NO781051L - CHINAZOLINE DERIVATIVES. - Google Patents

Abstract

Chinazoline derivatives.

Description

The present invention relates to new pyrido (2,1-b)-quinazoline derivatives with the general formula

where R^, R_ and R^ independently represent hydrogen, lower alkanoyl or lower alkyl and represent cyano, 5-tetrazolyl, halogen or a residue of the form 1ene-C-A, where A represents hydroxy, lower alkoxy, di-(C^-C7) -alkylamino-(C2~C7) alkoxy, pivaloyloxymethoxy or -NR^Rg, where R,, and Rg independently represent hydrogen, lower alkyl or di-(C^-Cy) alkylamino-(C2-.C7) alkyl, with the proviso that R^ is different from halogen when R^ , R 2 or R 3 is lower alkanoyl,

pharmaceutically acceptable acid addition salts thereof, and when A represents hydroxy, also pharmaceutically acceptable salts thereof with a base.

As used herein, the term "lower alkyl" denotes a straight or branched saturated hydrocarbon chain containing 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl and the like. The term "lower alkoxy" denotes an alkoxy group where the lower alkyl group is as described above, for example methoxy, ethoxy, propoxy, pentoxy and the like. The term "halogen" denotes the four forms bromine, chlorine, fluorine and iodine. The term "lower alkanoyl" denotes an alkanoyl group derived from an aliphatic carboxylic acid with 1 to 7 carbon atoms, for example formyl, acetyl, propionyl and the like. Examples of "di-(C^-C^)alkylamino-{C^-C^)alkoxy" groups are dimethylaminoethoxy, diethylaminoethoxy, dipropylaminoethoxy, diisopropylaminoethoxy, dibutylaminoethoxy, dipentylaminoethoxy and the like. Examples of "di-(C^-C^)alkylamino-(C2~C7)alkyl" groups are dimethylaminoethyl, diethylaminoethyl, ethylmethylaminoethyl, dipropylaminoethyl, etc.

Special compounds covered by the present invention are those of formula I above where , R2, R-. uavnenc?i represents hydrogen, lower alkyl, and R^ has the opposite meaning.

Further particular compounds of formula I above are those

where at least two of R^ , R 2 and R^ are different, from hydrogen and represent lower alkyl and R^ has the meaning indicated above.

In a further particular aspect, the invention comprises the compound

of formula I above, where R^ represents a residue of the formula -8-A , where A represents di-(C-^-C7) alkyl lamino-(C2~C7) alkoxy or pivaloyloxymethoxy and R^, R2 and R^ are independent represents hydrogen or lower alkyl.

Another group of special compounds of formula I above are those in which at least one of R 1 , R 2 and R 2 represents lower alkanoyl.

Preferred compounds of formula I above are those where

R 2 and R 4 represent hydrogen. In a preferred aspect, the invention comprises compounds of formula I above where R represents hydrogen or lower alkyl, preferably lower alkyl. R^ preferably represents a residue of the formula -C-A.

The preferred meanings for A are 'hydroxy and di-C 1 -C 4 ) alkylamino-(C 2 -C 7 ) alkoxy, where hydroxy is particularly preferred.

It follows from the above that the compounds of formula I are particularly preferred, where R2 and R^ represent hydrogen., R^represent-

er lower alkyl; and R^ represents

Videie preferred classes of compounds of formula I are those where R 2 and R 1 represent hydrogen, R 2 represents hydrogen, lower alkyl or lower alkanoyl and R 2 represents a residue of the formula -§-A/where A represents di-tC^-C ^) alkylamino-(C 1 -C 4 ) alkoxy.

Examples of preferred compounds of formula I are

the following:

8-methyl-11-oxo-11H-pyrido-(2,1-b)quinazoline-2-carboxylic acid;

8-isopropyl-ir-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid;

8-isopropyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2 carboxylic acid-(2-diethylaminoethyl) ester..

Examples of compounds of formula I are as follows: 8-n-propyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid;

8-n-Butyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid;

8-t-Butyl-11-oxo-11H-pyrido(2,1-b)quihazoline-2-carboxylic acid;

6-methyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid;

6-ethyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid;

6-n-propyl-ir-oxo-11H-pyrido(2,1-b)quinazoline-2 carboxylic acid;

6-n-butyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid;

6-t-butyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2

carboxylic acid;

and such.

According to the present invention, the compounds with pre-

mel I above and their pharmaceutically acceptable acid addition salts, and when A represents hydroxy also their pharmaceutically acceptable salts with a base, are prepared by a process characterized by

a) compounds of formula I above where ■represents halogen and R^,^ and R^ have the meaning indicated above are prepared by

treatment of a compound with the general formula

where R represents hydrogen or lower alkyl and X re-: presents halogen, with a halopyridiride derivative of the general formula where R^, R 2 , R 3 and X have the above meaning or b) compounds of the formula I above where R^ represents cyano and R ^, R2 and R^ have the meaning indicated above, i.e.

compounds with the general formula

where R-^, R 2 and R^ have the meaning indicated above, is prepared by treating a compound with the general formula

where X' represents bromine or iodine and R^, R2 and R^ have

the above meaning,

with copper (I) cyanide, or

c) compounds with Q formula. In above where R4.represents a

remainder of the formula

where A represents hydroxy, i.e. compounds with the general formula

where R 1 , R 1 , and R 2 have the meaning indicated above, is prepared by treating a compound of formula Ib above with nickel carbonyl under a carbon monoxide atmosphere in the presence of an alkaline earth hydroxide, or hydrolysis of a compound of formula Ia above , or

d) compounds of formula I above, where R 1 represents a

remainder with formula

where A represents lower alkoxy and R 1 , R 2 and has the meaning stated above, is produced by esterification of a compound of formula Ic above, or e) compounds of formula I above, where R represents a residue with the formula where A represents a residue of the formula -NR, -Rg and R^, R2, R^, R^ and Rg have the meanings given above, are produced by aminolysis of a compound of formula Ic above with an amino compound of the general formula

where R^ and Rg have the meaning indicated above, or

f) compounds of formula I above, where R. represents

a remainder with the formula

where A represents di-(C^-C-,)

alkylamino-(C 2 -C 7 ) alkoxy, and R-^, R 2 and R^ have the meanings given above, are prepared by treating a compound

with formula Ic above, with a di-(C^-C^)alkylamino-(C^-Cy)alkyl halide, or an acid chloride of a compound of formula Ic above is subjected to alcoholysis with a di-(C-^-C- ,) alkylamino-(C2_Cy)alkanol, or g) compounds with formula I above, where R. represents 5-tetrazolyl and R.sub.2, R.sub.2 and R.sub.2 have the meanings given above, are prepared by treating a compound with formula Ia above with a alkali metal azide, or h) compound of formula I above where R represents a residue of the formula -C-A/where A represents pivaloyloxymethoxy and

R1'R2oc', R3', having the meanings given above, are prepared by treating a compound of formula Ic above with a tertiary organic base and chloro7bromo- or iodomethyl-pivalate and

i) if desired, an obtained compound is transferred in a pharmaceutically acceptable salt.

According to method variant a), an anthranilic acid or ester of formula II, a known compound or a compound that can be prepared according to known methods is reacted with a halopyridine of formula III, also a known compound or a compound that can be prepared according to known methods, by temperature in the area approx. 100°C to 200°C with or without a solvent. The reaction is carried out in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, C2sium iodide, potassium iodide or the like. Solvents that can be used in the reaction are high-boiling solvents such as acetic acid, diglyme, triglyme or the like. The reaction is preferably carried out at atmospheric pressure. The reaction product can be worked up according to known methods such as crystallization or the like.

According to method variant b), the bromine or iodine residue of a compound of formula Ib can be transferred to a nitrile residue by treating the compound of formula Ib with copper (I) cyanide in an inert solvent such as l-methyl-2- pyrrolidinone or the like, at or near the reflux temperature of the reaction mixture. The reaction mixture is then treated with a solution of water, hydrochloric acid and ferric chloride. The desired nitrile with formula Ia is prepared according to known methods, such as crystallization or the like.

According to method variant c) a compound of formula can

Ib is converted to a compound of formula Ic by treating the compound of formula Ib with nickel carbonyl in the presence of an alkaline earth hydroxide such as calcium hydroxide, under pressure and in an atmosphere of carbon monoxide at a temperature of from 100 to 150°C. The reaction can preferably be carried out in a high-boiling polar solvent such as dimethylformamide or the like. A compound of formula Ic can be worked up according to known methods such as crystallization or the like.

Alternatively, a nitrile of formula Ia can be transferred to an acid of formula Ic by hydrolysis with a mineral acid, such as sulfuric acid, hydrochloric acid or the like in the presence of a solvent such as acetic acid, proteinic acid or the like.

According to process variant d), an acid of formula Ic can be converted into the corresponding ester by known methods. E.g. an alkali metal salt of an acid as described above, such as the sodium salt, can be reacted with a substituted or unsubstituted alkyl halide by using known reaction conditions, e.g.

in an inert solvent such as dimethylformamide or the like, at a temperature in the range from room temperature to the reflux temperature of the reaction mixture.

According to method variant e), an acid of formula Ic can be transferred to a corresponding amide by known methods. E.g. treated en-acid as described above with thionyl chloride, which gives the corresponding acid chloride. The latter is then treated with the corresponding amine, e.g. is treated with ammonia, dimethylamine, 3-diethylaminopropylamine or the like, in the presence of a solvent such as tetrahydrofuran. The desired amide is worked up according to known methods such as crystallization.

According to method variant f), an acid of formula Ic can be transferred to the corresponding di-(C-C-Cy)-alkyl lamino-{C^-C^) alkyl ester by known methods. E.g. an acid is treated as described above with the corresponding di-(C-^-Cy)-alkylamino-(C2-C-,)-alkyl halide under reflux conditions with a solvent, e.g. an alkanol such as isopropanol or the like, and the product is worked up according to known methods such as crystallization, or this product is treated with thionyl chloride, whereby the corresponding acid chloride is obtained, and the latter is reacted with a di-(C-^- C-j)-alkylamino-(C2 ~C7)alkanol in an inert solvent such as tetrahydrofuran or the like, at a temperature from about 0°C to 100°C, and then the desired product is worked up by known methods, such as crystallization or the like.

According to method variant g), a compound of formula I where R 1 is 5-tetrazolyl can be prepared from the corresponding compound of formula Ia. More specifically, the corresponding compound of formula Ia is treated with an alkali metal azide, such as potassium azide, sodium azide or the like, in the presence of ammonium chloride. The reaction is preferably carried out in the presence of a solvent such as a polar aprotic solvent, e.g. dimethylsulfoxide, dimethylformamide or the like. The desired tetrazolyl compound is then worked up by known methods, e.g. crystallization e . 1..-

According to process variant h) a compound of formula I where A is pivaloyloxymethoxy can be prepared by treating the corresponding compound of formula Ic with a tertiary organic base such as a tri-lower alkylamine and chloro-, bromo- or iodomethyl pivalate in an inert solvent such as dimethylformamide or similar, with a temperature from room temperature to approx. 120°C. The desired end product can be worked up according to known methods such as crystallization.

Connection^with formula. I, where A is hydroxy forms pharmaceutically acceptable salts with bases. Examples of such bases are alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc., alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide, etc., sodium alkoxides such as sodium ethanolate, potassium ethanolate, etc., organic bases such as piperidine, diethylamine, N-methylglucamine, etc.

Compounds of formula I also form pharmaceutically acceptable salts with acids. Examples of such acids are both pharmaceutically acceptable organic and inorganic acids such as methanesulfonic acid/p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

Compounds of formula I and their pharmaceutical counterparts

salts inhibit cutaneous aphylaxis in rats, and are therefore useful for preventing allergic reactions, e.g. can they be used in the prophylactic treatment of bronchial asthma. The anti-anaphylactic activity can be shown by the passive cutaneous anaphylaxis measurement (PCA test) in rats. This experiment involves passive local sensitization of rats by intra-dermal injection of anti-sera. After a latent period of 24 hours, the test compound, in this case a pyrido-(2,1-b)quinazoline is given intraperitoneally followed 5 minutes later by an intravenous injection of reagent and Evans blue dye. The consequences of the localized antigen-antibody reaction lead to the formation of skin blisters,

whose magnitudes are measured. The ability of the test compound to reduce the size of the blisters compared to controls is taken as a measure of activity.

When a compound according to the invention, such as 8-isopropyl-11-oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid is used as a test compound in a dose of 16 mg/kg intraperitoneally, the reduction of blister size is 81% .

The compound of formula I and their pharmaceutically acceptable salts can be administered orally or parenterally as anti-allergic agents, e.g. in the prophylactic treatment of bronchial asthma, with dosages regulated according to individual needs. It can be administered therapeutically, e.g. orally or parenterally by taking a therapeutic dose in a conventional dosage form, such as tablets, capsules, elixirs, suspensions, solutions or the like. It can be given in admixture with conventional pharmaceutical carriers or excipients, such as e.g. corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose etc. Furthermore, they can be given in the presence of buffers or agents to achieve isotonicity, and the pharmaceutical dosage forms can, if desired, be subjected to conventional pharmaceutical treatments such as e.g. sterilization. As stated above, the dosage can be adjusted according to individual needs. They may also contain other therapeutically valuable substances.

The amount of active drug present in any

of the dosage forms described above are variable. The

containing from about 10 to 20 mg of the compound of formula I as a base or an equivalent amount of a medically acceptable salt thereof.

The frequency with which such dosage forms will be given to a patient will vary depending on the amount of active drug present in it and the patient's needs. Under urinary conditions, however, up to about 20mg/kg of the compound can be given daily in several dosages.

However, it must be clear that the indicated dosages are only

examples and that they do not in any way limit the scope or practice of the present invention.

The following examples further illustrate the invention. All temperatures are given in degrees Centigrade.

EXAMPLE 1

Preparation of 2-bromo-11-oxo-11H-pyrido[2,1-b]quinazoline hydrochloride

A thorough mixture of 100.0 g of 2-chloropyridine, 83.0 g of 5-bromoanthranilic acid and 1.0 g of potassium iodide was heated to a bath temperature of 145-150° overnight under an argon stream. After cooling, the crude product was triturated with 150 ml of boiling ethanol to give 105.4 g (86%) of 2-bromo-11-oxo-11H-pyrido[2,1-b]quinazoline hydrochloride,

m.p. 280-282° (decomposition). The analytical sample was obtained from aqueous hydrochloric acid-dimethylformamide-ethanol and melted at 278-281°.

EXAMPLE 2

Preparation of 11-oxo-IIH-pyrido[2,1-b]quinazoline-2-carboxylic acid

A suspension of 15.00 g of 2-bromo-11-oxo-11H-pyrido[2,1-b]quinazoline hydrochloride and 3.60 g of calcium hydroxide in 105 ml of 5% aqueous dimethylformamide was placed in a 1.6 liter Fischer-Porter flask and the air was replaced with carbon monoxide. Approximately 10 ml of nickel carbonyl was introduced through a syringe needle and the carbon monoxide pressure was raised to 1.4 kg/cm 2 . 2. When the bath temperature was raised to 110-115°, the pressure rose to -2.8 kg/cm 2 , and the yellow suspension became a green solution. After a total of 25 hours, the mixture was allowed to cool, diluted with 300 ml of 1N brine and filtered. The filter cake was torn with hot ethanol-dimethylformamide and the filtrate precipitated 3.23 g of crude 11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, m.p. 310°. The filter cake was dissolved in 200 ml of dimethylformamide containing 10 ml of ammonia, the solution was filtered, and the filtrate was diluted with water and acetic acid to precipitate a further 3.37 g of 11-oxo-11H-pyrido[2,1-b] quinazoline-2-carboxylic acid, m.p. >310°. The two yields were combined and triturated with ethanol-dimethylformamide-acetic acid to give 6.35 g (48%) of 11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, m.p. 354°.

EXAMPLE 3

Preparation of 8-methyl-11-oxo-IIH-pyrido[2,1-b]quinazoline-2-carboxylic acid

A thorough mixture of 5.0 g of 5-bromoanthranilic acid, 6.7 g of 2-chloro-5-methylpyridine and 67 mg of potassium iodide was heated to a bath temperature of 145° for 8 hours. After cooling, the mixture was diluted with 15 ml of ethanol and filtered to give 3.57 g (48%) of 2-bromo-8-methyl-11-oxo-11H-pyrido[2,1-b]quinazoline, m.p. 277-281°.

A mixture of 3.00 g of the aforementioned pyridoquinazoline and 0.73 g of calcium hydroxide in 21 ml of 5% aqueous dimethylformamide was placed in a 0.8 liter Fischer-Porter flask under a carbon monoxide atmosphere. Approximately 3 ml of nickel carbonyl was added, and the flask was pressurized to 1.4 kg/cm<2> of•carbon monoxide. The bath temperature was raised to 115° for 24 hours and after cooling the mixture was diluted with 15 ml of 6N hydrochloric acid. After stirring overnight, the suspension was filtered and the collected solid was recrystallized from dimethylformamide and from dimethylformamide ether to give 1.54 g (67%) of 8-methyl-11-oxo-11H-pyrido-[ 2,1-b]quinazoline-2-carboxylic acid, m.p. 359°.

EXAMPLE ' 4

Preparation of 2-chloro-5-(1-hydroxy-1-methylethyl)pyridine

75 ml of phosphorus oxychloride and 144 g of phosphorus pentachloride were added

to 100 g of 6-chloronicotinic acid and carefully mixed. The reaction mixture was slowly heated in an oil bath to 80° over 25 minutes with stirring. The bath temperature was raised to 125° and the solution was stirred and refluxed for 1 hour. After concentration under reduced pressure, anhydrous toluene was added and the solution was concentrated again, finally, using an oil pump, to give 6-chloro-nicotinoyl chloride as a colorless solid.

This acid chloride was dissolved in 600 ml of anhydrous ether and added dropwise over 2 hours to a solution of methyl magnesium iodide prepared from 137 ml of methyl iodide and 50 g of magnesium in 700 ml of anhydrous ether. The reaction mixture was stirred and refluxed for 3 hours. After the cold reaction mixture was carefully poured onto ice and 200 mL of acetic acid, the aqueous layer was basified (pH 9) with 425 mL of 6N sodium hydroxide. The ether was separated and the aqueous layer was saturated with sodium chloride and extracted four times with ether. After drying the combined extract over anhydrous magnesium sulfate, the extract was concentrated in vacuo to a yellow solid (112 g). Crystallization from ethyl acetate-hexane gave 44.5 g, m.p. 70-74°, 2-chloro-5-(1-hydroxy-1-methylethyl)pyridine in the first yield. A second yield of 2-chloro-5-(1-hydroxy-1-methylethyl)pyridine (46.7 g, mp 67-71°) was obtained from ether-hexane.

EXAMPLE 5

Preparation of 2-chloro-5-isopropenylpyridine

A solution of 92.6 g of 2-chloro-5-(1-hydroxy-1-methylethyl)pyridine, 4.6 g of p-toluenesulfonic acid monohydrate and 0.9 g of hydroquinone in 1.5 liters of anhydrous xylene was stirred and refluxed under a Dean-Stark water separator for 4 1/2 hours. The xylene solution was washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The xylene was removed by distillation [40-48°/14 mm) through a Claisen top. Distillation of the remaining oil through a Vigreux column gave 75.6 g of pure 2-chloro-5-isopropenylpyridine, 110-114°/8 mm.

EXAMPLE 6

Preparation of 2-chloro-5-isopropylpyridine

A solution of 86.9 g of 2-chloro-5-isopropenylpyridine and 8.7 g of platinum oxide in 1 liter of ethanol was shaken at atmospheric pressure in a hydrogen atmosphere for 1 hour and 45 minutes. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give an oil. Distillation through a Vigreux column gave 76.0 g of pure 2-chloro-5-isopropylpyridine, 105-109°/8 mm.

EXAMPLE 7

Preparation of 2-bromo-3-isopropyl-ll-oxo-llH-pyrido[2,1-b]-quinazoline

A mixture of 58.5 g of 5-bromoanthranilic acid, 42.2 g of 2-chloro-5-isopropylpyridine and 1.7 g of powdered potassium iodide was stirred and heated at 170° under argon for 40 minutes. The bath temperature was lowered to 165°C for 4 1/2 hours and then to 155° for 7 hours. The solid purple cake was triturated with 250 ml of chloroform, stirred in an ice bath and filtered to give the product (34.9 g) as the hydrochloride. This was suspended in 500 ml saturated sodium bicarbonate solution and extracted with methylene chloride. The combined extract was dried over anhydrous magnesium sulfate, stirred briefly with charcoal, filtered and concentrated in vacuo to a yellow solid. Crystallization from methylene chloride-ether gave 21.8 g of pure 2-bromo-8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline, m.p. 191-194°,

in two dividends.

EXAMPLE 8

Preparation of 8-isopropyl-ll-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid

A mixture of 21.75 g of 2-bromo-8-isopropyl-11-.oxo-11H-pyrido-[2,1-b]quinazoline and 5.08 g of calcium hydroxide in 200 ml of dimethylformamide and 20 ml of water was placed in a Fischer-Porter flask under a carbon monoxide atmosphere. Approximately 20 ml of nickel carbonyl was

2

added and the flask was pressurized to 1.4 kg/cm with carbon monoxide. The reaction mixture was stirred and heated in an oil bath at 120° for 1 hour and after cooling it was diluted with 1.2 liters of water and 30 ml of 6N hydrochloric acid. After stirring overnight, the suspension was filtered and the resulting solid was taken up in dimethylformamide and filtered. The filtrate was concentrated in vacuo using the oil pump to a yellow solid. Water was added together with 5 ml of acetic acid and the product was removed by filtration to give 18.35 g of crude product. Crystallization from methanol gave 15.15 g of pure 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, m.p. 312-316°.

EXAMPLE 9

Preparation of 2-cyano-8-isopropyl-ll-oxo-llH-pyrido[2,1-b]-quinazoline

A solution of 0.412 g of 2-bromo-8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline and 0.233 g of cuprocyanide in 5 ml of 1-methyl-2-pyrrolidinone was stirred and heated at 180° in 10 hours. A solution of 0.52

g of ferric chloride hexahydrate, 0.13 ml of concentrated hydrochloric acid in 0.8 ml of water was added and the mixture was heated at 90° for 30 minutes. 25 ml of water was added after cooling and the reaction mixture

the material was extracted with chloroform. The extract was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated saline, dried over anhydrous magnesium sulfate and concentrated to a yellow solid which also contained some 1-methyl-2-pyrrolidinone. Ether was added and the product separated by filtration to give 0.240 g, m.p. 207-211°, 2-cyano-8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline. Preparative tic gave the pure compound, m.p. 212-214°.

EXAMPLE 10

Preparation of 8-isopropyl-ll-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid

A solution of 0.084 g of 2-cyano-8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline in 1 ml of acetic acid, 1 ml of concentrated sulfuric acid and 1 ml of water was stirred and refluxed for 45 minutes. The solution was concentrated using the oil pump to a small volume. After cooling in an ice bath, 50 ml of saturated sodium bicarbonate was carefully added. The mixture was then acidified with acetic acid and the resulting solid was filtered and washed with water to give 0.063 g, m.p. 313-314°, pure 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid.

EXAMPLE 11

Preparation of 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride

0.86 g of 2-diethylaminoethyl chloride was dissolved in 5 ml of water and 5 ml of saturated sodium bicarbonate solution was added and stirred in an ice bath for 5 minutes. This solution was extracted with ether, the extract dried over anhydrous magnesium sulfate and concentrated in vacuo to give the base as a colorless oil (0.41 g). This was added to 0.423 g of 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid in 10 ml of anhydrous isopropanol and the reaction mixture was stirred and refluxed for 3 hours. After cooling to room temperature, the product was removed by filtration and purified by crystallization from isopropanol and then from methylene chloride ether to give 0.25 g of pure 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline- 2-carboxylic acid (2-diethylaminoethyl) ester hydrochloride, m.p. 238-239°.

EXAMPLE 12

Capsule composition

Approach:

Mix the active ingredient with formula I, lactose and corn starch in a suitable mixing device. Grind through a suitable mill. Mix with magnesium stearate and talc and fill in capsule machine.

EXAMPLE 13

Tablet composition

Approach:

Mix the active ingredient with formula I, lactose, microcrystalline cellulose, modified starch and corn starch in a suitable mixing device for 1 to 15 minutes. Then add magnesium stearate and mix for 5 minutes. Compressed on a suitable pressing machine.

Claims (1)

EXAMPLE 14 Wet granulated tablet composition Approach: Mix the active ingredient with formula I, lactose and pregelatinized starch in a suitable mixing device. Grind through a suitable mill. Mix with modified starch and magnesium stearate and fill in capsule machine. 1. Procedure for the preparation of new pyrido[2,1-b]- quinazoline derivatives of the general formula where R^ , R 2 and R^ independently represent hydrogen, lower alkanoyl or lower alkyl, and R^ represents cyano, 5-tetrazolyl, halogen or a residue of the formula -^-A, where A represents hydroxyl, lower alkoxy, di-(C ^ -C^ )-alkylamino-(C2 -C7 alkoxy, pivaloyloxymethoxy or -NR^ Rg, where R^ and Rg independently represent hydrogen, lower alkyl or di-(C-j^-Cy) alkylamino-(C2~C7) alkyl, with with the proviso that R4 is different from halogen when R]_, R2 or R3 represents lower alkanoyl, pharmaceutically acceptable acid addition salts thereof, and when A represents hydroxy, also pharmaceutically acceptable salts thereof with a base, characterized in that a) compounds of formula I as above, where R₂ represents halogen and R₂, R₂ and R₂ have the meanings indicated above, are prepared by treating a compound with the general formula where R represents hydrogen or lower alkyl, and X represents halogen, with a halopyridine derivative of the general formula where R-^ , R2 , R3 and X have the meanings indicated above, or b) compounds of the formula I as above, where R^ represents cyano and R-^ , R 2 and R 3 have the meanings given above, i.e. compounds of the general formula 1 where R 1 , R 2 and R 3 have the meanings given above, are prepared by treating a compound with the general formula where X<1> represents bromine or iodine. and R] _, R 2 and R 3 have the meanings given above, with copper(I) cyanide, or c) compounds of formula I as above, where R., renresen- Q teres a residue of the formula -c"-A, where A represents hydroxy, i.e. compounds of the general formula where R-^ , R 2 and R 3 have the meaning given above, is prepared by treating a compound of formula IL as above with nickel carbonyl under a carbon monoxide atmosphere in the presence of an alkaline earth hydroxide or hydrolysis of a compound of formula Ia above, or d) compounds of formula I as above, where R, represent- teres a remainder with the formula , where A represents lower alkoxy, and R-^, R 2 and R 3 have the meanings given above, forward is set by the esterification of a compound of formula Ic as above, or e) compounds of formula I as above, where R, represent- teres a remainder with the formula , where A represents a residue of the formula -NR^Rg/ and R^ , R2 , R3 and Rg have the meaning indicated above, is prepared by subjecting a compound of formula Ic above to ammonolysis with an amino compound of the general formula where R5 and Rg have the above-mentioned meaning, or f) compounds of formula I above, where R, represents. 0 a residue of the formula -C-A, where A represents di-(C-^-C-,) alkyl-. amino-(C2-C7 ) alkoxy and R^ , R2 and R^ have the meaning indicated above, is prepared by treating a compound of the formula Ic above with a di-(C-^-C-,) alkylamino-(C2-C7 ) alkyl halide, or an acid chloride of a compound of formula Ic above subjected to alcoholysis with a di-(C 1 -C y )alkylamino-(C 2 -C 7 )alkanol, or g) compounds with the formula I as above, where R 1 represents 5-tetrazolyl and R 2 , R 2 and R 3 have the meanings given above/ are prepared by treating a compound with the formula Ia as above with an alkali metal azide, or h) compounds of the formula I as above, where R4 represents ff teres a residue of the formula -C-A, where A" represents pivaloyl- oxymethoxy and R] _, R 2 and R 3 have the meaning given above, is prepared by treating a compound of formula Ic as above with a tertiary organic base and chloro, bromo or iodomethyl pivalate, and i) if desired, an obtained compound is transferred in a pharmaceutical tolerable sa 2. Method according to claim 1, characterized in that R2 and R3 independently represent hydrogen or lower alkyl. 3. Method according to claim 2, characterized in that at least two of R-^ , R2 and R3. is different from hydrogen. 4. Method according to claim 2 or 3, characterized in that R represents a residue with the formula where A. represents di-(C 1 -C y )alkylamino-(C 2 -C 7 )alkoxy or pivaloyloxymethoxy. 5. Process according to claim 1, characterized in that at least one of R 1 , R 2 and R 1 represents lower alkanoyl. 6. Method according to any one of claims 1, 2, 4 and 5, characterized in that R, and R, represent hydrogen. 7. Method according to each of claims 1, 2, 4 or 6, characterized in that Ri represents hydrogen or lower alkyl. 8. Method according to claim 7, characterized in that Ry represents lower alkyl. 9. Method according to any one of claims 1-3 and 5-8, characterized in that R„ represents a residue with the formula 10. Method according to claim 9, characterized in that A represents hydroxy or di-(C-C-C-C) alkylamino-(C 2 -Cy) alkoxy. 11. Method as stated in claim 2, character 1-s e r t in that R2 and R^ represent hydrogen, R-^ represents lower alkyl and R^ represents a residue with the formula 12. Method according to claim 1,' characterized in that Rj and R^ represent hydrogen, R-^ represents hydrogen, lower alkyl or lower alkanoyl, and RA represents a remainder with the formula where A represents di-(C-, -C7) alkylamino(C2 - <C>7 ) <a> lkoxy. 13. Method according to claim 2, characterized in that 8-methyl-11-oxo-11H-pyrido[2,1-b]-quinazoline-2-carboxylic acid is produced. 14. Method according to claim 2, characterized in that 8-isopropyl-11-oxo-11H-pyrido[2,1-b]-quinazoline-2-carboxylic acids are produced 15. Process according to claim 12, characterized in that 8-isopropyl-11-oxo-11H-pyrido[2,1-b]-quinazoline-2-carboxylic acid (2-diethylaminoethyl) ester is produced. 16. Process for the production of preparations with anti-allergic properties, characterized in that a pyrido[2,1-b]quinazoline derivative of formula I as stated in claim 1 or a pharmaceutically acceptable salt thereof is mixed as active substance with non-toxic, inert , therapeutically tolerable solid or liquid carriers which are normally used in such preparations and/or excipients. 17. Compositions with anti-allergic properties, characterized in that they contain a pyrido[2,1-b]quinazoline derivative of formula I as stated in claim 1 or a pharmaceutically acceptable salt thereof and a carrier. 18. New pyrido[2,1-b]quinazoline derivatives of the general formula characterized by that R 1 , R 2 and R 3 independently represent hydrogen, lower alkanoyl or lower alkyl, and R 4 represents cyano-, 5-tetrazolyl, halogen or a residue 0 with the formula -C-A, where A represents hydroxy, lower alkoxy, di-(C^ -Cy)-alkylamino-(C^ -C^ ) alkoxy, pivaloyloxymethoxy or -NR^ Rg, where R5 and Rg independently represent hydrogen, lower alkyl or di -(Ci~C7 )alkylamino-(C2 -C7 )alkyl, with the proviso that R4 is different from halogen when R^ , R2 or R^ .re presents lower alkanoyl, pharmaceutically acceptable acid addition salts thereof, and when A represents hydroxy, also pharmaceutically acceptable salts thereof with a base. 19. Compounds according to claim 13, characterized in that R^ R 2 and R^ independently represent hydrogen or lower alkyl. 20. Compounds according to claim 19, characterized in that at least two of R-^ , R 2 and R^ are different from. hydrogen. 21. Compounds according to claim 19 or 20, characterized in that R represents a residue with the formula 9 -C-A, where A represents di-(C 1 -C y ) alkylamino-(C 2 -C 7 ) alkoxy or pivaloyloxymethoxy. 22. Compounds according to claim 18, characterized in that at least one of R 1 , R 2 and R 3 represents lower alkanoyl. 23. Compounds according to any one of claims 18, 19, 21 and 22, characterized in that R 2 and R 1 represent hydrogen. 24. Compounds according to any one of claims 18, 19, 21 and 2 3, characterized in that R 1 represents hydrogen or lower alkyl. 25. Compounds according to claim 24, characterized in that Ry represents lower alkyl. 26. Compounds according to any one of claims 18 - 20 and 22 - 25, characterized in that R. represents a residue with the formula 27. Compounds according to claim 26, characterized in that A represents hydroxy or di(C-^-Cy) alkylamino-(C 2 -C 6 ) alkoxy. 28. Compounds according to claim 19, characterized in that R, and R^ represent hydrogen, Rj_ represents lower alkyl and R4 represents a residue with the formula 29. Compounds according to claim 18, characterized in that Rj and R^ represent hydrogen, R-^ represents hydrogen, lower alkyl or lower alkanoyl, and R^ represents a remainder with formula where A represents di-(C-1-C7) alkylamino-(C2-Cy) alkoxy. 30. 8-Methyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid. 31, 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid. 3 2. 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid-(2-diethylaminoethyl)ester.