CA1189509A - Substituted 11-oxo-11h-pyrido [2,1-b] quinazolines - Google Patents
Substituted 11-oxo-11h-pyrido [2,1-b] quinazolinesInfo
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- CA1189509A CA1189509A CA000299683A CA299683A CA1189509A CA 1189509 A CA1189509 A CA 1189509A CA 000299683 A CA000299683 A CA 000299683A CA 299683 A CA299683 A CA 299683A CA 1189509 A CA1189509 A CA 1189509A
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Abstract
Abstract Novel pyrido[2,1-b]quinazoline derivatives of the formula wherein R1, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula , wherein A represents hydroxy, lower alkoxy, di-(C1-C7)-alkylamino-(C2-C7)alkoxy, pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(C1-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when R1, 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 as well as a process for preparing same.
These compounds exhibit useful anti-allergic properties.
These compounds exhibit useful anti-allergic properties.
Description
- 2 -l The present invention relates to novel pyridor2,1-b~-quinazoline derivatives of the general formula e ~ i J: R
wherein Rl, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula -C-A, wherein A represents hydroxy, lower alkoxy, di-(Cl-C7)-alkylamino-(c2-c7)alkoxy~ pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(Cl-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when Rl, R2 or R3 represents lower alkanoyl, pharmaceutically acceptable acid addition salts thereof, and when ~ represents hydroxy, also pharmaceutically acceptable salts thereoE with a base.
As used herein, the term "lower alkyl" denotes a straight or branched chain saturated hydrocarbon group containing l to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentvl, pentyl, heptyl and the like. The term "lower alkoxy" denotes an alkoxy group in which the lower alkyl group is as described above, for example, methoxy, ethoxy, Kbr/1.3.78
wherein Rl, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula -C-A, wherein A represents hydroxy, lower alkoxy, di-(Cl-C7)-alkylamino-(c2-c7)alkoxy~ pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(Cl-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when Rl, R2 or R3 represents lower alkanoyl, pharmaceutically acceptable acid addition salts thereof, and when ~ represents hydroxy, also pharmaceutically acceptable salts thereoE with a base.
As used herein, the term "lower alkyl" denotes a straight or branched chain saturated hydrocarbon group containing l to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentvl, pentyl, heptyl and the like. The term "lower alkoxy" denotes an alkoxy group in which the lower alkyl group is as described above, for example, methoxy, ethoxy, Kbr/1.3.78
- 3 ~
1 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 of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl and the like. Exemplary of "di-(Cl-C7)alkylamino-(C2-C7)alkoxy" groups are dimethylaminoethoxy, diethylaminoethoxy, dipropylaminoe-thoxy, diisopropylaminoethoxy, dibutylaminoethoxy, dipentylaminoethoxy and the like. Exemplary of "di-(Cl-C7)alkylamino-(C2-C7)alkyl" groups are dimethyl-lo aminoethyl, diethylaminoethyl, ethylmethylaminoethyl, dipro-pylaminoethyl and the like.
Particular compounds encompassed by the present invention are those of the formula I above wherein Rl, R2 and R3 indepen-dently represent hydrogen or lower alkyl and R4 has the meaning indicated above.
Further particular compounds of the formula I above are those wherein at least two of Rl, R2 and R3 are other than hydrogen and represents lower alkyl and R4 has the meaning indicated above.
In a further particular aspect, the invention comprises compounds of formula I above wherein R4 represents a radical of the formula -C-A wherein A represents di-(Cl-C7)alkyl-amino-(C2-C7)alkoxy or pivaloyloxymethoxy and Rl, R2 and R3 independently represent hydrogen or lower alkvl.
1 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 of 1 to 7 carbon atoms, for example, formyl, acetyl, propionyl and the like. Exemplary of "di-(Cl-C7)alkylamino-(C2-C7)alkoxy" groups are dimethylaminoethoxy, diethylaminoethoxy, dipropylaminoe-thoxy, diisopropylaminoethoxy, dibutylaminoethoxy, dipentylaminoethoxy and the like. Exemplary of "di-(Cl-C7)alkylamino-(C2-C7)alkyl" groups are dimethyl-lo aminoethyl, diethylaminoethyl, ethylmethylaminoethyl, dipro-pylaminoethyl and the like.
Particular compounds encompassed by the present invention are those of the formula I above wherein Rl, R2 and R3 indepen-dently represent hydrogen or lower alkyl and R4 has the meaning indicated above.
Further particular compounds of the formula I above are those wherein at least two of Rl, R2 and R3 are other than hydrogen and represents lower alkyl and R4 has the meaning indicated above.
In a further particular aspect, the invention comprises compounds of formula I above wherein R4 represents a radical of the formula -C-A wherein A represents di-(Cl-C7)alkyl-amino-(C2-C7)alkoxy or pivaloyloxymethoxy and Rl, R2 and R3 independently represent hydrogen or lower alkvl.
4 ~
1 Another group of particular compounds of the formula I above are those wherein at least one of Rl, R2 and R3 represents lower alkanoyl.
Preferred compounds of the formula I above are those wherein R2 and R3 represent hydrogen. In a preferred aspect, the inven-tion comprises compounds of the formula I above wherein Rl represents hydrogen or lower alkyl, preferably lower alkyl.
R4 represents preferably a radical of the formula -C-A. The preferred meanings of A are hydroxy and di-(Cl-C7)alkylamino-(C2-C7)alkoxy, with hydroxy being especially preferred.
From the above it follows that those compounds of formula I are especially preferred wherein R2 and R3 represent hydrogen, Rl represents lower alkyl and R4 represents C-OH.
Also a preferredgenus of compounds of formula I are those wherein R2 and R3 represent hydrogen, Rl represents hydrogen, lower alkyl F lower alkanoyl and R4 represents a radical of the formula -C-A wherein A represents di-(Cl-C7)alkylamino-(c2-C7)alkoxy-Examples of preferred compounds of formula I are the following:
8-methyl-11-oxo-llH-pyrido~2,1-b~quinazoline-2-carboxylic acid;
_ 5 ~ 50~
1 8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxyli.c acid;
8~isopropvl-ll-oxo-llH-pyrido[2,1-b]quina7.oline-2-carboxylic acid-(2-diethylaminoethyl~ester.
Examplary of the compounds of formula I are the following:
8-n-propyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
8-n-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
lo 8-t-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-methyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-ethyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-n-propyl-11-oxo-llH~pyrido[2,1-b]quinazoline-2-carboxylic aci.d;
6-n-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-t-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
and the like.
In accordance with the present invention the compounds of the formu].a I above and their pharmaceutically acceptable acid a~dition salts, and when A represents hydroxy~ also their 9~;Q~
1 pharmaceutically acceptable salts with a base, can be prepared by a process which comprises a) for preparincJ compounds of the formula I above wherein R4 represents halogen and Rl, R~ and R3 have the meaning indica-ted above, treating a compound of the general formula ~ COOR
X+ 11 11 ~ NH2 wherein R represents hydrogen or lower alkyl~and X
represents halogen, with a halopvridine derivative of the general formula lo R3~R 1 I
X ~ N ~
wherein Rl, R2, R3 and X have the meaning indicated above, or b) for preparing compounds of the formula I above wherein R4 represents cyano and Rl, R2 and R3 have the meaning indicated above, i.e. compounds of the general formula 'i~ "1 l~a 915~
1 wherein Rl, R2 and R3 have the meaning indicated above, treating a compound of the general formula X t , ,1~ R2 Ib wherein X represents bromine or iodine and Rl, R2 and R3 have the meaning indicated above, with cuprous cyanide, or c) for prepari.ng compounds of the formula I above wherein R4 represents a radical of the formula ~C-A wherein A represents hydroxy, i.e. compounds of the general formula HOOC ~ ; Ic wherein Rl, R2 and R3 have the meaning indicated above, treating a compound of the formula Ib above with nickel carbonyl under a carbon monoxide atmosphere in the presence of an alkaline earth hydroxide or hydrolyzing a compound of the formula Ia 1~ above, or d) for preparing compounds of the ~ormula I above wherein R4 represents a radical of the formula -C-A wherein A represents lower alkoxy and Rl, R2 and R3 have the meaning indicated above, esterifying a compound of the formula Ic above, or :' 1 e) for preparing compounds of the formula I above wherein R4 represents a radical of the formula -C-A wherein A represents a radical of the formula -NR5R6 and Rl, R2, 3, 5 6 the meaning indicated above, subjecting a compound of the formula Ic above to ammonolysis with an amino compound of the general formula ~NR5R6 IV
wherein R5 and R6 have the meaning indicated above, or f) for preparing compounds of the formula I above wherein R4 represents a radical of the formula -C-A wherein A represents di-(Cl-C7)alkylamino-(C2~C7)alkoxy and Rl, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a di-(Cl-C7)alkvlamino (C2-C7)alkyl halide or sub-jecting an acid chloride of a compound of the formula Ic above lS to alcoholysis with a di-(Cl-C7)alkylamino-(C2-C7)alkanol, or g) for preparing compounds of the formula I above wherein R4 represents 5-tetrazolyl and Rl, R2 and R3 have the meaning indicated above, treating a compound o:f the formula Ia above with an alkali metal azide, or h) for preparing compounds of the Eormula I above wherein R4 represents a radical of the formula -~ A wherein A represents pivaloyloxymethoxy and Rl, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a - g ~ !39 1 tertiary organic base and chloro~, bromo- or io'domethyl pivalate, and i) if desired, converting a compound obtained in-to a pharmaceu--tically acceptable salt.
~ lo~
1 According -to process embodiment a), an anthranilic acid or ester of formula II, a known compound or a compound which can be prepared according to known procedures, is reacted with a halopyridine of formula III, also a known compound or a com-pound which can be prepared according -to known procedures, at a temperature in the range of from about 100C. to about 200C., with or without a solvent. The reaction is conducted in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, potassium iodide,cesium iodide or the like. Solvents which may be utilized in the reaction are high boiling solvents such as acetic acid, diglyme, triglyme or the like. The reaction is conveniently carried out at atmos-pheric pressure. The reaction product can be recovered accor-din~ to known procedures, such as crystallization or the like.
According to process embodiment b), the bromo or iodo moiety of a compound of formula Ib can be converted -to a nitrile moiety by treating the compound of formula Ib with cuprous cyanide in an inert solvent such as l-methyl-2-pvrroli-dinone or the like, at or near the reflux tem~erature of the reaction mixture. Thereafter, the reaction mixture is treated with a solution of water, hydrochloric acid and ferric chloride.
The desired nitrile of formula Ia is recovered according to known procedures, such as crystallization or the like~
According to process embodiment c), a compound of the formula Ib can be converted to a compound of formula Ic by treating 1 the compound of formula Ib wi-th 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 in the range of 100C. to about 150C. The reaction conveniently can be carried out in a high boiling polar solvent such as dimethylformamide or the like. A compound of formula Ic can be recovered accordiny to known procedures, such as crystallization or the like.
Alternatively, a nitrile of formula Ia can be converted 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, propionic acid or the like.
According to process embodiment d), an acid of formula Ic can be converted to the corresponding ester by known procedures.
For instance, 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 utilizing known reaction conditions, for example, in an inert solvent such as dimethylformamide or the like, at a temperature in the range or from about room temperature to the reflux temperature of the reaction mixture.
According to process embodiment e), an acid of formula Ic can be converted to the corresponding amide by known proce-dures. For example, an acid as described above, is treated 1 with thionyl chloride whereby the corresponding acid chloride is obtained. The latter is then treated with the corresponding amine, for example, treated with ammonia, dimethylamine, 3-die-thylaminopropylamine or the like, in the presence of a solvent such as tetrahydrofuran. The desired amide is then recovered according to known procedures such as crystallization.
According to process embodiment f) r an acid of formula Ic, can be converted to the corresponding di-(cl-c7)alkylamino-(c2-c7)-alkvl ester by known procedures. For example, an acid as des-cribed above, is treated with the corresponding di-(Cl-C7)-alkylamino-(C2-C7)alkyl halide under reflux conditions in a solvent, for example, an alkanol such as isopropanol or the like, and the product is recovered according to ~nown proce-dures, such as crystallization; or said compound is treated with thionyl chloride whereby the corresponding acid chloride is obtained, the latter compound is reacted with a di-(Cl-C7)-alkylamino-(C2-C7)alkanol in an inert solvent, such as tetra-hydrofuran or the like, at a temperature in the range of from about 0C. to about 100C., and thereafter the desired end product is recovered by known procedures, such as crystalli-zation or the like.
~ccording to process embodiment g), a compound of formula I wherein P~4 is 5-tetrazolyl can be prepared from the corres-ponding compound of formula Ia. More specifically, the corres-ponding compound of formula Ia is treated with an al]cali metal .
- 13 - ~1~9~
1 azide, such as potassium azide, sodium azide or the like, in the presence of ammonium chloride. The reaction is suitably carried out in the presence of a solvent such as a polar aprotic solvent, for example, dimethylsulfoxide, dimethylforma- -mide or the like. The desired tetrazolyl compound is then reco-vered according to known procedures, for example, crystalli-zation or the like.
AccordincJ to process embodiment h), a compound of formula I wherein A is pivaloyloxymethoxy can be prepared by treating lo the corresponding compound of formula Ic with a tertiary orga-nic base, such as a tri-lower alkylamine and chloro-, bromo-or iodomethyl pivalate in an inert solvent such as dimethyl-formamide or the like, at a temperature in the range of from room temperature to about 120C~ The desired end product can be lS recovered according to known procedures, such as crystallization.
The compounds~of formula I wherein A is hydroxy, form phar-maceutically acceptable salts with bases. Exemplary 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 ethano-late and the like; organic bases such as piperidine, diethyl-amine, N-methylglucamine and the like.
The compounds of formula I also form pharmaceutically accep~
1 table salts with acids. Exemplary 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.
The compounds of formula I and their pharmaceutically acceptable salts inhibit cutaneous anaphylaxis in rats, and are therefore useful ln the prevention of allergic reactions, for example, they are useful in the prophylactic treatment of bronchial asthma. The anti-anaphylactic activity can be demon-strated by the passive cutaneous anaphylaxis assay ~PCA test) in the rat. This test 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-C2,1 b]quinazoliner is ~iven intraperitoneally followed after
1 Another group of particular compounds of the formula I above are those wherein at least one of Rl, R2 and R3 represents lower alkanoyl.
Preferred compounds of the formula I above are those wherein R2 and R3 represent hydrogen. In a preferred aspect, the inven-tion comprises compounds of the formula I above wherein Rl represents hydrogen or lower alkyl, preferably lower alkyl.
R4 represents preferably a radical of the formula -C-A. The preferred meanings of A are hydroxy and di-(Cl-C7)alkylamino-(C2-C7)alkoxy, with hydroxy being especially preferred.
From the above it follows that those compounds of formula I are especially preferred wherein R2 and R3 represent hydrogen, Rl represents lower alkyl and R4 represents C-OH.
Also a preferredgenus of compounds of formula I are those wherein R2 and R3 represent hydrogen, Rl represents hydrogen, lower alkyl F lower alkanoyl and R4 represents a radical of the formula -C-A wherein A represents di-(Cl-C7)alkylamino-(c2-C7)alkoxy-Examples of preferred compounds of formula I are the following:
8-methyl-11-oxo-llH-pyrido~2,1-b~quinazoline-2-carboxylic acid;
_ 5 ~ 50~
1 8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxyli.c acid;
8~isopropvl-ll-oxo-llH-pyrido[2,1-b]quina7.oline-2-carboxylic acid-(2-diethylaminoethyl~ester.
Examplary of the compounds of formula I are the following:
8-n-propyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
8-n-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
lo 8-t-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-methyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-ethyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-n-propyl-11-oxo-llH~pyrido[2,1-b]quinazoline-2-carboxylic aci.d;
6-n-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
6-t-butyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid;
and the like.
In accordance with the present invention the compounds of the formu].a I above and their pharmaceutically acceptable acid a~dition salts, and when A represents hydroxy~ also their 9~;Q~
1 pharmaceutically acceptable salts with a base, can be prepared by a process which comprises a) for preparincJ compounds of the formula I above wherein R4 represents halogen and Rl, R~ and R3 have the meaning indica-ted above, treating a compound of the general formula ~ COOR
X+ 11 11 ~ NH2 wherein R represents hydrogen or lower alkyl~and X
represents halogen, with a halopvridine derivative of the general formula lo R3~R 1 I
X ~ N ~
wherein Rl, R2, R3 and X have the meaning indicated above, or b) for preparing compounds of the formula I above wherein R4 represents cyano and Rl, R2 and R3 have the meaning indicated above, i.e. compounds of the general formula 'i~ "1 l~a 915~
1 wherein Rl, R2 and R3 have the meaning indicated above, treating a compound of the general formula X t , ,1~ R2 Ib wherein X represents bromine or iodine and Rl, R2 and R3 have the meaning indicated above, with cuprous cyanide, or c) for prepari.ng compounds of the formula I above wherein R4 represents a radical of the formula ~C-A wherein A represents hydroxy, i.e. compounds of the general formula HOOC ~ ; Ic wherein Rl, R2 and R3 have the meaning indicated above, treating a compound of the formula Ib above with nickel carbonyl under a carbon monoxide atmosphere in the presence of an alkaline earth hydroxide or hydrolyzing a compound of the formula Ia 1~ above, or d) for preparing compounds of the ~ormula I above wherein R4 represents a radical of the formula -C-A wherein A represents lower alkoxy and Rl, R2 and R3 have the meaning indicated above, esterifying a compound of the formula Ic above, or :' 1 e) for preparing compounds of the formula I above wherein R4 represents a radical of the formula -C-A wherein A represents a radical of the formula -NR5R6 and Rl, R2, 3, 5 6 the meaning indicated above, subjecting a compound of the formula Ic above to ammonolysis with an amino compound of the general formula ~NR5R6 IV
wherein R5 and R6 have the meaning indicated above, or f) for preparing compounds of the formula I above wherein R4 represents a radical of the formula -C-A wherein A represents di-(Cl-C7)alkylamino-(C2~C7)alkoxy and Rl, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a di-(Cl-C7)alkvlamino (C2-C7)alkyl halide or sub-jecting an acid chloride of a compound of the formula Ic above lS to alcoholysis with a di-(Cl-C7)alkylamino-(C2-C7)alkanol, or g) for preparing compounds of the formula I above wherein R4 represents 5-tetrazolyl and Rl, R2 and R3 have the meaning indicated above, treating a compound o:f the formula Ia above with an alkali metal azide, or h) for preparing compounds of the Eormula I above wherein R4 represents a radical of the formula -~ A wherein A represents pivaloyloxymethoxy and Rl, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a - g ~ !39 1 tertiary organic base and chloro~, bromo- or io'domethyl pivalate, and i) if desired, converting a compound obtained in-to a pharmaceu--tically acceptable salt.
~ lo~
1 According -to process embodiment a), an anthranilic acid or ester of formula II, a known compound or a compound which can be prepared according to known procedures, is reacted with a halopyridine of formula III, also a known compound or a com-pound which can be prepared according -to known procedures, at a temperature in the range of from about 100C. to about 200C., with or without a solvent. The reaction is conducted in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, potassium iodide,cesium iodide or the like. Solvents which may be utilized in the reaction are high boiling solvents such as acetic acid, diglyme, triglyme or the like. The reaction is conveniently carried out at atmos-pheric pressure. The reaction product can be recovered accor-din~ to known procedures, such as crystallization or the like.
According to process embodiment b), the bromo or iodo moiety of a compound of formula Ib can be converted -to a nitrile moiety by treating the compound of formula Ib with cuprous cyanide in an inert solvent such as l-methyl-2-pvrroli-dinone or the like, at or near the reflux tem~erature of the reaction mixture. Thereafter, the reaction mixture is treated with a solution of water, hydrochloric acid and ferric chloride.
The desired nitrile of formula Ia is recovered according to known procedures, such as crystallization or the like~
According to process embodiment c), a compound of the formula Ib can be converted to a compound of formula Ic by treating 1 the compound of formula Ib wi-th 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 in the range of 100C. to about 150C. The reaction conveniently can be carried out in a high boiling polar solvent such as dimethylformamide or the like. A compound of formula Ic can be recovered accordiny to known procedures, such as crystallization or the like.
Alternatively, a nitrile of formula Ia can be converted 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, propionic acid or the like.
According to process embodiment d), an acid of formula Ic can be converted to the corresponding ester by known procedures.
For instance, 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 utilizing known reaction conditions, for example, in an inert solvent such as dimethylformamide or the like, at a temperature in the range or from about room temperature to the reflux temperature of the reaction mixture.
According to process embodiment e), an acid of formula Ic can be converted to the corresponding amide by known proce-dures. For example, an acid as described above, is treated 1 with thionyl chloride whereby the corresponding acid chloride is obtained. The latter is then treated with the corresponding amine, for example, treated with ammonia, dimethylamine, 3-die-thylaminopropylamine or the like, in the presence of a solvent such as tetrahydrofuran. The desired amide is then recovered according to known procedures such as crystallization.
According to process embodiment f) r an acid of formula Ic, can be converted to the corresponding di-(cl-c7)alkylamino-(c2-c7)-alkvl ester by known procedures. For example, an acid as des-cribed above, is treated with the corresponding di-(Cl-C7)-alkylamino-(C2-C7)alkyl halide under reflux conditions in a solvent, for example, an alkanol such as isopropanol or the like, and the product is recovered according to ~nown proce-dures, such as crystallization; or said compound is treated with thionyl chloride whereby the corresponding acid chloride is obtained, the latter compound is reacted with a di-(Cl-C7)-alkylamino-(C2-C7)alkanol in an inert solvent, such as tetra-hydrofuran or the like, at a temperature in the range of from about 0C. to about 100C., and thereafter the desired end product is recovered by known procedures, such as crystalli-zation or the like.
~ccording to process embodiment g), a compound of formula I wherein P~4 is 5-tetrazolyl can be prepared from the corres-ponding compound of formula Ia. More specifically, the corres-ponding compound of formula Ia is treated with an al]cali metal .
- 13 - ~1~9~
1 azide, such as potassium azide, sodium azide or the like, in the presence of ammonium chloride. The reaction is suitably carried out in the presence of a solvent such as a polar aprotic solvent, for example, dimethylsulfoxide, dimethylforma- -mide or the like. The desired tetrazolyl compound is then reco-vered according to known procedures, for example, crystalli-zation or the like.
AccordincJ to process embodiment h), a compound of formula I wherein A is pivaloyloxymethoxy can be prepared by treating lo the corresponding compound of formula Ic with a tertiary orga-nic base, such as a tri-lower alkylamine and chloro-, bromo-or iodomethyl pivalate in an inert solvent such as dimethyl-formamide or the like, at a temperature in the range of from room temperature to about 120C~ The desired end product can be lS recovered according to known procedures, such as crystallization.
The compounds~of formula I wherein A is hydroxy, form phar-maceutically acceptable salts with bases. Exemplary 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 ethano-late and the like; organic bases such as piperidine, diethyl-amine, N-methylglucamine and the like.
The compounds of formula I also form pharmaceutically accep~
1 table salts with acids. Exemplary 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.
The compounds of formula I and their pharmaceutically acceptable salts inhibit cutaneous anaphylaxis in rats, and are therefore useful ln the prevention of allergic reactions, for example, they are useful in the prophylactic treatment of bronchial asthma. The anti-anaphylactic activity can be demon-strated by the passive cutaneous anaphylaxis assay ~PCA test) in the rat. This test 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-C2,1 b]quinazoliner is ~iven intraperitoneally followed after
5 minutes by an intravenous in]ection of reagen and Evans blue dye. The events associated with localized antigen-antibody reaction lead to the formation of skin wheals whose sizes are measured. The abilitv of the test compound to decrease the size of the wheals compared to controls is taken as a measure of its activity.
When a compound of the invention, such as 8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid is utilized as the test compound at a dose of 16 mg/kg intraperitoneally, the reduction in the wheal size is 81%.
- 15 ~ Q~
1 The compounds of formula I and their pharmaceutically acceptable salts can be administered orally or parenterally as anti-allergic agents, for example in the prophylactic treatment of bronchial asthma~ with dosage adjustments for individual requirements. They can be administered therapeutically, for example, orally or parenterally, by incorporating a therapeutic dosage in a conventional dosage form, such as -tablets, capsules, elixirs, suspensions, solutions or the like. They can be admini-stered in mixture with conventional pharmaceutical carriers or excipients, such as, for example, corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose and the like. Moreover, they can be administered in the presence of buffers, or agents used to adjust to isoto-nicity, and the pharmaceutical dosage forms can, if desired, be subjected to conventional pharmaceutical expedients such as, for example, sterilization. As stated above, the dosage can be adjusted to individual requirements. They can also contain other therapeutically valuable substances.
The quantity of active medicament which is present in any of the above described dosage forms is variable. It is preferred, however, to provide capsules or tablets containing from about 10 mg to about 20 mg of the formula I base or an equivalent amount of a medicinally acceptable salt thereof.
- 16 ~
1 The frequency with which any such dosage form will be administered to a patient will vary, depending upon the quantity of active medicament present therein and the needs and require-ments of the patient. Under ordinary circumstances, however, up to about 20 mg/kg. of the compound can be administered daily in several dosages~ It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this inven-tion.
lo The following Examples further illustrate the invention. All temperatures are in degrees Centigrade.
1 Exam~le 1 Preparation of 2-bromo-11-oxo=llH pyrido[2~l~b]~uinazoline hvdrochloride An intimate mixture of loo.o g of 2-chloropyridine, 83.0 g of 5-bromoar.thrarlilic acid and 1.0 g of potassium iodide was heated to a bath temperature of 145-150 overnight under a stream of argon. On cooling, the crude product was triturated wi-th 150 ml of boiling ethanol and was collected to give 105.4 g ~86%) of 2-bromo-11-oxo-llH-pyrido[2,1-b]quinazoline hydrochloride, mp 280-282 (dec.). The analytical sample was obtained from aqueous hydrochloric acid~dimethylformamide-ethanol and melted at 278-281 1 Example 2 Preparation of ll-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid A suspension of 15.00 g of 2-bromo-11-oxo-llH-pyrido-[2,1-b]quinazoline hydrochloride and 3.60 g of calcium hydroxide in 105 ml of 5% aqueous dimethylformamide was placed in a 6 oz. Fischer-Porter bottle and the atmosphere was repla-ced with carbon monoxide. Approximately 10 ml of nickel carbonyl was introduced through a syrinye needle and the carbon monoxide pressure was raised to 20 lbs~ As the bath temperature was raised to 110-115, the pressure rose to ~ 40 pounds and the yellow suspension became a green solution. After a total of 25 hours, the mixture was allowed to cool, was dilu-ted with 300 ml of 1~ hydrochloric acid and was filtered. The filter cake was triturated with hot ethanol-dimethvlformamide and the filtrate deposited 3.23 g of crude 11-oxo-llH-pyrido[2,1-b]-quinazoline-2-carboxylic acid, mp >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 an additional 3.37 g of 1.1-oxo-llH-pyrido[2~1-b]quinazoline-2-carboxylic acid, mp >310. The two crops were combined and triturated with ~- 19 ~
1 ethanol-dimethvlformamide-acetie aeid to give 6.35 g (48~) of 11-oxo-llH-pyrido[2,1-b~quinazoline-2-carboxylic acid, mp 354.
Example 3 Preparation of 8-methyl~ oxo-llH-pyrido[2,1-b]~uinazoline-2-carboxylic aeid An in-timate mixture of 5~0 g of 5-bromoanthranilie aeid,
When a compound of the invention, such as 8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid is utilized as the test compound at a dose of 16 mg/kg intraperitoneally, the reduction in the wheal size is 81%.
- 15 ~ Q~
1 The compounds of formula I and their pharmaceutically acceptable salts can be administered orally or parenterally as anti-allergic agents, for example in the prophylactic treatment of bronchial asthma~ with dosage adjustments for individual requirements. They can be administered therapeutically, for example, orally or parenterally, by incorporating a therapeutic dosage in a conventional dosage form, such as -tablets, capsules, elixirs, suspensions, solutions or the like. They can be admini-stered in mixture with conventional pharmaceutical carriers or excipients, such as, for example, corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc, lactose and the like. Moreover, they can be administered in the presence of buffers, or agents used to adjust to isoto-nicity, and the pharmaceutical dosage forms can, if desired, be subjected to conventional pharmaceutical expedients such as, for example, sterilization. As stated above, the dosage can be adjusted to individual requirements. They can also contain other therapeutically valuable substances.
The quantity of active medicament which is present in any of the above described dosage forms is variable. It is preferred, however, to provide capsules or tablets containing from about 10 mg to about 20 mg of the formula I base or an equivalent amount of a medicinally acceptable salt thereof.
- 16 ~
1 The frequency with which any such dosage form will be administered to a patient will vary, depending upon the quantity of active medicament present therein and the needs and require-ments of the patient. Under ordinary circumstances, however, up to about 20 mg/kg. of the compound can be administered daily in several dosages~ It is to be understood, however, that the dosages set forth therein are exemplary only and that they do not, to any extent, limit the scope or practice of this inven-tion.
lo The following Examples further illustrate the invention. All temperatures are in degrees Centigrade.
1 Exam~le 1 Preparation of 2-bromo-11-oxo=llH pyrido[2~l~b]~uinazoline hvdrochloride An intimate mixture of loo.o g of 2-chloropyridine, 83.0 g of 5-bromoar.thrarlilic acid and 1.0 g of potassium iodide was heated to a bath temperature of 145-150 overnight under a stream of argon. On cooling, the crude product was triturated wi-th 150 ml of boiling ethanol and was collected to give 105.4 g ~86%) of 2-bromo-11-oxo-llH-pyrido[2,1-b]quinazoline hydrochloride, mp 280-282 (dec.). The analytical sample was obtained from aqueous hydrochloric acid~dimethylformamide-ethanol and melted at 278-281 1 Example 2 Preparation of ll-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid A suspension of 15.00 g of 2-bromo-11-oxo-llH-pyrido-[2,1-b]quinazoline hydrochloride and 3.60 g of calcium hydroxide in 105 ml of 5% aqueous dimethylformamide was placed in a 6 oz. Fischer-Porter bottle and the atmosphere was repla-ced with carbon monoxide. Approximately 10 ml of nickel carbonyl was introduced through a syrinye needle and the carbon monoxide pressure was raised to 20 lbs~ As the bath temperature was raised to 110-115, the pressure rose to ~ 40 pounds and the yellow suspension became a green solution. After a total of 25 hours, the mixture was allowed to cool, was dilu-ted with 300 ml of 1~ hydrochloric acid and was filtered. The filter cake was triturated with hot ethanol-dimethvlformamide and the filtrate deposited 3.23 g of crude 11-oxo-llH-pyrido[2,1-b]-quinazoline-2-carboxylic acid, mp >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 an additional 3.37 g of 1.1-oxo-llH-pyrido[2~1-b]quinazoline-2-carboxylic acid, mp >310. The two crops were combined and triturated with ~- 19 ~
1 ethanol-dimethvlformamide-acetie aeid to give 6.35 g (48~) of 11-oxo-llH-pyrido[2,1-b~quinazoline-2-carboxylic acid, mp 354.
Example 3 Preparation of 8-methyl~ oxo-llH-pyrido[2,1-b]~uinazoline-2-carboxylic aeid An in-timate mixture of 5~0 g of 5-bromoanthranilie aeid,
6.7 g of 2-ehloro-5~methylpyridine, and 67 mg of potassium iodide was heated to a bath temperature of 145 for 8 hours. On 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-llH-pyrido[2,1-b]quinazoline, m~ 277-281.
A mixture of 3.00 g of the above pyridoquinazoline and 0.73 g of calcium hydroxide in 21 ml o~ 5~ aqueous dimethyl-formamide was plaeed in a 3 ounee, Fiseher-Porter bottle under a carbon monoxide atmosphere. Approximately 3 ml of niekel earbonyl was added and the bottle was pressurized to 20 pounds with carbon monoxide. ~he bath temperature was raised to 115 for 24 hours and on eooling, the mixture was diluted with 15 ml of 6N hydroehlorie aeid. After stirring overnight, the suspen-sion was filtered and the solid eollected was recrystallized from dimethylformamide and from dimethyl~ormamide-ether to give 1.54 g (67~) of 8-methyl-11-oxo-llH-pyrido~2,1-b]quinazoline~2-Q earboxylie acid, mp 359.
1 ExampLe 4 Preparation of 2-chloro-5-(l-hydroxy-l-methylethy~e~-idine .
75 ml of phosphorous oxychloride and 144 g of phosphorous pentachloride were added to 100 g of 6-chloronicotinic acid and intimately 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 Eor 1 hour. After concentration under reduced pres-sure, anhydrous toluene was added and the solution was concen-trated again, finally on the oil pump, to yield 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 pouring the cooled reaction mixture carefully into ice and 200 ml of acetic acid, the aqueous layer was made hasic (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 ethylace~ate-hexane gave 44~5 g, mp 70-74, of 2-chloro-5~ hydroxy-1-methylethyl)-pyridine in the first crop. A second crop of 2-chloro-5-(l-hydroxy-l-methylethyl)pyridine (46.7 g, mp 67-71) was obtained from ether-hexane.
1 Example 5 Preparation of 2-chloro~5-isopropenylpyridine A solution of 92.6 g of 2-chloro-5-(1-hydroxy-1-methyl-ethyl)pyridine, 4.6 g of p-toluenesulfonic acid monohydrate and 0.9 g of hydroquinone in 1.5 1 of anhydrous xylene was stirred and ref~uxed under a Dean-Stark water separatox for 4.5 hours.
The xylene solution was washed with saturated sodium bicar-bonate solution and dried over anhydrous magnesium sulfate.
The xylene was removed by distillation (~0-48/14 mm) through a Claisen head. Distillation of the residual oil through a vigreux column gave 75.6 g of pure 2-chloro-5-isopropenyl-pyridine, 110-114/8 mm.
Example 6 Preparatlon 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 1. of ethanol was shaken at atmos-pheric pressure in a hydrogen atmosphere for 1 hour 45 minutes.
The catalyst was removed by fil-tration and the filtrate was concentrated in vacuo to yield an oil~ Distillation through a vigreux column gave 76.0 g of pure 2-chloro~5-isopropylpyridine, 105-109/8 mm.
Example 7 ion of 2-bromo~8-isopropyl-11-oxo-11~1-pyrldo[2,1-b]-quina~oline A mixture of 58.5 g of 5-bromoanthranilic acid, 42.2 g of -- 22 ~ 95~
1 2-chloro-5-isopropylpyridine and 1.7 g of powdered potassium iodide was stirred and heated at 170 under argon for 40 minu-tes. The bath temperature was lowered -to 165 for 4.5 hours and then to 155 for 7 hours. The solid purple cake was -tritu-rated with 250 ml of chloroform, stirred in an ice bath, and filtered to yield the product (34.~ g) as the hydrochloride.
This was suspended in 500 ml of saturated sodium bicarbonate solution and extracted with methylene chloride. The combined extract was dried over anhydrous magnesium sulfate, stirred briefly with charcoal9 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-llH-pyrido-[2,1-b]~uinazoline, mp 191-194, in two crops.
Example 8 Preparation of ~-isopropyl-ll-oxo-llH-~yridol2,1-b]quinazoline-2-carbox~lic acid A mixture of 21.75 g oE 2-bromo-~-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline and 5.08 g of calcium hydroxide in 200 ml dimethy:Lformamide and 20 ml of water was placed in a Fischer-Porter bottle under a carbon monoxide atmosphere.
Appro~imately 20 ml of nickel carbonyl was added and the bottle was pressurized to 20 p.s.i. 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 1 o~
water and 30 ml of 6~ hydrochloric acid. After stirring over-night, the suspension was filtered and th~ resultant solid was taken up in dimethylformamide and filtered. The Eiltrate was - 23 ~
1 concen-trated in vacuo on the oil pump to a yellow solid. ~ater was added along 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-isopro-pyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid, mp 312-316.
Example 9 Prepara-tion of 2-cyano-8-isopropyl-ll-oxo-llH-pvrido[2/l-b]~
quinazoline lo A solution of 0.412 g of 2-bromo-8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline and 0.233 g of cuprous cyanide in 5 ml of 1 methyl-2-pyrrolidinone was stirred and heated at 180 for 10 hours. A solution of 0.52 g of ferric chloride hexahydrate, 0.13 ml 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 was extracted with chloroform. The extract was washed with lN
hydrochloric acid, lN sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate and concentrated to a yellow solid which also contained some l-methyl 2-pyrrolidinone.
Ether was added and the product was separated by filtration to give 0.240 g, mp 207-211, of 2-cyano-8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline. Preparative tlc gave the pure com-pound, mp 212-214.
1 Example 10 Preparation of 8-isopropyl~ oxo-llH-~yrido[2,1-b]~uinazoline-2-carboxylic acid A solution of 0.084 g of 2~cyano-8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline in 1 ml of acetic acid, 1 ml of concen-trated sulfuric acid and 1 ml of water was stirred and refluxed for ~5 minutes. The solu-tion was concentrated on the oil pump to a small volume. After cooling in an ice bath, 50 ml of sa-tu-ra-ted sodium biearbonate was added carefully. The mixture was then acidified wi-th acetic acid and the resultant solid was fil-tered and washed with water to yield 0.063 g, mp 313-314, of pure 8-isopropyl ll-oxo-llH-pyrido[2,1-b~quinazoline-2-carboxylic acid.
Exam~le 11 ~reparation of 8-isoprop~l-ll-oxo-llH-pyrido[2~l-b]qu-i-nazoline 2-car~o ethylaminoeth ~ ter_hydrochloride 0~86 g of 2-diethylaminoethyl chloride was dissolved in 5 ml of water and 5 ml of saturated sodium bicarbonate solu-tion was added and stirred in an iee bath for 5 minutes. This solution was extraeted with ether, the extraet was 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-llH~pyrido[2,1-b]quinazoline-2-carbox~lie acid in 10 ml of anhydrous isopropanol and the reaetion mixture was stirred and refluxed for 3 hours. After cooling to room temperature~ the produet was removed by filtra-t~on ancl - 25 ~
purified by crystallization from isopropanol and then from methylene chloride ether to give ~.25 g of pure 8-isopropy].~
ll~oxo-llH-pyrido[2,1-b]quinazoline 2-carboxylic acid-(2-diethylaminoethyl)ester hydrochloride, mp 238-239.
- 26 ~ 5~
1 Example 12 Capsule Formulation mg/capsule 10 mg 20 mg Active ingredient of formula I 10.0 20.0 Lactose 215.0 205.0 Cornstarch 60.0 60.0 Magnesium Stearate 3.0 3.0 Talc 12.0 _2.0 Total 300 mg300 mg Procedure:
.... _ Mix the act:Lve ingredient of formula I, lactose and cornstarch in a suitable m:ixer. Mill through suitable mill.
Mix with magnesium stearate and talc and fill on capsule machine.
- 27 - ~ 9 1 Example 13 Tablet Formulation mg/tablet __ 10 mg 20 mg Active ingredient of formula I 10.0~ 20.0 Lactose 182.0 172.0 Microcrystalline Cellulose 60.0 60.0 Modified Starch 15.0 15.0 Cornstarch 30.0 30.0 Magnesium Stearate 3.0 3.0 . . ~ .
Total300 mg 300 mg Procedure:
Mix the active ingredient of formula I, ]actose, micro-crystalline cellulose, modified starch and cornstarch in a suitable mixer for 1 to 15 minutes. Then, add magnesium stearate and mix for 5 minutes. Compress on a suitable press.
- 28 ~ 3~
1 Exam~le 14 We-t Granulation Tablet Formulation , . _, .
mg!tablet__ _ lO mg 20 mg Active ingredient of formula I 10.0 20.0 Lactose 264.0 254.0 Pregelatinized Starch 17.5 17.5 Cornstarch 35.0 35.0 Modified Starch 17.5 17.5 Magnesium Stearate 6.0 6.0 Total 350 mg 350 mg Procedure:
Mix -the active ingredient of formula I, lactose and pregelatinized starch in a suitable mixer. Mill through suitable mill. Mix with modified starch and magnesium stearate and fill on capsule machine.
A mixture of 3.00 g of the above pyridoquinazoline and 0.73 g of calcium hydroxide in 21 ml o~ 5~ aqueous dimethyl-formamide was plaeed in a 3 ounee, Fiseher-Porter bottle under a carbon monoxide atmosphere. Approximately 3 ml of niekel earbonyl was added and the bottle was pressurized to 20 pounds with carbon monoxide. ~he bath temperature was raised to 115 for 24 hours and on eooling, the mixture was diluted with 15 ml of 6N hydroehlorie aeid. After stirring overnight, the suspen-sion was filtered and the solid eollected was recrystallized from dimethylformamide and from dimethyl~ormamide-ether to give 1.54 g (67~) of 8-methyl-11-oxo-llH-pyrido~2,1-b]quinazoline~2-Q earboxylie acid, mp 359.
1 ExampLe 4 Preparation of 2-chloro-5-(l-hydroxy-l-methylethy~e~-idine .
75 ml of phosphorous oxychloride and 144 g of phosphorous pentachloride were added to 100 g of 6-chloronicotinic acid and intimately 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 Eor 1 hour. After concentration under reduced pres-sure, anhydrous toluene was added and the solution was concen-trated again, finally on the oil pump, to yield 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 pouring the cooled reaction mixture carefully into ice and 200 ml of acetic acid, the aqueous layer was made hasic (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 ethylace~ate-hexane gave 44~5 g, mp 70-74, of 2-chloro-5~ hydroxy-1-methylethyl)-pyridine in the first crop. A second crop of 2-chloro-5-(l-hydroxy-l-methylethyl)pyridine (46.7 g, mp 67-71) was obtained from ether-hexane.
1 Example 5 Preparation of 2-chloro~5-isopropenylpyridine A solution of 92.6 g of 2-chloro-5-(1-hydroxy-1-methyl-ethyl)pyridine, 4.6 g of p-toluenesulfonic acid monohydrate and 0.9 g of hydroquinone in 1.5 1 of anhydrous xylene was stirred and ref~uxed under a Dean-Stark water separatox for 4.5 hours.
The xylene solution was washed with saturated sodium bicar-bonate solution and dried over anhydrous magnesium sulfate.
The xylene was removed by distillation (~0-48/14 mm) through a Claisen head. Distillation of the residual oil through a vigreux column gave 75.6 g of pure 2-chloro-5-isopropenyl-pyridine, 110-114/8 mm.
Example 6 Preparatlon 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 1. of ethanol was shaken at atmos-pheric pressure in a hydrogen atmosphere for 1 hour 45 minutes.
The catalyst was removed by fil-tration and the filtrate was concentrated in vacuo to yield an oil~ Distillation through a vigreux column gave 76.0 g of pure 2-chloro~5-isopropylpyridine, 105-109/8 mm.
Example 7 ion of 2-bromo~8-isopropyl-11-oxo-11~1-pyrldo[2,1-b]-quina~oline A mixture of 58.5 g of 5-bromoanthranilic acid, 42.2 g of -- 22 ~ 95~
1 2-chloro-5-isopropylpyridine and 1.7 g of powdered potassium iodide was stirred and heated at 170 under argon for 40 minu-tes. The bath temperature was lowered -to 165 for 4.5 hours and then to 155 for 7 hours. The solid purple cake was -tritu-rated with 250 ml of chloroform, stirred in an ice bath, and filtered to yield the product (34.~ g) as the hydrochloride.
This was suspended in 500 ml of saturated sodium bicarbonate solution and extracted with methylene chloride. The combined extract was dried over anhydrous magnesium sulfate, stirred briefly with charcoal9 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-llH-pyrido-[2,1-b]~uinazoline, mp 191-194, in two crops.
Example 8 Preparation of ~-isopropyl-ll-oxo-llH-~yridol2,1-b]quinazoline-2-carbox~lic acid A mixture of 21.75 g oE 2-bromo-~-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline and 5.08 g of calcium hydroxide in 200 ml dimethy:Lformamide and 20 ml of water was placed in a Fischer-Porter bottle under a carbon monoxide atmosphere.
Appro~imately 20 ml of nickel carbonyl was added and the bottle was pressurized to 20 p.s.i. 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 1 o~
water and 30 ml of 6~ hydrochloric acid. After stirring over-night, the suspension was filtered and th~ resultant solid was taken up in dimethylformamide and filtered. The Eiltrate was - 23 ~
1 concen-trated in vacuo on the oil pump to a yellow solid. ~ater was added along 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-isopro-pyl-11-oxo-llH-pyrido[2,1-b]quinazoline-2-carboxylic acid, mp 312-316.
Example 9 Prepara-tion of 2-cyano-8-isopropyl-ll-oxo-llH-pvrido[2/l-b]~
quinazoline lo A solution of 0.412 g of 2-bromo-8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline and 0.233 g of cuprous cyanide in 5 ml of 1 methyl-2-pyrrolidinone was stirred and heated at 180 for 10 hours. A solution of 0.52 g of ferric chloride hexahydrate, 0.13 ml 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 was extracted with chloroform. The extract was washed with lN
hydrochloric acid, lN sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate and concentrated to a yellow solid which also contained some l-methyl 2-pyrrolidinone.
Ether was added and the product was separated by filtration to give 0.240 g, mp 207-211, of 2-cyano-8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline. Preparative tlc gave the pure com-pound, mp 212-214.
1 Example 10 Preparation of 8-isopropyl~ oxo-llH-~yrido[2,1-b]~uinazoline-2-carboxylic acid A solution of 0.084 g of 2~cyano-8-isopropyl-11-oxo-llH-pyrido[2,1-b]quinazoline in 1 ml of acetic acid, 1 ml of concen-trated sulfuric acid and 1 ml of water was stirred and refluxed for ~5 minutes. The solu-tion was concentrated on the oil pump to a small volume. After cooling in an ice bath, 50 ml of sa-tu-ra-ted sodium biearbonate was added carefully. The mixture was then acidified wi-th acetic acid and the resultant solid was fil-tered and washed with water to yield 0.063 g, mp 313-314, of pure 8-isopropyl ll-oxo-llH-pyrido[2,1-b~quinazoline-2-carboxylic acid.
Exam~le 11 ~reparation of 8-isoprop~l-ll-oxo-llH-pyrido[2~l-b]qu-i-nazoline 2-car~o ethylaminoeth ~ ter_hydrochloride 0~86 g of 2-diethylaminoethyl chloride was dissolved in 5 ml of water and 5 ml of saturated sodium bicarbonate solu-tion was added and stirred in an iee bath for 5 minutes. This solution was extraeted with ether, the extraet was 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-llH~pyrido[2,1-b]quinazoline-2-carbox~lie acid in 10 ml of anhydrous isopropanol and the reaetion mixture was stirred and refluxed for 3 hours. After cooling to room temperature~ the produet was removed by filtra-t~on ancl - 25 ~
purified by crystallization from isopropanol and then from methylene chloride ether to give ~.25 g of pure 8-isopropy].~
ll~oxo-llH-pyrido[2,1-b]quinazoline 2-carboxylic acid-(2-diethylaminoethyl)ester hydrochloride, mp 238-239.
- 26 ~ 5~
1 Example 12 Capsule Formulation mg/capsule 10 mg 20 mg Active ingredient of formula I 10.0 20.0 Lactose 215.0 205.0 Cornstarch 60.0 60.0 Magnesium Stearate 3.0 3.0 Talc 12.0 _2.0 Total 300 mg300 mg Procedure:
.... _ Mix the act:Lve ingredient of formula I, lactose and cornstarch in a suitable m:ixer. Mill through suitable mill.
Mix with magnesium stearate and talc and fill on capsule machine.
- 27 - ~ 9 1 Example 13 Tablet Formulation mg/tablet __ 10 mg 20 mg Active ingredient of formula I 10.0~ 20.0 Lactose 182.0 172.0 Microcrystalline Cellulose 60.0 60.0 Modified Starch 15.0 15.0 Cornstarch 30.0 30.0 Magnesium Stearate 3.0 3.0 . . ~ .
Total300 mg 300 mg Procedure:
Mix the active ingredient of formula I, ]actose, micro-crystalline cellulose, modified starch and cornstarch in a suitable mixer for 1 to 15 minutes. Then, add magnesium stearate and mix for 5 minutes. Compress on a suitable press.
- 28 ~ 3~
1 Exam~le 14 We-t Granulation Tablet Formulation , . _, .
mg!tablet__ _ lO mg 20 mg Active ingredient of formula I 10.0 20.0 Lactose 264.0 254.0 Pregelatinized Starch 17.5 17.5 Cornstarch 35.0 35.0 Modified Starch 17.5 17.5 Magnesium Stearate 6.0 6.0 Total 350 mg 350 mg Procedure:
Mix -the active ingredient of formula I, lactose and pregelatinized starch in a suitable mixer. Mill through suitable mill. Mix with modified starch and magnesium stearate and fill on capsule machine.
Claims (39)
1. A process for the manufacture of novel pyrido[2,1-b]-quinazoline derivatives of the general formula I
wherein R1, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula , wherein A represents hydroxy, lower alkoxy, di-(C1-C7)-alkylamino-(C2-C7)alkoxy, pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(C1-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when R1, 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, which process comprises a) for preparing compounds of the formula I above wherein R4 represents halogen and R1, R2 and R3 have the meaning indica-ted above, treating a compound of the general formula II
wherein R represents hydrogen or lower alkyl and X
represents halogen, with a halopyridine derivative of the general formula III
wherein R1, R2, R3 and X have the meaning indicated above, or b) for preparing compounds of the formula I above wherein R4 represents cyano and R1, R2 and R3 have the meaning indicated above, i.e. compounds of the general formula Ia wherein R1, R2 and R3 have the meaning indicated above, treating a compound of the general formula Ib wherein X' represents bromine or iodine and R1, R2 and R3 have the meaning indicated above, with cuprous cyanide, or c) for preparing compounds of the formula I above wherein R4 represents a radical. of the formula wherein A represents hydroxy, i.e. compounds of the general formula Ic wherein R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ib above with nickel carbonyl under a carbon monoxide atmosphere in the presence of an alkaline earth hydroxide or hydxolyzing a compound of the formula Ia above, or d) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents lower alkoxy and R1, R2 and R3 have the meaning indicated above, esterifying a compound of the formula Ic above, or e) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents a radical of the formula -NR5R6 and R1, R2, R3, R5 and R6 have the meaning indicated above, subjecting a compound of the formula Ic above to ammonolysis with an amino compound of the general formula wherein R5 and R6 have the meaning indicated above, or f) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents di-(C1-C7)alkylamino-(C2-C7)alkoxy and R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a di-(C1-C7)alkylamino-(C2-C7)alkyl halide or sub-jecting an acid chloride of a compound of the formula Ic above to alcoholysis with a di-(C1-C7)alkylamino-(C2-C7)alkanol, or g) for preparing compounds of the formula I above wherein R4 represents 5-tetrazolyl and R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ia above with an alkali metal azide, or h) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents pivaloyloxymethoxy and R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a tertiary organic base and chloro-, bromo- or iodomethyl pivalate, and i) if desired, converting a compound obtained into a pharma-ceutically acceptable salt.
wherein R1, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula , wherein A represents hydroxy, lower alkoxy, di-(C1-C7)-alkylamino-(C2-C7)alkoxy, pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(C1-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when R1, 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, which process comprises a) for preparing compounds of the formula I above wherein R4 represents halogen and R1, R2 and R3 have the meaning indica-ted above, treating a compound of the general formula II
wherein R represents hydrogen or lower alkyl and X
represents halogen, with a halopyridine derivative of the general formula III
wherein R1, R2, R3 and X have the meaning indicated above, or b) for preparing compounds of the formula I above wherein R4 represents cyano and R1, R2 and R3 have the meaning indicated above, i.e. compounds of the general formula Ia wherein R1, R2 and R3 have the meaning indicated above, treating a compound of the general formula Ib wherein X' represents bromine or iodine and R1, R2 and R3 have the meaning indicated above, with cuprous cyanide, or c) for preparing compounds of the formula I above wherein R4 represents a radical. of the formula wherein A represents hydroxy, i.e. compounds of the general formula Ic wherein R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ib above with nickel carbonyl under a carbon monoxide atmosphere in the presence of an alkaline earth hydroxide or hydxolyzing a compound of the formula Ia above, or d) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents lower alkoxy and R1, R2 and R3 have the meaning indicated above, esterifying a compound of the formula Ic above, or e) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents a radical of the formula -NR5R6 and R1, R2, R3, R5 and R6 have the meaning indicated above, subjecting a compound of the formula Ic above to ammonolysis with an amino compound of the general formula wherein R5 and R6 have the meaning indicated above, or f) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents di-(C1-C7)alkylamino-(C2-C7)alkoxy and R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a di-(C1-C7)alkylamino-(C2-C7)alkyl halide or sub-jecting an acid chloride of a compound of the formula Ic above to alcoholysis with a di-(C1-C7)alkylamino-(C2-C7)alkanol, or g) for preparing compounds of the formula I above wherein R4 represents 5-tetrazolyl and R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ia above with an alkali metal azide, or h) for preparing compounds of the formula I above wherein R4 represents a radical of the formula wherein A represents pivaloyloxymethoxy and R1, R2 and R3 have the meaning indicated above, treating a compound of the formula Ic above with a tertiary organic base and chloro-, bromo- or iodomethyl pivalate, and i) if desired, converting a compound obtained into a pharma-ceutically acceptable salt.
2. A process as claimed in Claim 1 wherein R1, R2 and R3 independently represent hydrogen or lower alkyl.
3. A process as claimed in Claim 2 wherein at least two of R1, R2 and R3 are other than hydrogen.
4. A process as claimed in Claim 2 wherein R4 represents a radical of the formula wherein A represents di-(C1-C7)alkylamino-(C2-C7)alkoxy or pivaloyloxymethoxy.
5. A process as claimed in Claim 3 wherein R4 represents a radical of the formula wherein A
represents di-(C1-C7)alkylamino-(C2-C7)alkoxy or pivaloyloxy-methoxy.
represents di-(C1-C7)alkylamino-(C2-C7)alkoxy or pivaloyloxy-methoxy.
6. A process as claimed in Claim 1 wherein at least one of R1, R2 and R3 represents lower alkanoyl.
7. A process as claimed in Claim 1 wherein R2 and R3 represent hydrogen.
8. A process as claimed in Claim 2 wherein R2 and R3 represent hydrogen.
9. A process as claimed in Claim 4 wherein R2 and R3 represent hydrogen.
10. A process as claimed in Claim 5 wherein R2 and R3 represent hydrogen.
11. A process as claimed in Claim 1 wherein R1 represents hydrogen or lower alkyl.
12. A process as claimed in Claim 7 wherein R1 represents hydrogen or lower alkyl.
13. A process as claimed in Claim 11 wherein R1 represents lower alkyl.
14. A process as claimed in Claim 1, wherein R4 represents a radical of the formula .
15. A process as claimed in Claim 2, wherein R4 represents a radical of the formula .
16. A process as claimed in Claim 3, wherein R4 represents a radical of the formula .
17. A process as claimed in Claim 1, wherein R4 represents a radical of the formula , wherein A represents hydroxy or di-(C1-C7)alkylamino-(C2-C7)alkoxy.
18. A process as claimed in Claim 2, wherein R4 represents a radical of the formula , wherein A represents hydroxy or di-(C1-C7)alkylamino-(C2-C7)alkoxy.
19. A process as claimed in Claim 3, wherein R4 represents a radical of the formula , wherein A represents hydroxy or di-(C1-C7)alkylamino-(C2-C7)alkoxy.
20. A process as claimed in Claim 1 wherein R2 and R3 represents hydrogen, R1 represents lower alkyl and R4 represents a radical of the formula .
21. A process as claimed in Claim 1 wherein R2 and R3 represent hydrogen, R1 represents hydrogen, lower alkyl or lower alkanoyl and R4 represents a radical of the formula wherein A represents di-(C1-C7)alkylamino(C2-C7)alkoxy.
22. A process as claimed in Claim 2, wherein 2-bromo-8-methyl-11-oxo-11H-pyrido[2,1-b]quinazoline is treated with nickel carbonyl, to prepare 8-methyl-11-oxo-11H-pyrido[2,1-b]
quinazoline-2-carboxylic acid.
quinazoline-2-carboxylic acid.
23. A process as claimed in Claim 2, wherein 2-bromo-8-isopropyl-11-oxo-11H-pyrido[2,1-b]uinazoline is treated with nickel carbonyl or 2-cyano-8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline is hydrolyzed, to prepare 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid.
24. A process as claimed in Claim 12, wherein 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid is treated with 2-diethylaminoethyl chloride, to prepare 8-isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid (2-diethylaminoethyl)ester.
25. Novel pyrido[2,1-b]quinazoline derivatives of the general formula I
wherein R1, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula .
wherein A represents hydroxy, lower alkoxy, di-(C1-C7)-alkylamino-(C2-C7)alkoxy, pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(C1-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when R1, 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, whenever prepared according to the process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
wherein R1, R2 and R3 independently represent hydrogen, lower alkanoyl or lower alkyl and R4 represents cyano, 5-tetrazolyl, halogen or a radical of the formula .
wherein A represents hydroxy, lower alkoxy, di-(C1-C7)-alkylamino-(C2-C7)alkoxy, pivaloyloxymethoxy or -NR5R6, wherein R5 and R6 independently represent hydrogen, lower alkyl or di-(C1-C7)alkylamino-(C2-C7)alkyl, with the proviso that R4 is other than halogen when R1, 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, whenever prepared according to the process as claimed in Claim 1 or by an obvious chemical equivalent thereof.
26. Compounds as claimed in Claim 25 wherein R1, R2 and R3 independently represent hydrogen or lower alkyl, whenever prepared according to the process as claimed in Claim 2 or by an obvious chemical equivalent thereof.
27. Compounds as claimed in Claim 25 wherein R1, R2 and R3 independently represent hydrogen or lower alkyl, wherein at least two of R1, R2 and R3 are lower alkyl, whenever prepared according to the process as claimed in Claim 3 or by an obvious chemical equivalent thereof.
28. Compounds as claimed in Claim 25 wherein R1, R2 and R3 independently represent hydrogen or lower alkyl, wherein R4 represents a radical of the formula wherein A represents di-(C1-C7)alkylamino-(C2-C7)alkoxy or pivaloyl-oxymethoxy, whenever prepared according to the process as claimed in Claim 4 or by an obvious chemical equivalent thereof.
29. Compounds as claimed in Claim 25 wherein at least one of R1, R2 and R3 represents lower alkanoyl, whenever prepared according to the process as claimed in Claim 6 or by an obvious chemical equivalent thereof.
30. Compounds as claimed in Claim 25 wherein R2 and R3 represent hydrogen, whenever prepared according to the process as claimed in Claim 7 or by an obvious chemical equivalent thereof.
31. Compounds as claimed in Claim 25 wherein R1 represents hydrogen or lower alkyl, whenever prepared according to the process as claimed in Claim 11 or by an obvious chemical equivalent thereof.
32. Compounds as claimed in Claim 25 wherein R1 represents lower alkyl, whenever prepared according to the process as claimed in Claim 13 or by an obvious chemical equivalent thereof.
33. Compounds as claimed in Claim 25 wherein R4 represents a radical of the formula , whenever prepared according to the process as claimed in Claim 14 or by an obvious chemical equivalent thereof.
34. Compounds as claimed in Claim 25 wherein R4 represents a radical of the formula , and wherein A
represents hydroxy or di-(C1-C7)alkylamino-(C2-C7)alkoxy, whenever prepared according to the process as claimed in Claim 17 or by an obvious chemical equivalent thereof.
represents hydroxy or di-(C1-C7)alkylamino-(C2-C7)alkoxy, whenever prepared according to the process as claimed in Claim 17 or by an obvious chemical equivalent thereof.
35. Compounds as claimed in Claim 25 wherein R2 and R3 represent hydrogen, R1 represents lower alkyl and R4 represents a radical of the formula , whenever prepared according to the process as claimed in Claim 20 or by an obvious chemical equivalent thereof.
36. Compounds as claimed in Claim 25 wherein R2 and R3 represent hydrogen, R1 represents hydrogen, lower alkyl or lower alkanoyl and R4 represents a radical of the formula wherein A represents di-(C1-C7)alkylamino-(C2-C7)alkoxy, whenever prepared according to the process as claimed in Claim 21 or by an obvious chemical equivalent thereof.
37. 8-Methyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, whenever prepared according to the process as claimed in Claim 22 or by an obvious chemical equivalent thereof.
38. 8-Isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid, whenever prepared according to the process as claimed in Claim 23 or by an obvious chemical equivalent thereof.
39. 8-Isopropyl-11-oxo-11H-pyrido[2,1-b]quinazoline-2-carboxylic acid-(2-diethylaminoethyl)ester, whenever prepared according to the process as claimed in Claim 24 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000299683A CA1189509A (en) | 1978-03-23 | 1978-03-23 | Substituted 11-oxo-11h-pyrido [2,1-b] quinazolines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000299683A CA1189509A (en) | 1978-03-23 | 1978-03-23 | Substituted 11-oxo-11h-pyrido [2,1-b] quinazolines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1189509A true CA1189509A (en) | 1985-06-25 |
Family
ID=4111066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000299683A Expired CA1189509A (en) | 1978-03-23 | 1978-03-23 | Substituted 11-oxo-11h-pyrido [2,1-b] quinazolines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1189509A (en) |
-
1978
- 1978-03-23 CA CA000299683A patent/CA1189509A/en not_active Expired
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