NO157142B - 6-phenyl-hydrazono-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazolin-11-ones. - Google Patents

Description

The present invention relates to new 6-phenyl-hydrazone-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones and salts thereof, geometric and optical isomers and tautomers thereof.

The new compounds are used as starting material for the production of therapeutically active indolo[2<1>,3<1>;3,4]pyrido-[2,1]quinazolin-5-ones as stated in Norwegian patent application no. 812142.

Pyrido[2,1-b]quinazolin-11-ones are known in part as alkaloids [Chem. Comm. 267 (1965)} Austral J. Chem 151

(1966); Chem. Pray. 68, 2221 (1935); J. Chem. Soc. 4694

(1956); Chem. Pray. 95, 2182 (1962)] and partly as compounds exhibiting favorable pharmacological properties (DE-PS 2 812 585, BE-PS 849 542 and BE-PS 847 Oll).

The invention relates to new 6-phenyl-hydrazone-6,7,8,9-tetra-hydro-11H-pyrido[2,1-b]quinazolin-11-ones, acid addition salts and optical and geometric isomers and tautomers thereof of general formula I

wherein R denotes hydrogen or C^_^-alkyl, is hydrogen, halogen, C, ,-alkyl, cyano or phenyloxy,

R 2 and R 3 are hydrogen or halogen, and the dashed lines denote possibly possible double bonds.

The known pyrido[2,1-b]quinazolin-11-ones are described

in Moshy: "Heterocyclic Systems with bridgehead nitrogen atoms, Vol. 2, 1153-1159, Interscience Publishers, Inc., New York, 1961.

The new pyridot2,l-b]quinazolin-ll-ones of formula II and acid addition salts, geometric and optical isomers thereof, can be prepared by

a) a pyridote 2,1-b]quinazolin-11-one derivative of general formula

in which R and the dotted line are as defined above and R is hydrogen or formyl, is reacted with a diazonium salt of the general formula in which R 4 is as previously defined and the dotted line is as defined above, or b) that a pyridote2,l-b]quinazoline -II-one derivative of general formula in which R and the dashed line are as defined above and R^ denotes an alkyl group with 1-4 carbon atoms, is reacted with a diazonium salt of general formula III in which R 4 is as defined above, or c) that a pyridot2,l-b]quinazolin-ll-one derivative of general formula in which R and the dashed line are as defined above and Ro denotes hydrogen or halogen, and R 9 is halogen, is reacted with a hydrazine derivative of general formula

wherein R 4 is as indicated above.

Process variant a), i.e. the reaction of the compound of general formula II with the diazonium salt of general formula III is carried out as described by [Parmerter: Org. Reactions. 10, pp. 1-142 (1959); Philips: Org. Reactions 10, pp. 143-178 (1959)].

According to a preferred embodiment of the method, the reaction is carried out below 50° C, preferably at -10 to 20° C. The components can be added by adding a given compound of formula II to the solution of the diazonium salt of general formula III or vice versa. The components can preferably be used in equimolar amounts, but one of the components can optionally be used in a small excess. The reaction can preferably be carried out in an aqueous medium, if desired in the presence of a water-miscible inert organic solvent.

Alkane carboxylic acids, preferably acetic acid, propionic acid, acid amides, preferably N,N-dimethylformamide, alcohols, preferably methanol, ethanol, propanol, isopropanol, ketones such as acetone, methyl ethyl ketone, preferably pyridine can be used as inert organic solvents. The reaction can preferably be carried out in the presence of an acid-binding agent. Alkali alkanoates, preferably sodium acetate, potassium acetate or alkali hydroxides, preferably sodium hydroxide, potassium hydroxide or alkali carbonates, preferably sodium carbonate, potassium carbonate, sodium bicarbonate etc. can be used as acid binding agents.

According to method variant b), a compound of general formula IV is reacted with a diazonium salt of general formula III. A preferred embodiment is described for method variant a).

According to process variant c), a compound of general formula V is reacted with a hydrazine of general formula VI. As a compound of general formula V, such compounds are preferably used which contain chlorine or

8 9

bromine as halogen instead of R and R . Compounds of general formula V and VI are preferably reacted in the presence of an inert solvent. As inert solvents can be used alkanols, preferably methanol, ethanol, propanol, isopropanol etc., alkane-carboxylic acids, preferably acetic acid, propionic acid, acid amides such as N,N-dimethylformamide, aromatic bases, preferably pyridine. The specified solvents can optionally be mixed with water and the reaction can be carried out in a mixture of water and a water-miscible organic solvent. If desired, an acid-binding agent can be used. Those described for method variant a) can be used as acid-binding agents. An excess of hydrazine of general formula VI can also serve as an acid scavenger. According to a preferred embodiment of the method, 1-8 mol, preferably 2.5-4.8 mol of hydrazine of general formula VI are used for 1 mol of the compound of general formula V. The reaction can be carried out at a temperature from 0 to 160°C , preferably at the boiling point of the solvent or solvent mixture used. The reaction time can vary from 30 minutes to 10 hours depending on the reactants. Compounds of general formula I obtained by process variant a), b) or c) are precipitated from the reaction mixture or precipitated by aqueous dilution thereof, and can be isolated by filtration, centrifugation or other conventional methods.

The compounds of general formula I form salts with organic or inorganic acids, thus salts such as hydrochloride, hydrobromide, sulphate, phosphate, perchlorate, maleate, acetate etc. can be prepared.

The compounds can exist as optical and geometric isomers and tautomers thereof. Optical isomerism occurs when R in formula I is different from hydrogen. The structure of the geometric isomers is illustrated in the following general formula IA

The structure of possible tautomers is shown by reaction nucleus A:

4

wherein R is as previously indicated.

A compound of general formula I can be released

from their salts formed with an acid or base by methods known per se.

An obtained compound of general formula I can be converted into an acid addition salt by reacting this with an organic or inorganic acid. The salt formation can be carried out according to known methods and comprises reacting a compound of formula I with a corresponding molar acid. equivalent amounts or in excess, in the presence of an inert organic solvent.

Most of the starting materials are known. Starting materials of general formulas II, IV and V are described in Koksi Tokkya Koho 78 130 435 and BE-PS 849 542 and 847 011 and DE-PS 2 812 585 and 2 812 586, Mosby: Heterocyclic Systems with bridgehead nitrogen atoms, Vol. 2. pp. 1153-1159, Interscience Publishers, Inc. New York, 1951, Him. Heterocycl. Soot. 1976, 1564-1569, 1979, 684-691 or can be prepared according to methods described in the above-mentioned references.

Compounds of general formula I are intermediates for Rutecarpine alcoholoids and Rutecarpine analogues.

The following examples illustrate the invention.

Example 1-22

0.1 mol of aniline derivative was mixed with 5 ml

28 v/w% hydrochloric acid solution in 1:1 dilution, and the mixture was cooled to -5° C. A solution of 0.69 g (0.01 mol) sodium nitrite in 5 ml water was slowly added dropwise with continuous stirring and cooling. The reaction mixture was then stirred for 30 minutes at a temperature varying from -5 to 0° C, after which the pH of the reaction mixture was adjusted to 4 by adding sodium acetate. The mixture was diluted with 5 ml of glacial acetic acid and a solution of 2.0 g (0.01 mol) 11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-a]-quinazoline in 10 ml of 50 vol % acetic acid was added dropwise. The reaction mixture was stirred for 3 hours at -5 - 0° C. The mixture was then allowed to stand overnight in a refrigerator.

The precipitated crystals were filtered and washed with water. The 6-phenylhydrazone-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolines obtained were purified if necessary by recrystallization from n-propanol. The prepared compounds are listed in Table 1.

Example 23 - 24

One proceeded as described in example 1-22, but used as starting material 11-oxo-1,2,3,4,6,7,8,9-octa-hydro-11H-pyrido[2,1-b]quinazoline in instead of 11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline.

The prepared compounds are listed in Table 2.

Example 13

10.8 g (0.03 mol) 6,6-dibromo-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline and 13.0 g (0.12 mol) of phenylhydrazine was heated in 120 ml of ethanol for 4 hours.

The precipitated crystals were filtered after cooling. Upon evaporation of the mother liquor, additional crystals were precipitated, which were filtered and washed with some alcohol. The combined filtered product was suspended in 150 ml of water containing 8.4 g (0.06 mol) of sodium acetate, after which it was filtered and washed with water. 8.4 g (81%) of 6-phenylhydrazone-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline was obtained, which after recrystallization from isopropanol melts at 17 7 - 17 9° C, and which gives no melting point reduction when mixed with the product according to example 1. Example 14

3.74 g (0.01 mol) 6,6-dibromo-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-a]quinazline and 4.32 g (0.04 mol) of phenylhydrazine was heated in 40 ml of ethanol for 10 hours. The precipitated crystals were filtered after cooling. The filtered product was suspended in 100 ml of water containing 2.72 g (0.02 mol) of sodium acetate, filtered and washed with water. 2.4 g (75%) of orange 6-phenylhydrazone-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline were obtained, which after recrystallization from ethanol melts at 185 - 187° C.

Analysis for the formula C-^gH^gN^O:

Example 15

2.79 g (0.01 mol) of 6-bromo-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline and 2.16 g (0.02 mol) of phenylhydrazine was heated in 30 ml of ethanol for 6 hours at 80° C. The ethanol was then concentrated to one third of the volume. The mixture was then allowed to crystallize in a refrigerator. The precipitated yellow crystals were filtered and washed with ethanol and water. 2.1 g (69%) of 6-phenyl-hydrazono-11-oxo-6,7,8,9-tetrahydro-pyrido[2,1-b]quinazoline were obtained, which after recrystallization from isopropanol melts

at 179 - 180° C and which, when mixed with the product according to example 1 or example 13, does not give any melting point reduction.

Analysis for the formula C^8H16N40:

Example 16

0.93 g (0.9 mL, 0.01 mol) of aniline was dissolved in

5 ml of 38 v/w % hydrochloric acid in 1:1 dilution and the solution was cooled to -5° C. A solution of 0.65 g (0.01 mol) sodium nitrite in 5 ml of water was added dropwise with continuous cooling and stirring. The reaction mixture was stirred for 30 minutes at a temperature of -5 - 0° C, after which the pH of the solution was adjusted to 4 by adding sodium acetate and was diluted with 10 ml of acetic acid. To the solution of the diazonium salt was added dropwise a solution of 2.55 g of 9-(dimethylamino-methylene)-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline in 25 ml of dimethylformamide slowly at -5° C. The reaction mixture was stirred at 0° C for 3 hours, after which it was allowed to stand overnight in a refrigerator. The mixture was then diluted with water and the precipitated crystals were filtered and washed with water. 2.61 g (86%) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-HH-pyrido[2,1-b]quinazoline was obtained, which after recrystallization from isopropanol melts at 182 - 184 ° C, and the product did not produce a melting point depression when mixed with the product of Example 1.

Analysis for the formula C^gH^N^O:

Example 17

0.93 g (0.01 mol) of aniline was dissolved in 5 ml of 38 v/w % hydrochloric acid in a 1:1 dilution and was cooled to -5° C. A solution of 0.6 9 g (0, 01 mol) of sodium nitrite in 5 ml of water was added dropwise with continuous stirring and cooling. The reaction mixture was stirred for 1/2 hour at -5 to 0°C, after which the pH of the solution was adjusted to 4 by addition of sodium acetate, and the solution was diluted

with 10 ml of acetic acid. To the reaction mixture was added dropwise a solution of 2.28 g (0.01 mol) 6-formyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline in 30 ml acetic acid. The mixture was stirred for 1 hour at a temperature below 0° C, and the solution was then allowed to stand in a refrigerator.

The precipitated crystals were filtered and washed with water.

3.1 g (91%) of 6-phenyl-hydrazono-6,7,8,9-tetrahydro-11-oxo-11H-pyrido[2,1-b]quinazoline hydrochloride was obtained, m.p. 255°C.

Analysis on the basis of C,gH-,7N4OCl

Example 18-28

The procedure was as described in examples 11 to 12 and 11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazolines were used as starting materials, which resulted in 6-phenyl-hydrazono-4-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido-[2,1-b]quinazolines as listed in Table 4.

In Examples 26 and 27, crystals were precipitated from the diazo-coupling reaction mixture and suspended in a 5 v/w% sodium hydroxide solution, and the aqueous solution was shaken out with chloroform1. The chloroform solution was dried over anhydrous sodium sulfate and was evaporated and the residue recrystallized.

Example 2 9

0.46 g (0.005 mol) of aniline was dissolved in 3 ml of hydrochloric acid (36 v/w%) at a dilution of 1:1, and the solution was cooled to -5° C. A solution of 0.35 g (0.005 mol )

sodium nitrite in 3 ml of water was added dropwise. The reaction mixture was stirred for 1/2 hour at -5 to 0° C., after which the pH of the solution was adjusted to 4 by adding sodium acetate. A solution of 1.23 g (0.005 mol) of 6-formyl-11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1 -b]quinazoline in 15 ml of 75 vol% acetic acid, and the solution was stirred for 3 hours at a temperature below 0° C, after which the mixture was allowed to stand overnight in a refrigerator and was diluted with 30 ml of water. The precipitated crystals were filtered and washed with

water. 1.3 g (73%) of 6-phenyl-hydrazono-11-oxo-1,2,3,4,6,7,8,9-octahydro-11-pyrido[2,1-b]quinazoline hydrochloride was obtained, with sm.p. 242 - 244° C.

Analysis for the formula C^gH23N4OCl

Claims (1)

6-phenyl-hydrazone-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones, acid addition salts and optical and geometric isomers and tautomers thereof, characterized in that they have general formula I in which R denotes hydrogen or C^_4~alkyl, R"*" is hydrogen, halogen, C,.-alkyl, cyano or phenyloxy, 2 3 R and R are hydrogen or halogen, and the dashed lines denote possibly possible double bonds.