7,8,9-tetiahydro-1 H -pyrido [2,1b] quinazolin-11-one hydrochloride was added to 10 g of polyphosphoric acid preheated to 180 ° C and stirred for 30 minutes. After cooling, the reaction mixture was diluted with water (50 mL) and the precipitate was filtered off, basified to pH 5 with 25% aqueous ammonium hydroxide solution, suspended in 50 mL of water, filtered and washed with water. The product obtained after drying was crystallized from a mixture of diethylformamide / ethyl acetate and 0.63 g (67%) of 7-methyl-7,8-dihydro-5H, 13H-indolo [2 ', 3': 3,4] pyrido [2,1b] quinazoline. M.p. 227-228 ° C, and when mixed with the product of Example 9, gives no melting point reduction.

Example 11 6 - [(4-Methoxyphenyl) hydrazono] -6,7,8,9-tetrahydro-1H-pyrido [2,1-b] quinazolin-11-one was added to 15 g of 160 ° C polyphosphoric acid in five minutes, with stirring. After 20 minutes the reaction mixture was 160 ^u C htítjük room temperature and diluted with 50 mL water and the pH was adjusted to between 6-7 to 25 percent ammonium hydroxide mixed. The precipitated crystals are filtered off and washed with water. 0.62 g (65%) of 10-methoxy-6,7-dihydro-5H, 13H-indolo [2 ', 3': 3,4-dihydro [2,1-b] quinazolin-5-one is obtained which is crystallized from ethyl acetate 252- 253 ° C.

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Analysis based on the formula C ^ HuNjO ^:

Calculated: C, 71.91; H, 4.76%; N, 13.24%; Found: C, 71.32%; H, 4.66%; N, 13.30%.

Example 12

750 mg of 10-methyl-7,8-dihydro-5H, 13H-indolo [2 ', 3': 3,4] pyrido [2,1-b] quinazolin-5-one is homogenized with 1050 g of crystalline cellulose] with 140 g of amylopectin. The mixture was then granulated with 150 g of Eudragit lacquer solution, after drying and regranulation at 40 ° C, homogenized with a powder mixture of 20 g of talc and 20 g of magnesium stearate and tabletted at 200 mg in a manner known per se.

Claims (7)

1. A method of indolo [2 ', ^3,: 3,4] of the formula (I) pyrido [2, lb] quinazolin-5-ones for preparing - wherein R is hydrogen or (1-4C) alkyl, R * is hydrogen, R ² is hydrogen or optionally R ¹ and R ² together form - (CH = CH) ₂ - which is bonded to two adjacent carbon atoms of the benzene ring, R ³ is hydrogen, halogen, C 1 -C 4 alkyl, cyano, phenyloxy or C 1 -C 4 alkoxy, characterized in that a 6-hydrazono-6,7,8,9-tetrahydro-1 The 1H-pyrido [2,1-b] quinazcinol-1-one derivative or acid addition salt thereof, wherein R, R ', R ² and R ³ are as defined above, is heated in the presence of an acid. 2. The process of claim 1, wherein the acid is an inorganic acid or a Lewis acid. 3. A process according to claim 2 wherein the inorganic acid is polyphosphoric acid. 4. A process according to claim 2 wherein the Lewis acid metal alkali metal halides are preferably zinc chloride. 5. A process according to claim 1 wherein the acid addition salt of the compound of formula (I) wherein R, R ¹ , R ² and R ³ are as defined in claim 1 is hydrochloride. 6. A process according to any one of claims 1 to 3, wherein the compound of formula (III) or an acid addition salt thereof, wherein R, R ¹ , R ² and R ³ are as defined in claim 1, at a temperature of 160 to 220 ° C. heated. 7. Procedure for favorable circulatory pharmacology. for the preparation of a pharmaceutical composition having a dmretic effect, characterized in that the pharmaceutically acceptable inert compounds of the formula (I) prepared according to claim 1, wherein R, R 1, R ² and R ³ are one or more representative compounds of the mixed with carriers to form a pharmaceutical composition.