NO781053L - CHINAZOLINE DERIVATIVES. - Google Patents

Description

The present invention relates to new pyrido[2;1-b]quinazoline derivatives with the general formula

where R^, and independently represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl or hydroxy, and R^ represents cyano, 5-tetrazolyl, hydroxy-lower alkyl, acyloxy-lower alkyl or a residue with the formula

where A represents lower alkyl, hydroxy,

lower alkoxy, di-(C-^-C^) alkylamino-(C2-C^) alkoxy, pivaloyloxymethoxy or a residue of the formula -N^5, where R,-o-Rg independently represents hydrogen lower alkyl or<6>di-( C-^-C^) alkylamino-(C2_C^) alkyl, Y represents hydrogen or methyl and n represents the integer 0

or 1, with the proviso that at least one of R-^, R 2 and R^

is different from hydrogen,

pharmaceutically acceptable acid addition salts thereof, and when A represents hydroxy, also a pharmaceutically acceptable salt thereof

off with a base.

As used herein, the term "lower alkyl" denotes - alone

or in combination - a straight or branched saturated hydrocarbon chain containing 1 to 7 carbon atoms, e.g. 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, e.g. methoxy, ethoxy, propdoxy, pentoxy and the like. The term "halogen" denotes the four forms bromine, chlorine, fluorine and iodine. The term "acyl" denotes an "alikanoyl" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, e.g. formyl, acetyl, propionyl and the like, and an "aroyl" group derived from an aromatic carboxylic acid, such as benzoyl and the like. The term "acyloxy" denotes an "alkanoyloxy" group derived from an aliphatic carboxylic acid of 1 to 7 carbon atoms, e.g. formyloxy, acetoxy, propionyloxy and the like and an "aroyloxy" group derived from an aromatic carboxylic acid such as benzoyloxy and the like. Examples of "di-(C-^-C^) alkylamino-(C2-C^) alkyloxy" groups are dimethylaminoethoxy, diethylaminoethoxy, dipropylaminoethoxy, diisopropylaminoethoxy, dibutylaminoethoxy, dipentylaminoethoxy, and the like. Examples of "di-(C-C-C-C) alkylamino-(C2-C-C)alkyl" groups are dimethylaminoethyl, diethylaminoethyl, ethylmethylaminoethyl, dipropylaminoethyl and the like. Examples of "acyloxy-lower alkyl" groups are formyloxymethyl, acetyloxymethyl, propionyloxymethyl, benzoyloxymethyl and the like.

Special compounds covered by the present invention

are such with the general formula

where R-j^' , R?' and R^<1>independently represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or hydroxy and R^ has the meaning indicated above. Further special compounds are those of the formula .1' above, where at least one of R-^' , R 2' and R 3 < 1> represents lower alkylthio. In a particular aspect, the invention also comprises compounds of formula I<1,> in front, where R^ represents acyloxy-lower alkyl or a residue of the formula

where Y and A have the above meaning. Furthermore, special compounds are also those with the formula I', where R,, represents a residue with the formula

where A represents lower alkyl, di-(C-^-C^) al-

alkylamino-(C-C-C-y) alkoxy or pivaloyloxymethoxy.

Another group of special compounds covered by the present invention are those with formula I above, where at least one of R1'R2°9R3 represents cyclopropyl or cyclobutyl.

Preferred compounds of formula I above are those wherein R 2 and

Ro represents hydrogen and R, represents a residue with form-

len

where A represents di-(C-^-C^)alkylamino-(C2-C^)alco-

sy and R-^ have the meanings given above.

In a further preferred aspect, the invention comprises compounds of formula I, where at least one of R 1 , R 2 and R 2 represents lower alkyl, lower alkoxy or lower alkylthio and R 2 represents a substituent in the 8-position. In a further preferred aspect, the invention comprises compounds of formula I, where R 2 represents hydrogen, R-^ and/or R^ is different from hydrogen and R^ represents a substituent in the 8-position. Even more strongly preferred compounds of formula I, where R 2 represents hydrogen, R 1 and/or R 2 , independently, represent lower alkyl, lower alkoxy or lower alkylthio, and R 2 represents hydroxy

lower alkyl, 5-tetrazolyl or

where A represents hydroxy or di-(C-3-C4) alkylamino-(C2-C7) alkoxy. Most preferred are compounds of formula I, where one of , R? and R 1 represents lower alkyl, lower alkoxy or lower alkylthio, and R 1 represents

Examples of . preferred compounds of formula I are the following: 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazolin-8-carboxylic acid;

2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, and

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

Examples of the compounds of formula I are the following: 4-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

4-isopropoxy-11-oxo-11H-pyrido t 2,1-b]quinazoline-8-carboxylic acid; 4-methyl-thio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

2,4-diisopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

2,4-diisopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

2,4-dimethylthio-11-oxo-11K-pyrido[2,1-b]quinazoline-8-carboxylic acid;

11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid;

2-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid;

3-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid;

3-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid\ 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-7-acetic acid;

2-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-7-acetic acid y 2-methoxy-11-oxo-11H-pyrido t 2,1-b]quinazoline-8-a-methylacetic

acid;

2-chloro-11-oxo-11H-pyrido 12,1-b]quinazoline-8-a-methylacetic acid;

3-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-a-methylacetic acid;

3-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-8-a-methylacetic acid;

2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-7-a-methylacetic acid; 2-chloro-11-oxo-11H-pyrido[2,1-b]quinazoline-7-a-methylacetic acid; 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl ester);

2-isopropylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylamino-ethyl) ester;

2-isopropyl-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1-b]-quinozoline;

2-cyclobutyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid;

4

2-methylthio-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1-b]quinazoline;

2-isopropylthio-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido-[2,1-b]quinazoline;

8-hydroxymethyl-2-isopropyl-11H-pyrido[2,1-b]quinazolin-11-one; 8-Hydroxy-methyl-2-isopropoxy-11H-pyrido[2,1-b]quinazolin-11-one; 8-hydroxymethyl-2-methylthio-11H-pyrido 12,1-b]quinazolin-11-one; 8-hydroxymethyl-2-isopropylthio-11H-pyrido[2,1-b]quinazoline-11-

on and the like, also including compounds mentioned below.

According to the present invention, the compounds with the preceding formula I and their pharmaceutically acceptable acid addition salts are prepared, and when A represents hydroxy, also their pharmaceutically acceptable salts with a base, by

a) compounds of formula I above, where R, represents cyano, acyloxy-lower alkyl or a residue of the formula

where A represents lower alkyl, hydroxy, lower-

alkoxy or a residue of the formula -NR^Rg and , R2, R3, R5/

Rg, Y and n have the meaning indicated above, except: when treating the compound with the general formula

where R represents hydrogen or lower alkyl, and R^, R 2 and R^ have the meanings given above, with a halopyridine derivative of the general formula' where -R„ ' represents cyano, acyloxy-lower alkyl or a residue of the formula

where A repre-

centers lower alkyl, hydroxy, lower alkoxy or a residue of the formula -NR^Rg, Y represents hydro-

gen or methyl and n represents the integer 0 or 1, R^ and Rg independently represent hydrogen, lower-alkyl' or di-(C-^-C^) alkylamino (C2-C^) alkyl, and X represents halogen,

or

b) compounds of formula I as above, where R₂ represents 5-tetrazolyl and R₂, R₂ and R₂ have the meanings indicated above, are prepared by treating a compound of the general formula

where R-^, R2 and R3 have the meanings given above/

with an alkali metal azide, or

c) compounds of formula I as above, where R₂ represents hydroxy-lower alkyl and R₂, R₂ and R₂ have the above indicated

meaning, is produced by hydrolysis of a compound with the general formula

where R 7 represents acyloxy-lower alkyl, and R 1 , R 2 and R 1 have the meanings given above,

or

d) compounds of formula I as above, where R^represent- , solve a remainder with the formula -

where A represents di-

(C 1 -C 7 )alkyl amino-(C 2 -C 4 ) alkoxy and R 1 , R 2 , R 3 , and ^ have the meanings given above, are prepared by treating a compound with the general formula

where R-^, R2;R3, Y and n have the meaning indicated above. with a di-(C-^-C^) alkylamino-(C2-C7) alkyl halide/ or an acid chloride of a compound of formula Ic above is subjected to alcoholysis with a di-(C-^-C^) alkylamino-(C2- C-,) alkanol, or e) compounds of formula I as above, where R* represents a residue of the formula where A represents pivaloyloxymethoxy and R-^ , R2;R37Y and n have the meaning indicated above, are prepared by treating a compound of formula.Ic as above with a tertiary organic base and chloro, bromo or iodomethylpivalate, or f) compounds of formula I as above, where.R, represents a residue of the formula where A represents lower-alkoxy and R-^, R2 1 1 Y and n have the meanings given above, are produced by esterification of a compound with. formula Ic as above, or g) compounds of formula I as above, where R. represents a residue of the formula where A represents a residue of the formula -NR^R^ and R^, R0, R3, R^, Rg, Y and n has the meaning indicated above, is prepared by subjecting a compound of formula Ic as above to ammonolysis with an amino compound of the general formula; 1 where R^ and Rg have the meanings given above, or, h) compounds of formula Ib as above are prepared by treating a compound of formula II as above with a halopyridine derivative of the general formula; where R 7 and X have the meanings indicated above, ; and ;i) if desired, a compound obtained is transferred in a pharmaceutically acceptable salt. According to method variant a) an anthranilic acid or ;-ester of formula II, a known compound, one or a compound that can be prepared according to known methods, is reacted with a halopyridine of formula III, which is also a known compound or can be prepared according to known methods, at a temperature in the range from 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, potassium iodide, cesium 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. A compound of formula I, where R 1 is 5-tetrazolyl, can be prepared according to process variant b) from the corresponding precursor 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 conveniently 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 according to known methods, e.g. crystallization or the like.

According to method variant c) the compound is hydrolysed with

formula Ib in a manner known per se, e.g. by treatment with one mineral acid such as concentrated hydrochloric acid, in the presence of a solvent, e.g. an alkanol, such as ethanol, and the desired end product is then worked up according to known methods, e.g.

by recrystallization from methanolic hydrogen chloride.

According to process variant d), a compound of formula I, where A is di-(ci~c-j)alkylamino-{C^-C-j) alkoxy, can be prepared from the corresponding compound of formula Ic by treating this compound, f .ex. with a di-(C-^-Cy)alkylamino-(C2-Q3)alkyl halide under reflux conditions in a solvent, e.g.

e.g. an alkanol such as isopropanol or the like, and work up the product according to known methods, such as crystallization or the like, or treat this compound with thionyl chloride, whereby the corresponding acid chloride is obtained, and the latter compound is reacted with a di-(C-^-C ^)alkylamino-(C 2 -C 4 )-alkanol in an inert solvent, such as tetrahydrofuran.

or similar, at a temperature in the range from approx. 0°C to 100°C, and then the desired end product is worked up by known methods, such as crystallization or the like.

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

tion.

According to method variant .f), an acid of formula Ic can be transferred to the corresponding ester according to 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

tuated alkyl halide using known reaction conditions, e.g. in an inert solvent such as dimethylformamide, or similar at a temperature in the range from approx. room temperature

turn to the reflux temperature of the reaction mixture.

According to process variant g), an acid of formula Ic can be converted to the corresponding amide by known methods. E.g. an acid is treated as described above with thionyl chloride, whereby the corresponding acid chloride is obtained. The latter is 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 then worked up according to known methods, such as crystallization.

According to method variant h) the ethhalogenpyridine derivative of formula V is condensed with an anthranilic acid or -ester with for-

mel II, at a temperature in the range from approx. 100°C to approx. 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, potassium iodide, cesium 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 by known methods such as crystallization or the like.

The compounds of formula I, where A is hydroxy, form pharmaceutically acceptable salts with bases. Examples of such bases are alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide and the like; alkaline earth hydroxides, such as calcium hydroxide, barium hydroxide and the like; sodium alkoxides such as sodium ethanolate, potassium ethanolate and the like; organic bases such as piperidine, diethylamine, N-methylglucamine and the like.

The compounds of formula I also form pharmaceutical tolerance

give salts with acids. Examples of such acids are both organic and inorganic acids, such as methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

The compounds of formula V above are known or can be prepared by known methods. Thus, e.g. a hydroxy-lower alkyl-substituted 2-halopyridine with an acyl halide such as benzoyl chloride, using known reaction conditions which gives the corresponding acyloxy-lower alkyl-substituted halopyridine, which is converted to the corresponding N-oxide of formula V with a peroxidizing agent such as m- chloroperbenzoic acid in the presence of an inert solvent, e.g. a halogenated hydrocarbon such as methylene chloride. The resulting reaction mixture is hypertralized with an alkali metal hydroxide such as sodium hydroxide, and then the resulting N-oxide is worked up.

The compounds of formula I as well as their pharmaceutically acceptable salts inhibit cutaneous anaphylaxis in rats and are therefore useful in 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 anaphylactic. the test (PCA test) in rats. This sample includes

ter 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 after 5 minutes by an intravenous injection of reagent and Evans blue dye. The results of localized antigen-antibody reaction lead to the formation of skin blisters whose size is measured. The test compound's ability to reduce the size of these blisters compared to controls is taken as a measure of activity.

When a compound according to the invention, such as 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, is used as the test compound in a dose of 16 mg/kg intraperitoneally, the reduction of blister size is 63 %. When the sodium salt of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is used as the test compound in a dose of 16 mg/kg intraperitoneally, the reduction in blister size is 86%.

The anti-allergic activity of the compounds of formula I

can also appear in actively sensitized guinea pigs (IgC). In this experiment, the guinea pig is sensitized intraperitoneally with horse-

serum on day 1 and then the animal is given intravenously on days 11-

14 antigen (horse serum) which immediately initiates the immediate hypersensitive reaction (IHR bronchospasm).. When

an anti-allergic compound is given intravenously.before the antigen, IHR is blocked and thereby bronchospasm is prevented.

When 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxyl-

acid is used in the previous experiment with an oral dose of 200 mg per kg is the percentage inhibition of bronchospasm 65%. When the preceding compound is given intravenously at a dose of 20 mg/kg, the percent inhibition of bronchospasm is 54%.

The anti-allergic effect can also be shown in passively sensitized rats (IgE). In this experiment, a rat receives anti-sera intravenously 18 hours before the intravenous antigen (egg albumin) injection. The antigen injection induces IHR. When an anti-allergic compound is administered intravenously before the antigen injection, it inhibits IHR and prevents bronchospasm.

When 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxyl- . acid is used in the previous experiment at an oral dosage of 10 mg/kg, the percent inhibition of bronchospasm is 59%. When the preceding compound is given intravenously at a dose of 10 mg/kg

percent inhibition of bronchospasm is 83%.

The compounds 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 dosage adjustments according to individual needs. They can be given therapeutically, e.g. orally or parenterally, by incorporating a therapeutic dose in a conventional dosage form, such as tablets, capsules, elixirs, suspensions, solutions or the like. They 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 and the like. Moreover, they may be administered in the presence of buffers or agents used to adjust to isotonic conditions, and the pharmaceutical dosage forms may, if desired,

are subjected to conventional pharmaceutical treatments, such as

e.g. sterilization. As indicated above, the dosage can be adjusted according to individual needs. They may also contain other therapeutic

tically valuable substances.

The amount of active drug present in each of the above-mentioned dosage forms is variable. However, it is preferred to produce capsules or tablets containing from approx. 10

to 20 mg of a base of formula I or an equivalent amount of a medically acceptable salt thereof.

The frequency with which such a dosage form is to be given to a patient will vary, depending on the amount of active drug present in it and the patient's needs. Under normal conditions, however, up to approx. 20 mg/kg of the compound is given daily in several doses. However, it must be clear that the indicated dosage

are only examples and that they in no way limit the scope or practice of the present invention.

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

EXAMPLE 1

Preparation of 6-chloro-3-(N-diethylaminoethylcarbamoyl)pyridine hydrochloride

A solution of 5.0 g of 6-chloronicotinic acid and 8.56 ml of diphenylphosphoryl azide in 25 ml of dimethylformamide was cooled in an ice bath and 4.27 ml of N,N-diethylethylenediamine was added dropwise. After the addition was complete, the reaction mixture was allowed to stand overnight

room temperature and then poured into 500 ml of water. The aqueous solution was extracted with 3 x 500 ml of dichloromethane and the combined organic layers were washed with water, dried over potassium carbonate and evaporated to an oil which was dissolved in 15 ml of ethanol and carefully acidified with hydrochloric acid in tetrahydrofuran. After cooling it was 5.62

g (61%) 6-chloro-3-(N-diethylaminoethylcarbamoyl)-pyridine hydrochloride, m.p. 182-184°, obtained. The filtrate gave a further 1.74 g (19%) of 6-chloro-3-(N-diethylaminoethylcarbamoyl)pyridine hydrochloride, m.p. 171-181°.

EXAMPLE 2

Preparation of N-(2-diethylaminoethyl)-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxamide hydrochloride

A suspension of 4.4 g of 6-chloro-3-(N-diethylaminoethylcarbamoyl)-pyridine hydrochloride, 3.28 g of 5-methoxyanthranilic acid methyl ester hydrochloride and 0.2 g of potassium iodide in 4 ml of triglyme was heated to a bath temperature of 150° under a argon flow for 5 hours. After cooling, the reaction mixture was triturated with ether and filtered to give a yellow solid which was recrystallized from ethanol-ether to give 3.47 g (57.%) of N-(2-diethylaminoethyl)-2-methoxy-11-oxo- 11H-pyrido[2,1-b]quinazoline-8-carboxamide hydrochloride, m.p. 249-251°.

EXAMPLE . 3

Preparation of 2-methoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxamide

A suspension of 10.24 g of 2-chloro-5-carbamoylpyridine, 14.26 g

.5-methoxyanthranilic acid and 300 mg of potassium iodide in. 30 ml of triglyme was heated to a bath temperature of 155° overnight. After cooling, the mixture was diluted with 30 ml of ethanol and the precipitate

was collected to give 15.21 g (76%) of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxamide, m.p. ±310°. Recrystallization from dimethylformamide-acetic acid and from acetic acid gave the analytical sample, m.p. 32 6°.

EXAMPLE 4

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

A mixture of 8.3 g of 2-chloro-5-cyanopyridine, 13.04 g of 5-methoxyanthranilic acid and 0.2 g of potassium iodide in 10 ml of triglyme was heated to a bath temperature of 170° for 4 hours under a slow stream of argon. After cooling, the mixture was triturated with methanol and ether

and filtered. The solid thus obtained was recrystallized

from methanol and gives 6.02 g (40%) of 8-cyano-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline, m.p. 282-284°. A further crystallization from methanol-methylene chloride gave the analytical sample, m.p. 284-285°.

EXAMPLE 5

Preparation of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids

Procedure A

The synthesis of 2-substituted pyrido[2,1-b]quinazoline-8-carboxylic acids via condensation of the appropriate anthranilic acid with 6-chloronicotinic acid is shown by the synthesis of 2-methyl-11-oxo-11H-pyrido[2,1- b]quinazoline-8-carboxylic acid: A suspension of 28.7 g of 5-methyl-anthranilic acid, 25.0 g of 6-chloronicotinic acid and 1.32 g of potassium iodide in 50 ml of triglyme was heated to a bath temperature of 150° overnight under a argon flow. After cooling, the mixture was triturated with ethanol and filtered to give 31.8 g of a yellow solid, m.p. 295-310°. Recrystallization from dimethylformamide-acetic acid gave 15.3 g (38%) of 2-methyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. >310°.

Procedure B

The reaction of an anthranilic acid hydrochloride with 6-chloronicotinic acid is illustrated by the preparation of 2-ethoxy-11-oxo-11H-pyrido-

[2,1-b]quinazoline-8-carboxylic acid: A suspension of 7.5 g of 5-ethoxy-anthranilic acid hydrochloride, 6.3 g of 6-chloronicotinic acid and 1,2

g of potassium iodide in. 12 ml of triglyme was heated to a bath temperature of 145-150° overnight. After cooling, the mixture was triturated with ethanol and filtered to give 7.7 g, m.p. 260-265°. Recrystallization from dimethylformamide gave 4.14 g (42%) of 2-ethoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 285-287°.

Procedure C

The reaction of substituted methylanthranilate hydrochlorides with 6-chloronicotinic acid is shown in the synthesis of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid: A suspension of 134

g of methyl 5-methoxyanthranilate hydrochloride, 106.7 g of 6-chloronicotinic acid and 9.0 g of potassium iodide in 300 ml of triglyme were heated to a bath temperature of 150° overnight. The resulting suspension was diluted with 200 ml of ethanol and filtered to give 177.9 g,

m.p. 278-290°. Recrystallization from 2.5 L of dimethylformamide and 500 ml of glacial acetic acid gave 93.3 g (56%) of 2-methoxy-11-oxo-11H-pyrido-2,1-b]quinazoline-8-carboxylic acid, m.p. 310°.

a) DMF = dimethylformamide; HOAc = acetic acid;

Pr = isopropyl alcohol, DMEA = N,N-dimethylethanolamine

b) Melting point was determined on a Dupont Instruments Model 900 thermal analyzer c) Compounds recrystallized from this solvent were obtained as the free acids by precipitation from water with

acetic acid

EXAMPLE 6

Preparation of 2-methoxy-11-oxo-11H-8-(1H-tetrazol-5-yl)-pyrido[2,1-b]quinazoline hemihydrochloride

A suspension of 7.0 g of 8-cyano-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline, 2.24 g of sodium azide and 1.89 g of ammonium chloride in 70 ml of dimethylformamide was heated to a bath temperature of 100° overnight and a further 2.24 g of sodium azide and 1.89 g of ammonium chloride

ride was added. After an additional 6 hours, the reaction mixture was allowed to cool and was filtered. The collected yellow solid was recrystallized from aqueous methanol containing hydrochloric acid to give 5.55 g (68%) of 2-methoxy-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1- b]quinazoline, m.p. 286° (decomposition). The filtrate gave a second yield of 2.28 g (29%)., m.p. 285° (decomposition).

EXAMPLE 7

Preparation of methyl 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate hydrochloride

A. A suspension of 6.10 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]-quinazoline-8-carboxylic acid and 2.52 g of sodium bicarbonate in 20 ml of hexamethylphosphoramide and 3.0 ml of methyl iodide was stirred at room temperature for 72 hours, and an additional 2.52 g of sodium bicarbonate and

3.0 ml of methyl iodide was added. After a further 48 hours,

.the reaction mixture was diluted with water and the precipitate was collected. Trituration of the filter cake with boiling methanol gave 0.69 g (11%) of methyl 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxy-

lazy, smp. 205-208° and a second yield which amounted to 0.43 g

(7%), m.p. 195-200°. Part of this material was crystallized

separated from methanol-ether-hydrochloric acid and gives the hydrochloride salt, m.p. 235-238°.

B. A suspension of 2.40 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid and 2.4 g of potassium carbonate in 25 ml of dimethylformamide and 2.5 ml of methyl iodide was stirred at room temperature for 4 8 hours. The resulting mixture was diluted with 75 mL of water and the yellow precipitate was collected, 2.36 g (94%), m.p. 188-19 5°. Recrystallization from methanol-hydrochloric acid-acetic acid gave 2.24

g (79%) methyl 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate hydrochloride, m.p. 228^231°.

EXAMPLE 8

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

A 12.5 g portion of diethylaminoethyl chloride hydrochloride was partitioned between 50 ml of 1N sodium hydroxide and 60 ml of ether. The combined ether layers were washed with water and brine, dried over potassium carbonate and evaporated cold. The resulting oil was added to a mechanically stirred suspension of 5.00 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid in 60 ml of dry isopropanol and the mixture was heated to reflux in 2 ten-

more. After cooling, the solids were collected and recrystallized from methanol-ether to give 5.72 g (76%) of 2-methoxy-11-oxo-HH-pyrido[2,1-b]quinazoline-8-carboxylic acid - (2-die ty laminoethyl) - ester hydrochloride, m.p. 250-253°. A further crystallization from dimethylformamide-acetic acid raised the melting point to 255-258°.

EXAMPLE 9

Preparation of 8-(N,N-dimethylcarbamoyl)-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline

A solution of 6.0 g of 2-methoxy-11-oxo-11H-pyridof 2,1-b]quinazoline-8-carboxylic acid in 100 ml of thionyl chloride was refluxed for 3 hours. The reaction mixture was evaporated to dryness and the solid residue was suspended in 200 ml of dry tetrahydrofuran. Dimethylamine was bubbled through the mixture until the color had changed from yellow to greenish-yellow and the solids were collected. The solids were dissolved in methanol, the solution was filtered and evaporated to dryness. The residue was recrystallized from 500 mL of ethyl acetate to give 4.0 g (61%) of O-(N,N-dimethylcarbamoyl)-2-methoxy-11-oxo-11'H-pyrido[2,1-b]quinazoline , m.p. 190-196°. Recrystallization from ethyl acetate-hexane and then from ethyl acetate raised the melting point to 197-99°.

EXAMPLE 10 Preparation of 6-chloro-3-pyridine methanol benzoate

To an ice-cooled solution of 24.41 g of 2-chloro-5-hydroxymethyl-pyridine in 250 ml of dry methylene chloride and 27.0 ml of dry triethylamine was added 23.0 ml of benzoyl chloride dropwise. The resulting mixture was stirred at 0° for 1 hour and at room temperature for 2 hours. It was then diluted with 500 ml methylene chloride and washed with 100 ml portions of water, saturated sodium bicarbonate and saturated sodium chloride. Drying over potassium carbonate and evaporation gave 45.4 g of a yellow semi-solid, which was distilled through short-circuit apparatus to give 41.51 g (98%) of crude 6-chloro-3-pyridinemethanolbenzoate, bp 150-160 °/0.1-0.2 mm.

Recrystallization from ether-ligroin gave, after filtration to remove some insoluble material, 33.42 g (79%), m.p. 58-60°. The analytical sample was obtained from ether-hexane and melted at 59-62°.

EXAMPLE 11

Preparation of 6-chloro-3-pyridinemethanolbenzoate, N-oxide

A solution of 33.42 g of 6-chloro-3-pyridine metriolbenzoate and 75 g of m-chloroperbenzoic acid in 1800 ml of methylene chloride was stirred at room temperature for 5 days and was washed with 2 x 500 ml of 1N sodium hydroxide, 2 x 500 ml of water and 1 X 500 ml salt solution and was dried over potassium carbonate. Evaporation gave a yellow solid which, after crystallization from ethyl acetate-hexane, gave 25.87 g (73%) of 6-chloro-3-pyridinemethanolbenzoate, N-oxide, m.p. 116-121°. The analytical sample was obtained from ethyl acetate, m.p. 120-123°.

EXAMPLE 12

Preparation of 8-hydroxymethyl-2-methoxy-llH-pyrido[2,1-b]quinazolin-ll-one-benzoate

A suspension of 5.00 g of 5-methoxyanthranilic acid and 3.90 g of 6-chloro-3-pyridinemethanolbenzoate,N-oxide in 9 ml of triglyme was heated to a bath temperature of 120° overnight. After cooling, the reaction mixture was triturated with 15 ml of ethanol and was filtered to give 3.79 g (71%) of crude 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]-quinazolin-11-one benzoate, m.p. 206-219°. Trituration with boiling methanol gave 1.75 g (33%), m.p. 226-229°. Two recrystallizations from aqueous acetic acid gave a sample, m.p. 228-230°.

EXAMPLE 13

Preparation of 8-hydroxymethyl-2-methoxy-llH-pyrido[2,1-b]-quinazolin-ll-one hydrochloride

A solution of 1.75 g of 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]-quinazolin-11-one benzoate in 10 ml of concentrated hydrochloric acid and 7 ml of ethanol was refluxed overnight. After cooling, 0.60 g (42%) of 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]quinazolin-11-one hydrochloride, m.p. 248-251° (dec.), separated and the filtrate yielded an additional 0.72 g (51%), m.p. 244-248°. The analytical sample was obtained from methanolic hydrochloric acid ether and. melted, 253-255° (cleaved).

EXAMPLE 14

Preparation of 2-nitro-5-methylthiobenzoic acid

To a solution of 50 ml of methyl mercaptan in 200 ml of dimethylformamide, 48 g of sodium hydride was added in portions at -40°. After completion of the following reaction, 100.0 g of 5-chloro-2-nitrobenzoic acid was added. The reaction temperature was allowed to rise to -10°, was again lowered to -40° and the excess reaction medium was quenched with 1N hydrochloric acid. After 2 hours of stirring at room temperature, the product was collected, 102.3 g (97%), m.p. 165-169°. Recrystallization from methanol-ethyl acetate gave 52.14 g, m.p. 173-174°. The analytical sample was obtained from ethyl acetate, m.p. 174- , 175°.

EXAMPLE 15

Preparation of methyl 2-amino-5-methylthiobenzoate

To an ice-cold solution of 52.1 g of 2-nitro-5-methylthiobenzoic acid

in 250 ml of methanol was added an ethereal solution of diazomethane until thin layer chromatography showed that the reaction was complete.

The resulting solution was evaporated to dryness and used

as such. In one case the crude product was crystallized from methanol to give yellow needles of methyl 2-nitro-5-methylthiobenzoate,

m.p. 53-54°.

The crude product from above, 55.5 g, was suspended with

55.5 g iron powder in 280 ml glacial acetic acid. The bath temperature was raised to 125° over 30 minutes and the resulting gray suspension was allowed to cool and filtered through Celite. Evaporation gave a dark oily residue which was triturated with methanolic hydrochloric acid to give a white solid which was crystallized from methanol ether to give 33.32 g (58%) of methyl 2-amino-5-methylthiobenzoate hydrochloride, m.p. 193-194°. A second yield of 7.35 g (13%), m.p. 191-192° was obtained from the filtrate. The analytical sample was obtained from methanol-ether, m.p. 196-197°.

EXAMPLE 16

Preparation of crude 2- methoxy- ll- oxo- llH- pyrido[ 2, 1-b] quinazoline- 8- carboxy 1 sy rehydrochlor id

A 1.0 liter three-necked bottle was equipped with a mechanical stirrer, argon inlet, short-path condenser and receiver, oil bath, hot plate, thermometer, temperature control device and bath thermometer. The bottle was flushed with argon and 135 g of 5-methoxyanthranilic acid, 135 g of 6-chloronicotinic acid, 2.0 g of potassium iodide and 400 ml of tri-ethylene glycol dimethyl ether (triglyme) were added. This reaction mixture was stirred and heated under a slow flow of argon. When the bath temperature reached approx. At 140°, most of the solid had dissolved. After continued heating, the product slowly precipitated as a yellow solid. The bath temperature was maintained at 150° overnight and a slow flow of argon was maintained over the stirred reaction mixture. The resulting thick mixture was cooled to less than 50° and then triturated with 200 ml of ethanol. The resulting slurry was vacuum filtered, washed with 100 ml of absolute ethanol, pressed dry and then dried overnight at 60°C under high vacuum to give 326 g of crude product. This material is 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid hydrochloride.

EXAMPLE 17

Purification of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid hydrochloride via the ethylenediamine salt

326 g of crude hydrochloride in Example 16 was dissolved in 6.2 liters of pyridine (25 ml/g assuming 100% theoretical yield) and heated to reflux in a 12 liter three-necked flask. To the stirred and refluxed solution was added 81.1 ml of distilled ethylenediamine over 5 minutes, and the resulting slurry was refluxed for 10 minutes. The heating mantle was then removed and the stirred reaction was allowed to cool (about 4 hours) to room temperature. The crystals were collected by vacuum filtration, washed with 3 x 250 ml pyridine, pressed dry and dried to constant weight in vacuo at 60° overnight to give 189.8 g of the product ethylenediamine salt as a yellow solid. This material was recrystallized by dissolving it in 500 ml of hot water. The hot aqueous solution was introduced into a 12 liter three-necked bottle containing 500 ml of refluxing pyridine and then 5.2 liters of pyridine was added slowly to the refluxing solution. After completion of the addition, an atmospheric distillation of the pyridine-water azeotrope was begun. During the distillation became further. 1.0 liter of pyridine slowly added (over a period of 1 hour), until the mixture was stirred and product began to separate. Distillation was continued until the distillation temperature had reached 110° and was then stopped (approximately 2.7 liters of distillate was collected) and the mixture was allowed to cool to below reflux temperature. 27 ml of distilled ethylenediamine was then added and the stirred mixture was allowed to cool to room temperature for 3 hours. The resulting crystals were collected, washed with a small amount of pyridine and pressed dry quickly. The product (approx. 200 g) was used directly or stored in a vacuum. ,

EXAMPLE 18

Regeneration of purified 2-methoxy-11-oxo-11H-pyrido[2,1-b]-quinazoline-8-carboxylic acid

200 g of the total recrystallized ethylenediamine salt of the above-mentioned quinazoline was dissolved in 1.0 liters of water and stirred at room temperature while a solution of 300 ml of glacial acetic acid dissolved in 1.5 liters of water was added dropwise over the course of 2 hours. The final pH of the mixture was approx. 4 according to "Accutint" paper, area no. 70. The resulting crystals were collected, washed with 2x. 1.0 liters of water and dried overnight at 100° in vacuo to give 95 g of a yellow solid melting at 322°. This material was crystallized by dissolution in 1.25 liters of refluxing pyridine. The hot solution was quickly vacuum-filtered through a Buchner funnel fitted with a steam jacket. The filter and flask were washed with 300 ml of boiling pyridine. The filtrate was transferred to a 2 liter Erlenmeyer flask with a wide mouth and heated to redissolve all the solids. The resulting solution was allowed to cool slowly to room temperature and the slurry was then carefully cooled to 0°C for 2 hours. The crystals were filtered, washed with 200 ml of cold pyridine, pressed dry and dried in vacuo at 115° overnight under a slow stream of nitrogen to give 87.6

g product, m.p. 32 5°.

EXAMPLE 19

. Preparation of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid sodium salt monohydrate

27.023 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid was stirred in 50 ml of water at room temperature while 100 ml of 1.0

N sodium hydroxide solution was added. The resulting mixture was stirred for approximately 30 minutes until most of the solids had dissolved. The solution was then vacuum-filtered to remove insolubles, and the filtrate was poured into a 5 liter three-necked flask along with 1.0 liter pyridine. The resulting slurry was heated to reflux,

at which temperature all the solids dissolved. Atmospheric distillation of the solvent was begun while ex-

another 1.0 liter of pyridine was slowly added. The quinazoline product began to separate, but distillation was continued until a distillation temperature of 100° was reached (about 1

liters of distillate). The slurry was then cooled to room temperature for 3 hours, filtered, washed with 2 x 100 ml pyridine and dried in vacuum at 95° overnight under a weak stream of nitrogen. This gave 30.2 g (97.0%) of the above monohydrated sodium salt as a pale yellow solid.

EXAMPLE 20 Preparation of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-7-carboxylic acid

A suspension of 2.80 g of 5-methoxyanthranilic acid, 2.65 g of 2-chloroisonicotinic acid and 0.135 g of potassium iodide in 13 ml of triglyme was stirred and heated at a bath temperature of 150° for 21 hours under an argon stream. After cooling, 40 ml of methanol was added and the yellow solid was removed by filtration. The crude product was purified by recrystallization of the ethylenediamine salt from pyridine, conversion back to the free acid by treatment with acetic acid and recrystallization from acetic acid to give 0.42 g (9%) of pure 2-methoxy-11-oxo-11H-pyrido[2 ,1-b]quinazoline-7-carboxylic acid, m.p. 32 3-327°.

EXAMPLE 21

Preparation of 2-methoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-6-carboxylic acid

A suspension of 1.05 g of 5-methoxyanthranilic acid, 0.99 g of 2-chloronicotinic acid and 0.050 g of potassium iodide in 5 ml of triglyme was stirred and heated at a bath temperature of 150° for 17 hours under a stream of argon. After cooling, 15 ml of methanol was added and the yellow solid was removed by filtration. The crude material was purified by recrystallization from N,N-dimethylformamide/acetic acid.

and gives 0.67 g (40%) of pure 2-methoxy-11-oxo-11H-pyrido[2,1-b]-quinazoline-6-carboxylic acid, m.p. 272-273.5°.

EXAMPLE 2 2

Preparation of pivaloyloxymethyl-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate

To 0.40 g of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid suspended in 30 ml of dimethylformamide was added 0.4 ml of triethylamine. To the clear solution was added 0.4 ml of chloromethyl pivalate and the mixture was stirred and heated at a bath temperature of 100° for 19 hours. An additional 0.3 mL of chloromethylpivalate was added and heating was continued at 100° for 4 1/2 hours. The solvent was removed by means of the oil pump, water was added, and the crude product was removed by filtration. Purification was carried out by chromatography on 15 g of silica gel and elution with 60%<1>s ethyl acetate-benzene. Recrystallization from methanol-water gave 0.37 g (65%) of pure pivaloyloxymethyl-2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylate, m.p. 129-131°.

EXAMPLE 2 3

Preparation of 2-methoxy-8-acetyl-ll-oxo-llH-pyrido[2,1-b]-quinazoline

A suspension of 0.526 g of 5-methoxyanthranilic acid, 0.490 g of 2-chloro-5-acetylpyridine and 0.030 g of potassium iodide in 2.5 ml of triglyme was stirred and heated at a bath temperature of 150° for 21 hours under an argon stream. After cooling, 8 ml of methanol was added and the brown solid was removed by filtration. Purification was carried out by chromatography on silica gel and elution with 40% ethyl acetate-benzene. The combined pure fractions were recrystallized from methylene chloride-ether to give 0.13 g (14%) of pure 2-methoxy-8-acetyl-11-oxo-11H-pyrido[2,1-b]quinazoline, m.p. 194^196°.

EXAMPLE 24

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

A mixture of 0.836 g of 5-methoxyanthranilic acid, 0.858 g of 2-chloro-pyridine-5-acetic acid and 15 mg of potassium iodide was stirred and heated at a bath temperature of 150° under argon for 1 1/4 hours. After cooling, the solid was triturated with isopropyl alcohol and the yellow solid was filtered. The crude product was purified by recrystallization of the ethylenediamine salt from pyridine and conversion back to the free acid by treatment with acetic acid to give 0.054 g (3.8%) of pure 2-methoxy-11-oxo-11H-pyrido[2,1- b]quinazoline-8-acetic acid, m.p. 281-282°.

EXAMPLE 25

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

A suspension of 11.6 g of 5-n-butylanthranilic acid, 9.4 g of 6-chloronicotinic acid and 0.1 g of potassium iodide in 20 ml of triglyme was heated to a bath temperature of 150° overnight under an argon stream. After cooling, the mixture was triturated with ethanol and water and filtered to give 7.6 g of a dark yellow solid, m.p. 265-292°. Formation of the ethylenediamine salt in hot pyridine gives a salt soluble in pure water. This salt is dissolved in water and the pure acid bottom is combined with dilute acetic acid and recrystallized from dimethylformamide-acetic acid-water to give 1.8 g (10.1%) of pure 2-n-butyl-11-oxo-11H- pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 250-25 3°.

EXAMPLE 2 6

Preparation of 2-ethyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid This compound was synthesized according to the procedure described in example 25, yield 26.4%, m.p. 313-315°.

EXAMPLE 2 7

Preparation of 2-isopropoxy-ll-oxo-llH-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride

A 9.2 g portion of diethylaminoethyl chloride hydrochloride was prepared

partitioned between 50 ml of 4N sodium hydroxide and 100 ml of ether. The combined ether layers were washed with water and brine,

was dried over potassium carbonate and was evaporated to a faintly colored oil. To this oil were added 100 ml of dry isopropanol and 4.0 g of pure 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. The mixture was heated to reflux

for 3 hours and cooled. The solids were collected and recrystallized from methanol to give 3.22 g (57.5%) of 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylamino -ethyl) ester hydrochloride, m.p. 208-209°.

EXAMPLE 28

Manufacturing a? 8- cyano- 2- isopropoxy- ll- oxo- llH- pyrido[ 2, 1-b]-quinazoline

A mixture of 16.7 g of 5-isopropoxyanthranilic acid, 10.0 g of 2-chloro-5-cyanopyridine and 0.01 g of potassium iodide in 30 ml of triglyme was heated to a bath temperature of 150° overnight under an argon stream. After cooling, the mixture was triturated with ethanol and water. A gummy solid was collected, dissolved in hot ethyl acetate, filtered and the filtrate was evaporated to give 8.4 g of crude product (38% yield). Two recrystallizations of this solid from dimethylformamide-acetic acid-water give pure 8-cyano-2-isopropoxy-11-oxo-11H-pyridot2,1-b]quinazoline, m.p. 234-236°.

EXAMPLE 29

Preparation of 8-hydroxymethyl-2-isopropoxy-llH-pyrido[2,1-b]-quinazolin-ll-one-benzoate

A suspension of 1.0 g of 5-isopropoxyanthranilic acid, 1.1 g of 6-chloro-3-pyridine methanol benzoate and 0.01 g of potassium iodide in 10 ml of triglyme. was heated to 150° overnight under an argon stream. After cooling, the reaction mixture was dissolved in hot methanol, filtered and evaporated to an orange colored oil. Chromatographic separation and recrystallization from hexane-dichloromethane gave 8-hydroxymethyl-2-isopropoxy-11H-pyrido[2,1-b]quinazolin-11-one benzoate,

m.p. 123-126°.

EXAMPLE 30

Preparation of 2-bromo-4-isopropyl-acetanilide

A solution of 50 g of 4-isopropylaniline in 160 ml of glacial acetic acid

was stirred and refluxed for 2 hours. The solution was then cooled to 45° and the dropwise addition of 60 g of bromine was begun. The addition was continued in such an amount that the temperature for

the reaction solution was kept below 55°. After completion of the addition, the reaction was allowed to stir for 1 hour. The dark liquid was then poured onto 2 liters of crushed ice with stirring. The resulting suspension was allowed to stir for 10 minutes while 5.0 g of sodium bisulfite was added. This suspension was stirred until the bromine color was removed. The solid was then filtered, washed with water and air-dried overnight.

The moist solid (115 g) was recrystallized from 1.0 L of 50% aqueous ethanol to give 64.4 g (68.2%) of 4-isopropyl-2-b-rom-acetanilide, m.p. 12 2-126°.

EXAMPLE 31

Preparation of 2-cyano-4-isopropylacetanilide

A solution of 1.0075 g of 2-bromo-4-isopropylacetanilide and 0.7308

g cuprocyanide in 10 ml N-methylpyrrolidinone was heated and stirred at 180° for 7 hours. The reaction mixture was poured into 1 ml of ethylenediamine in 50 ml of water and stirred vigorously for 5 minutes. After extraction with chloroform, the extract was washed with 10% sodium cyanide solution, washed with water, dried over magnesium sulfate and concentrated in vacuo to an oil. Remaining N-methylpyrrolidinone was removed by distillation (b.p. 33-37°/0.1 mm) and the viscous residue crystallized on cooling. Recrystallization from ether-hexane gave 2-cyano-4-isopropylacetanilide (0.5920 g, mp 98--100°).

EXAMPLE 32

Preparation of 5-isopropylanthranilic acid

A solution of 0.4870 g of 2-cyano-4-isopropylacetanilide in 5 ml of acetic acid and 10 ml of 50% sulfuric acid was refluxed for 2 1/2 hours. The solution was concentrated using an oil pump

pretty for a small volume. Water (5 mL) was added and the pH was adjusted to 4 by addition of 6N sodium hydroxide. After queuing

ling, the precipitate was filtered and dried to give 0.3426 g of material. Recrystallization from ligroin gave 5-isopropylanthranilic acid

(0.3010 g, m.p. 75-80°.

IN

r

EXAMPLE 33

Preparation of 2-bromo-4-cyclopropylacetanilide

To 15.20 g of 4-cyclopropylacetanilide (R.C.Hahn et al., J, Amer. Chem.Soc, 9Q, 3404 (1968) and 10.45 g of acetamide dissolved in 1 li-

ter chloroform and cooled at -25° was added a solution of 13.8

g of bromine in 300 ml of chloroform dropwise with stirring over the course of 2 hours. The reaction mixture was stirred at -25° for 70 hours and then allowed to warm to 5°. After filtration to remove the precipitate, the filtrate was concentrated in vacuo. The crude product was dissolved in ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange solid. This was chromatographed on 1.2 kg of silica gel and eluted with 40% ethyl acetate-toluene. The combined pure fractions were concentrated in vacuo to give 11.22 g, m.p. 108.5-110°, pure 2-bromo-4-cyclopropyl-acetanilide.

EXAMPLE 34

Preparation of 2-cyano-4-cyclopropylacetanilide

A solution of 11.22 g of 2-bromo-4-cyclopropylacetanilide in 500 ml of anhydrous dimethylformamide and 3.96 g of cuprocyanide was stirred and refluxed for 3 hours. After cooling to 25°, the dimethylformamide was removed in vacuo. The residue was stirred with 15 ml of ethylenediamine in 500 ml of water for 30 minutes and then extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo to a solid. Crystallization from ethyl acetate-hexane gave 6.45 g, m.p. 140-141°, pure 2-cyano-4-cyclopropylacetanilide.

EXAMPLE 35

Preparation of 5-cyclopropylanthranilic acid

To a solution of 6.30 g of 2-cyano-4-cyclopropylacetanilide in a mixture of 60 ml of ethylene glycol and 60 ml of water was added 8.86 g of potassium hydroxide. The reaction mixture was stirred and refluxed for 19 hours. After cooling, 1 liter of water was added. The solid which settled was removed by filtration, and the filtrate was extracted several times with ethyl acetate. The basic aqueous layer was acidified to pH 3 with acetic acid and ex-

extracted with ethyl acetate. The dried (over sodium sulfate) ex-

funnel was concentrated in vacuo to a solid. Krystallisa-

tion from ether-hexane gave 2.31 g, m.p. 157.5-158.5°, pure 5-cyclopropylanthranilic acid.

EXAMPLE 36

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

A suspension of 6.0 g of 5-isopropylanthranilic acid, 5.4 g of 6-chloronicotinic acid and 0.05 g of potassium iodide in 10 ml of triglyme was heated overnight (bath temperature 150°) under an argon stream. After cooling, the mixture was triturated with ethanol and water and filtered to give 5.89 g of crude product, m.p. 280-287°. This material was dissolved in hot pyridine and treated with ethylenediamine to give the corresponding salt which was collected by filtration. This salt was dissolved in water and the pure acid was precipitated with dilute acetic acid. Recrystallization from dimethylformamide-acetic acid-water gave 2.5 g (26.6%) of 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 314-316°.

EXAMPLE 3 7

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

5.8 g of diethylaminoethyl chloride hydrochloride was partitioned between 100 ml of 2N sodium hydroxide and 100 ml of ether. The ethereal layer was separated, washed with water and saturated brine, dried over potassium carbonate and evaporated to a faintly colored oil. To this oil were added 200 ml of isopropanol and 2.4 g of pure 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. The mixture was refluxed for 3 hours and cooled. The solids were collected and recrystallized from methanol to give 1.87 g

(53.4%) 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-S-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride, m.p. 220-222°.

EXAMPLE 38

Preparation of 5-hydroxy-2-nitrobenzoic acid

A mixture of 5.0 liters of water, 800 g of sodium hydroxide and 504 g of 5-chloro-2-nitrobenzoic acid was refluxed for 24 hours. The solution was cooled and acidified with 1.75 liters of concentrated hydrochloric acid. The acidic aqueous mixture was extracted three times

with 1.5 liters of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, filtered through Celite, and evaporated

to a pale yellow solid (473 g). This material was recrystallized from ether-petroleum ether to give 298 g of 5-hydroxy-2-nitrobenzoic acid, m.p. 167-169° (65.2%).

EXAMPLE 39

Preparation of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester

A mixture of 55.3 g of 5-hydroxy-2-nitrobenzoic acid, 450 ml of dimethylformamide and 93.9 g of anhydrous potassium carbonate was stirred at room temperature for 10 minutes. 100 ml of isopropyl bromide was then added and the mixture was stirred and heated to 100° for five hours. The reaction mixture was then cooled and diluted with ice water. The pH of the mixture was adjusted to -~8 with 4N sodium hydroxide solution. The mixture was then extracted three times

ger with 500 ml of ether. The combined ether extracts were washed with 500 ml of saturated brine, dried over anhydrous potassium carbonate, filtered through "Celite" and evaporated to a yellow oil which crystallized on cooling to give 74.0 g of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester, m.p. 45-50° (91.7%). This material can be distilled under high vacuum and gave pure product, m.p. 51-52°.

EXAMPLE 40

Production of 5-isopropoxy-anthranilic acid

74.0 g of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester was dissolved in 650 ml of ethanol and 145 ml of 4N sodium hydroxide solution. This solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 2.0 liters of water and washed three times with 1.1 liters of dichloromethane. The aqueous layer was then acidified

pH <. 2 with concentrated hydrochloric acid and extracted three times with 1.0 liters of ether. The combined ether extracts were washed with 1.0 L of saturated brine, dried over anhydrous sodium sulfate, filtered through celite and evaporated to an orange oil (65.9 g) which solidified on cooling, mp 129-131°.

The above-mentioned solid was dissolved in 1.0 liters of ethyl acetate and hydrogenated using 3.1 g of 10% palladium on carbon as a catalyst. When the hydrogen uptake had ceased, the catalyst was removed by filtration; and the filtrate was evaporated to a yellow solid, 49.5 g (m.p. 120-122°).

EXAMPLE 41 Preparation of 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid

A mixture of 23.2 g of 5-isopropoxyanthranilic acid, 15.7 g of 6-chloronicotinic acid, 0.1 g of potassium iodide and 50 ml of triglyme was heated to 150° under a constant flow of argon for 16 hours. The reaction mixture was cooled, diluted with approx. 50 ml of ethanol and filtered to give 18.9 g of crude product, m.p. 256-267°. This material was dissolved in approx. 50 ml of hot pyridine. To the boiling solution was added 4.8 ml of ethylenediamine. This mixture was allowed to cool, and the crystals that had precipitated were filtered, washed with pyridine, pressed dry and dissolved in 50 ml of water. This aqueous solution was stirred and carefully acidified with dilute acetic acid. The crystals that precipitated were collected, washed with water, ethanol and ether and dried to give 9.8 g of 2-isopropoxy-11-oxo-11H-pyrido-[2,1-b]quinazoline-8-carboxylic acid, m.p. 278-280°.

EXAMPLE 4 2

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

A stirred intimate mixture of 50 g of methyl 5-methyl-mercapto-anthranilate hydrochloride, 34.7 g of 6-chloronicotinic acid and 0.1 g of potassium iodide was immersed in an oil bath preheated to 150°. 40 ml of triglyme was carefully added to the mixture. The reaction mixture was heated to 175° for 16 hours under a slow stream of argon. The reaction was cooled and the solid residue was dissolved in hot dimethylformamide and glacial acetic acid, filtered and cooled. The precipitated product was collected, washed with ethanol and dried to give 31.3 g (51%) of 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, m.p. 303-320°..

The crude material (10 g) was dissolved in 150 ml of hot pyridine. To this warm solution was added approx. 1.25 ml of ethylenediamine. The resulting mixture was stirred while cooling. The resulting crystals were collected, pressed dry and dissolved in water. This solution was carefully acidified with dilute acetic acid and the precipitated product was filtered and dried to give 1.7 g of purified product, m.p. 337°.

EXAMPLE 4 3 Preparation of 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl) ester hydrochloride

2.5 g of N,N-diethylaminoethyl chloride hydrochloride was partitioned between 50 ml of ether and 50 ml of 2N sodium hydroxide solution. The aqueous layer was extracted twice with 50 ml of ether and the combined ether layers were washed with 50 ml of water and 50 ml of saturated saline. The organic phase was then dried over anhydrous potassium carbonate, filtered through Celite and evaporated to a slightly colored oil (1.61 g). This oil was dissolved in 35 ml of isopropanol and to this stirred solution was added 1.15 g of purified 2-methylthio-11-oxo-11.H-pyrido-[2,1-b]quinazoline-8-carboxylic acid. The resulting reaction mixture was refluxed for 4 hours and cooled. The crystalline product was collected by filtration and recrystallized from methanol to give 1.16 g (92%) of the desired 2-methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid -(2-Diethylaminoethyl)ester as its hydrochloride salt, m.p. 236-238°..

EXAMPLE 4 4

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

A solution of 2.12 g of 5-cyclopropylanthranilic acid and 1.89 g of 6-chloronicotinic acid in 20 ml of toluene was boiled to remove the toluene. The resulting solid mixture was heated at 150 for 25 min-

ter. After cooling, the solid residue was triturated with ether and

tired. The resulting solid was crystallized from acetic acid and then from ethanol to give 0.275 g, m.p. 316-313°, pure 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid.

The acid is reacted with 2-diethylaminoethyl chloride in isopropanol, as follows

as described in Example 37, giving 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid-(2-diethylaminoethyl)-ester hydrochloride.

EXAMPLE 4 5

Preparation of 8-acetyl-2-bromo-ll-oxo-llH-pyrido[2,1-b]-quinazoline

A suspension of 15.50 g of 5-bromoanthranilic acid, 11.9 g of 2-chloro-5-acetylpyridine and 0.50 g of potassium iodide in 20 ml of triglyme was heated at a bath temperature of 150° under an argon atmosphere for 7 hours. 40 ml of methanol was added and the mixture was stirred in an ice bath for 30 minutes and filtered. The product was suspended in 500 ml of saturated sodium bicarbonate solution and extracted with chloroform. The extract was concentrated to a yellow solid (9.70 g) which

was crystallized and recrystallized from methylene chloride-ether to give 5.10 g (m.p. 221-224°) of pure 8-acetyl-2-bromo-11-oxo-11H-pyrido[2,1-b]quinazoline.

EXAMPLE 4 6

Preparation of 4- isopropyl isonitrosoacetanilide

To a stirred solution of 1480 g sodium sulfate decahydrate dissolved

in 1.8 liters of water the following solutions were added: 100 g of p-isopropylaniline dissolved in 440 ml of water and 66 ml of concentrated hydrochloric acid, 244 g of chloral hydrate dissolved in 2.6 liters of 90% aqueous ether

nol and 162 g of hydroxylamine hydrochloride dissolved in 700 ml of water.

This reaction mixture was refluxed for 12 hours,

cooled to room temperature and extracted with 1.8 liters of dichloromethane. The organic layer was separated and evaporated to a dark oil. This oil was partitioned between 1.0 liters of 10% sodium hydroxide solution and 500 ml of ether. The aqueous layer was separated and washed with 2500 mL portions of ether. The aqueous layer was then acidified

with concentrated hydrochloric acid and extracted with three 500-ml portions of ether. The combined ether extracts were dried over anhydrous sodium sulfate, filtered through "Celite" and evaporated to dryness to give 160 g of 4-isopropyl-isonitrosoacetanilide. This crude product was recrystallized from 250 ml of benzene to give 46.6 g of product,

m.p. 126-130°.

EXAMPLE 4 7

Preparation of 5-isopropylanthranilic acid

460 ml of concentrated sulfuric acid was stirred and heated to 70°.

46.6 g of 4-isopropylisonitrosoacetanilide was then added in such an amount that the temperature of the reaction mixture was maintained at between 70-80°. Water cooling was carried out if necessary. After completion of the addition, the temperature of the mixture was maintained at 80° for 30 minutes. The reaction mixture was cooled to room temperature and poured onto 4 liters of crushed ice. The resulting suspension was stirred for 15 minutes and the precipitated 5-isopropylisatin was filtered. The solid was washed with water, collected and dissolved in 460 mL of 1N sodium hydroxide solution. This mixture was filtered to remove insolubles, and the filtrate was treated with 30% peroxide until a positive starch iodide sample was obtained.

The above-mentioned reaction mixture was cooled in an ice bath and acidified with 6N hydrochloric acid solution until a pH of approximately 4

was obtained. The precipitated product was collected and dried to give 28.0 g of 5-isopropylanthranilic acid, m.p. 90-96°. This product was

of sufficient purity for further application.

EXAMPLE 4 8

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 49

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. Compress on a suitable press machine.

EXAMPLE 50

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.

Claims (8)

1. Procedure for the preparation of new pyrido[2,1-b]-quinazoline derivatives with the general formula where , R2 and R^ independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl or hydroxy, and R^ represents cyano, 5-tetrazolyl, hydroxy-lower alkyl, acyloxy-lower alkyl or a residue of the formula where A represents lower alkyl, hydroxy, lower alkoxy, di-(C-L~C7) alkylamino-(C2-C^) alkoxy, pivaloyloxymethoxy or a residue of the formula where Rc; and Rg independently represents nyarogen, xavereaxxyx exxer ai-;axKyxamxno-(C2-C7)alkyl, Y represents hydrogen or methyl and n represents the integer 0 or 1, with the proviso that at least one of R-^, R2 and R3 is different from hydrogen, 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 above, where R represents cyano, acyloxy-lower alkyl or a residue of the formula where A represents lower alkyl, hydroxy , lower alkoxy or a residue of the formula -NR^Rgdg , R2,R3, R^, Rg, Y and n have the meanings given above, are prepared by treating a compound with the general formula where R represents hydrogen or lower alkyl and , R2 and R3 have above stated meaning, with a halopyridine derivative of the general formula where Ra' represents cyano, acyloxy-lower alkyl v q or a remainder with the formula. -(CH) -fc-A, where A represents lower alkyl, hydroxy, lower alkoxy or a residue of the formula -NR^Rg, Y represents hydrogen or methyl and n represents the integer 0 or 1, R^ and Rg independently represent hydrogen, lower- alkyl or di-(C-^-C-j)alkylamino-(C2-C-,)alkyl and X represents halogen, or b) compounds of formula I as above where R^ represents 5-tetrazolyl and R-^, R 2 and R3 has the above meaning, is prepared by treating a compound with the general formula where, R2 and R^ have the above meaning with an alkali metal azide, or c) compounds of formula I as above, where R^ represents hydroxy-lower alkyl and R- ^, R and R^ have the meaning stated above, are produced by hydrolysis of a compound with the general formula where Ry represents acyloxy-lower alkyl, and R-^, R 2 and R 3 have the meaning stated above, or d) compounds of formula I as above, where R, represent- fill in a remainder with the formula where A represents di-(C-^-Cy) alkylamino-(C2-Cy) alkoxy and R-^, R 2 , R 3 , Y and n have the above meaning, is prepared by treating a compound with the general formula where R -^, R2, R^ f Y and n have the meaning given above, with a di-(C^-C^) alkylamino-(C2-C7) alkyl halide, or an acid chloride of a compound of formula Ic above is subjected to alcoholysis with a di-(C-^-C^) alkylamino- (C-p-C-y ) alkanol, or e) compounds of formula I as above, where R4represent- fill in a remainder with the formula where A represents pivaloyloxymethoxy and R^, R9, R^, Y and n have the above meaning, is prepared by treating a compound of the formula Ic as above with a tertiary organic base and chloro, bromo or iodomethyl pivalate, or f) compounds with the formula I as above, where R. represents fill in a remainder with the formula where A represents lower alkoxy and R 1 , R 2 , R 3 f Y and n have the meanings given above, are produced by esterification of a compound with the formula Ic as above, or g) compounds with the formula I as above, where R 4 represents teres a remainder with the formula where A represents a residue of the formula -NR^R^ and R^, R2, R^, R5, R^, Y and n has the above meaning, is prepared by subjecting a compound of the formula Ic as above to ammonolysis with an aminophorbin -division with the general formula where Rg and R^ have the above meaning, or h) compounds of the formula I as above, are prepared by treating a compound of the formula II as above with a halopyridine derivative of the general formula where Ry and X have the above indicated meaning,. and i) if desired, a compound obtained is transferred in a pharmaceutically acceptable salt. 2. Method as stated in claim 1, characterized in that compounds are produced with the gene regular formula where R^ 1 , ' and R-^' independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or hydroxy, and R 4 has the same meaning as stated in claim 1. 3. Method as set forth in claim 2, characterized in that at least one of R 1 , R 2 0 < 3 R 3 , represents lower alkylthio. 4. Procedure as specified in claim 2 or 3, para terized by the fact that R. represents acyloxy low area cool or a residue with the formula ■ where Y and A have the meanings specified in claim 1. 5. Method as stated in claim 2 or 3, characterized in that R represents a residue with the formula where A represents lower alkyl, di-(C 1 -C 7 )-alkylamino-(C 1 -C 4 )alkoxy or pivaloyloxymethoxy. 6. Method as set forth in claim 1, characterized in that at least one of R-1, R2 and R3 represents cyclopropyl or cyclobutyl. 7. Method as stated in claim 1, characterized in that R2 and R^ represent hydrogen and R 4 represents centers a remainder with the formula where A represents di-(C-^-Cy) alkylamino-(C 2 -C 7 ) alkoxy. 8. Method as stated in claim 1, characterized in that at least one of R-^, R2 and R^ represents lower alkyl, lower alkoxy or lower alkylthio, and R^ represents a substituent in the 8-position 9. Method as stated in claim 1, characterized in that Rj represents hydrogen, R-^ and/or R^ is different from hydrogen and R^ represents a substituent in the 8-position. 10. Method as stated in claim 1, characterized in that Rj represents hydrogen, R-^ and/or R^ independently represents lower alkyl, lower alkoxy or lower alkylthio, and R. represents hydroxy-lower alkyl 5-tetrazolyl or a remainder with the formula where A represents hydroxy or di-(C-^-C-,) alkylamino-(C-j-C^) alkoxy. 11. Method as stated in claim 1, characterized in that one of R^, Rj and R^ represents lower alkyl, lower alkoxy or lower alkylthio. and R, represents 12. Method as stated in claim 2, characterized in that one prepares 2-methoxy -11-oxo-11H-pyridotic 2,1-b]quinazoline-8-carboxylic acid. 13. Method as stated in claim 3, characterized in that 2-methyl-thio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is prepared. 14.. Method as stated in claim 2, characterized in that 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is produced. 15. Process as stated in claim 6, characterized in that 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is produced. 16. Method as stated in claim 5, characterized in that 2-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylaminoethyl)ester is prepared. 17. Process as stated in claim 2, characterized in that 2-methoxy-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1-b]quinazoline is prepared. 13. Process as stated in claim 5, characterized in that 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylaminoethyl) ester is prepared. 19. Process as stated in claim 2, characterized in that 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]quinazolin-11-one is prepared. 20. Process as stated in claim 2, characterized in that 2-isopropoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is prepared. 21. Process as stated in claim 2, characterized in that 2,4-dimethoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is prepared. 22. Process as stated in claim 2, characterized in that 4-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid is prepared. 23. Method as stated in claim 4, characterized in that 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid is produced. 24. Process as stated in claim 6, characterized in that 2-cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid (2-diethylaminoethyl)ester is prepared. 25. Process for the production of preparations with anti-allergic properties, characterized in that a pyrido[2,1-b]quinazoline derivative with the formula I as stated in claim 1 or a pharmaceutically acceptable salt thereof is mixed as active ingredient with non-toxic, inert, therapeutically tolerable solid or liquid carriers, which are normally used in such preparations and/or excipients. 26. Compositions with anti-allergic properties, characterized in that they contain a pyrido-[2,1-b]quinazoline derivative of the formula I as stated in claim 1 or a pharmaceutically acceptable salt thereof and a carrier. 27. Pyrido[2,1-b]quinazoline derivatives of the general formula Characterized in that R^, Rj and independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl or hydroxy, and R^ represents cyano, 5-tetrazolyl, hydroxy-lower alkyl, acyloxy- Y lower alkyl or a residue of the formula - (CH) -C-A, where A represents lower alkyl, hydroxy, lower alkoxy, di-(C^-Cy) hydrogen, lower alkyl or di-(C 1 -C 2 )-alkylamino-(C 2 -C 7 )alkyl, Y represents hydrogen or methyl, and n represents the integer 0 or 1, with the proviso that at least one of R-^, R 2 and R 3 is different from hydrogen, pharmaceutically acceptable acid addition salts thereof, and when A represents hydroxy, also pharmaceutically acceptable salts thereof with a base. 28. Compounds as set forth in claim 27 with the general formula characterized in that R1', R2' and R3' independently represent hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or hydroxy, and R^ has the meaning indicated in claim 27. 29. Compounds as stated in claim 28, characterized in that at least one of R2<1> and R3<1> represents lower alkylthio. 30. Connections as stated in claim 28 or 29, ka characterized by R. represents acyloxy- lower alkyl or a residue of the formula where Y and A have the meaning specified in claim 27. 31. Compounds as stated in claim 28 or 29, characterized by R, represents a residue with the formula where A represents lower alkyl, di-tC 1 -C 4 ) alkylamino-(C 1 -C y ) alkoxy or pivaloyloxymethoxy. 32. Compounds as set forth in claim 27, characterized in that at least one of R 1 , R 2 and R 2 represents cyclopropyl or cyclobutyl. 33. Connections as stated in claim 27, character raised by R2 and R^ represents hydrogen and R. represents a remainder with the formula where A represents di-(C-^-Cy) alkylamino-(C 2 -Cy) alkoxy. 34. Compounds as set forth in claim 27, characterized in that at least one of R 1 , R 2 and R 2 represents lower alkyl, lower alkoxy or lower alkylthio and R 2 represents a substituent in the 8-position. 35. Compounds as stated in claim 27, characterized in that R 2 represents hydrogen, R 2 and/or R 2 are different from hydrogen, and R 2 represents a substituent in the 8-position. 36. Compounds as stated in claim 27, characterized in that R, represents hydrogen, R-^ and/or R, independently represents lower alkyl, lower alkoxy or lower alkylthio, and R 1 represents hydroxy-lower alkyl, 5- tetrazolyl or a residue of the formula where A represents hydroxy or di-(C 1 -C 7 )alkylamino-(C 2 -C 7 ) alkoxy. 37. Compounds as stated in claim 27, characterized in that one of R-^, R, and R^ represents lower alkyl, lower alkoxy or lower alkylthio, and R, represents 38. 2-methoxy-11-oxo-11H-pyrido[ 2,1-b]quinazoline-8-carboxylic acid. 39. 2-Methylthio-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. 40. 2-iso<p>rop<y>l-ll-oxo-llH-pyrido[2,i-b]quinazoline-8-carboxylic acid. 41. 2-Cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. 42. 2-Isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylaminoethyl) ester. 43. 2-Methoxy-11-oxo-11H-8-(1H-tetrazol-5-yl)pyrido[2,1-b]-quinazoline. 44. 2-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid (2-diethylaminoethyl) ester. 45. 8-Hydroxymethyl-2-methoxy-11H-pyrido[2,1-b]quinazolin-11-one. 46. 2-Isopropoxy-11-oxo-11H-pyridotic 2,1-b]quinazoline-8-carboxylic acid. 47. 2,4-Dimethoxy-11-oxo-11H-pyrido[2,1-b]quinazplin-8-carboxylic acid. 48. 4-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid. 49. 2-Methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline-8-acetic acid. 50. 2-Cyclopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid-(2-diethylaminoethyl)ester.