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GB1601371A - Pyridol(2,1-b)quinazoline derivatives - Google Patents

Pyridol(2,1-b)quinazoline derivatives Download PDF

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GB1601371A
GB1601371A GB11704/78A GB1170478A GB1601371A GB 1601371 A GB1601371 A GB 1601371A GB 11704/78 A GB11704/78 A GB 11704/78A GB 1170478 A GB1170478 A GB 1170478A GB 1601371 A GB1601371 A GB 1601371A
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quinazoline
oxo
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
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    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/59—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Description

(54) PYRIDO[2, 1-biQUINAZOLINE DERIVATIVES (71) We, F. HOFFMANIA-LA ROCHE & CO., AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to pyrido[2, l-b]quinazoline derivatives. More particularly, the invention is concerned with pyrido[2,1-blquinazoline derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.
The pyrido[2, 1 -b]quinazoline derivatives provided by the present invention are compounds of the general formula
wherein R, R2 and R3 each independently represent a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkylthio, cyclopropyl, cyclobutyl or hydroxy group and R4 represents a cyano, 5-tetrazolyl, hydroxy-(lower alkyl) or acyloxy (lower alkyl) group or a group of the formula
in which A represents a lower alkyl, hydroxy, lower alkoxy, di(C1-C7 alkyl)amino (C7,C, alkoxy) or pivaloyloxymethyl group or a group of the formula
in which R5 and R6 each independently represent a hydrogen atom or a lower alkyl or di(C1-C7 alkylamino-(C2-C7 alkyl) group, Y represents a hydrogen atom or a methyl group and n stands for zero or 1, with the proviso that at least one of R1, R2 and R3 represents other than a hydrogen atom and with the proviso that at least one of R1, R2 and R3 represents a lower alkylthio, cyclopropyl or cyclobutyl group and/or R4 represents an acyloxy-(lower alkyl) group or a group of the formula
in which A, Y and n have the significance given above, except that in the case where n stands for zero, A cannot represent a hydroxy or lower alkoxy group or the group of the formula
said provisos not acting to exclude compounds of general formula I wherein (a) R4 represents a carboxy group in the 8-position and either (aa) R, represents ethyl, isopropyl, butyl, ethoxy, propoxy, isopropoxy, butoxy or amyloxy and R2 and R3 represent hydrogen or (ab) R1 represents hydrogen and either one of R2 and R3 represents methoxy and the other represents hydrogen or R2 represents hydrogen and R3 represents chlorine or (ac) R1 and R3 represent methoxy and R2 represents hydrogen or methoxy; (b) R1 represents methoxy, R2 and R3 represent hydrogen and R4 represents (ba) a carboxy group in the 6- or 7- position, or (bb) 5-tetrazolyl, hydroxymethyl, cyano or the group -COA in the 8-position wherein A represents diethylaminoethylamino, amino, dimethylamino, methoxy or pivaloyloxymethoxy, and (c) R1 represents isopropoxy, R2 and R3 represent hydrogen and R4 represents cyano in the 8-position; pharmaceutically acceptable acid addition salts thereof and, when A represents a hydroxy group, pharmaceutically acceptable salts thereof with a base.
As used in Specification, the term "lower alkyl", alone or in combination. denotes a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 7 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, neopentyl, pentyl and heptyl. The term "lower alkoxy" denotes an alkoxy group in which the lower alkyl group is as defined earlier (e.g. methoxy. ethoxy. propoxy and pentyloxy). The term "halogen" denotes bromine, chlorine, fluorine and iodine. The term "acyl" denotes an alkanoyl group derived from an aliphatic carboxylic acid containing 1 to 7 carbon atoms (e.g. formal, acetvl and propionyl) or an arovl group derived from an aromatic carboxylic acid (e.g. benzoyl). the term "acyloxy" denotes an alkanoyloxy group derived from an aliphatic carboxylic acid containing I to 7 carbon atoms (e.g. formyloxy, acetoxy and propionyloxv) or an "aroyloxy" group derived from an aromatic carboxylic acid (e.g. benzoyloxy).
Examples of di(C1-C7 alkyl)amino-(C2-C7 alkyloxy) groups are dimethylaminoethoxy, diethylaminoethoxy, dipropylaminoethoxy, diisopropylaminoethoxy, dibutylaminoethoxy and dipentylaminoethoxy. Examples of di(C1-C7 alkyl)amino-(C2-C7 alkyl) groups are dimethylaminoethyl, diethylaminoethyl, ethylmethylaminoethyl and dipropylaminoethyl. Examples of acyloxy-(lower alkyl) groups are formyloxymethyl, acetoxymethyl, propionyloxymethyl, benzoyloxymethyl.
Particular compounds encompassed by formula I hereinbefore are those of the general formula
wherein R'1, R'2 and R'3 each independently represent a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkythio or hydroxy group and R4 has the significance given earlier, with the proviso that at least one of R'1, R'2 and R'3 represents other than a hydrogen atom and with the proviso that at least one of R'l, R'2 and R'3 represents a lower alkylthio group and/or R4 represents an acyloxy (lower alkyl) group or a group of the formula
in which A, Y and n have the significance given above, except that in the case where n stands for zero. A cannot represent a hydroxy or lower alkoxy group or the group of the formula
Further particular compounds are those of formula I' in which at least one of R', R'2 and R'3 represents a lower alkylthio group. In a particular aspect, the invention also comprises compounds of formula I' in which R4 represents an acyloxy-(lower alkyl) group or a group of the formula
wherein Y and A have the significance given earlier. Furthermore, particular compounds are also those of formula I' in which R4 represents a group of the formula
wherein A represents a lower alkyl, di(C1-C7 alkyl)amino-(C2-C7 alkoxy) or pivaloyloxymethoxy group.
Another class of particular compounds of formula I comprises those in which at least one of R1, R2 and R3 represents a cyclopropyl or cyclobutyl group.
Preferred compounds of formula I are those in which R2 and R3 each represent a hydrogen atom and R4 represents a group of the formula 0 -C-A wherein A represents a di(C1--C7 alkyl)amino-(C2-C7 alkoxy) group and R1 has the significance given earlier.
In a further preferred aspect. the invention comprises compounds of formula I in which at least one of R,. R2 and R3 represents a lower alkyl, lower alkoxy or lower alkvthio group and R4 represents a substituent in the 8-position. In a more preferred aspect, the invention comprises compounds of formula I in which R2 represents a hydrogen atom, R, and/or R3 represents other than a hydrogen atom and R4 represents a substituent in the 8-position. Still more preferred are compounds of formula I in which R2 represents a hydrogen atom. R1 and/or R3 independently represents a lower alkyl, lower alkoxy or lower alkythio group and R4 represents a hydroxy-(lower alkyl) or 5-tetrazolyl group or a group of the formula
wherein A represents a hydroxy or di(C1-C7 alkyl)amino-(C2-C7 alkoxy) group.
Most preferred are compounds of formula I in which one of R1, R2 and R3 represents a lower alkyl, lower alkoxy or lower alkylthio group and R4 represnets a carboxy group.
Examples of preferred compounds of formula I are the following: 2 - methylthio - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid, -2 - isopropyl - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 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 other compounds of formula I are the following: 4 - methylthio - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid, 2,4-dimethylthio - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic 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, 2 - methoxy - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - α methylacetic acid, 2 - chloro - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - a - methylacetic acid, 3 - methoxy - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - α - methylacetic acid, 3 - chloro - 11 - oxo - 1 1H - 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 - 1 lH - pyrido[2,1-b]quinazoline - 7 - a - methylacetic acid, 2 - methylthio - 11 - oxo - 1 IH - pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2 - diethylaminoethyl) ester, 2 - isopropylthio - 11 - oxo - 11H - pyrido[2, 1 -blquinazoline - 8 - carboxylic acid (2 - diethylaminoethyl) ester, 2 - cyclobutyl - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid, 2 - methylthio - 11 - oxo - 1111 - 8 - (IR - tetrazol - 5 - yl)pyrido[2,1- b]quinazoline.
2 - isopropylthio - 11 - oxo - 11H - 8 - (1H-tetrazol - 5 - yl)pyrido[2,1b]quinazoline, 8 - hydroxymethyl - 2 - methylthio - 11H - pyrido[2,1-b]quinazolin - 11 one and 8 - hydroxymethyl - 2 - isopropylthio - 11H - pyrido[2,1-b]quinazolin - 11 one, including compounds hereinafter set forth.
According to the process provided by the present invention, the pyrido[2,1b]quinazoline derivates aforesaid (i.e. the compounds of formula I hereinbefore and their pharmaceutically acceptable acid addition salts and, when A represents a hydroxy group their pharmaceutically acceptable salts with a base) are manufactured by (a) for the manufacture of a compound of formula I in which R4 represents a cyano or acyloxy-(lower alkyl) group or a group of the formula
wherein A represents a lower alkyl, hydroxy or lower alkoxy group or a group of the formula -N(R5) (R6) and R1, R2, R3, R5, Rs, Y and n have the significance given earlier, treating an anthranilic acid or ester thereof of the general formula
wherein R represents a hydrogen atom or a lower alkyl group and R1, R2 and R3 have the significance given earlier, with a halopyridine derivaive of the general formula
wherein R'4 represents a cyano or acyloxy-(lower alkyl) group or a group of the formula
wherein A represents a lower alkyl, hydroxy or lower alkoxy group or a group of the formula -N(R5) (R6), Y represents a hydrogen atom or a methyl group and n stands for zero or 1, R5 and R8 each independently represent a hydrogen atom or a lower alkyl or di(C1-C7 alkyl)amino-(C2-C7 alkyl) group and X represents a halogen atom, or (b) for the manufacture of a compound of formula I in which R4 represents a 5tetrazolyl group and R1, R2 and R3 have the significance given earlier, treating a compound of the general formula
wherein R1, R2 and R3 have the significance given earlier, with an alkali metal azide, or (c) for the manufacture of a compound of formula I in which R4 represents a hydroxy-(lower alkyl) group and R1, R2 and R3 have the significance given earlier. hydrolysing a compound of the general formula
wherein R7 represents an acyloxy-(lower alkyl) group and R1, R2 and R3 have the significance given earlier, or (d) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a di(C1-C7 alkyl)amino-(C2-C7 alkoxy) group and R1, R2, R3, Y and n have the significance given earlier, treating a compound of the general formula
wherein Rl, R2, R3, Y and n have the significance given earlier, with a di(CIC7 alkyl)amino-(C2-C7 alkyl) halide or subjecting an acid chloride of a compound of formula Ic to alcoholysis with a di(C,C, alkyl)amino-(C2-C7 alkanol), or (e) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a pivaloyloxymethoxy group and R1, R2, R3, Y and n have the significance given earlier, treating a compound of formula Ic with a tertiary organic base and chloromethyl pivalate, bromomethyl pivalate or iodomethyl pivalate, or (f) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a lower alkoxy group and R1, R2, R3, Y and n have the significance given earlier, esterifying a compound of formula Ic, or (g) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a group of the formula -N(R5) (R6) and R1, R2, R3, Rs, R6, Y and n have the significance given earlier, subjecting a compound of formula Ic to ammonolysis with a compound of the general formula HN(Rs)(R6) (IV) wherein Rs and R6 have the significance given earlier, or (h) for the manufacture of a compound of formula Ib, condensing an anthranilic acid or ester thereof of formula II with a halopyridine derivative of the general formula
wherein R7 and X have the significance given earlier, and (i) if desired, converting a compound obtained into a pharmaceutically acceptable salt.
According to embodiment (a) of the process, an anthranilic acid or ester of formula II, a known compound or a compound which can be prepared according to known procedures, is treated with a halopyridine of formula III, which is also a known compound or which can be prepared according to known procedures, at a temperature of from 100 C to 200 C in the presence of absence of a solvent. The treatment is preferably carried out in the presence of a catalytic amount of an alkali metal iodide, such as sodium iodide, potassium iodide, and caesium iodide.
Solvents which may be used in the treatment are high boiling solvents such as acetic acid, diglyme and triglyme. The treatment is conveniently carried out at atmospheric pressure. The product can be recovered according to known procedures such as crystallisation.
A compound of formula I in which R4 represents a 5-tetrazolyl group can be manufactured according to embodiment (b) of the process from a compound of formula Ia. More specifically, a compound of formula Ia is treated with an alkali metal azide such as potassium azide or sodium azide, preferably in the presence of ammonium chloride. The treatment is suitably carried out in the presence of a solvent such as a polar aprotic solvent (e.g. dimethyl sulphoxide, or dimethylformamide. The desired tetrazolyl-substituted compound is then recovered according to known procedures (e.g. crystallisation).
According to embodiment (c) of the process, a compound of formula Ib is hydrolysed in a manner known per se; for example, by treatment with a mineral acid such as concentrated hydrochloric acid in the presence of a solvent (e.g an alkanol such as ethanol). The desired product is then recovered according to known procedures (e.g. by recrystallisation from methanolic hydrogen chloride).
According to embodiment (d) of the process, a compound of formula I in whch A represents a di(C,C, alkyl)amino-(C2C7 alkoxy) group can be manufactured from a compound of formula Ic by treatment with, for example, a di(C1-C7 alkyl)amino-(C2-C3 alkyl) halide under reflux conditions in a solvent (e.g. an alkanol such as isopropanol), the product being recovered according to known procedures such as crystallisation. Alternatively, a compound of formula Ic is treated with thionyl chloride to give the corresponding acid chloride which is reacted with a di(C1-C7 alkyl)amino-(C2-C7 alkanol) in an inert solvent such as tetrahydrofuran at a temperature of from 00C to 1000C and thereafter the desired product is recovered by known procedures such as crystallisation.
According to embodiment (e) of the process, a compound of formula I in which A represents a pivaloyloxymethoxy group can be manufactured from a compound of formula Ic by treatment with a tertiary organic base such as a tri (lower alkyl)amine and chloromethyl pivalate, bromomethyl pivalate or iodomethyl pivalate in an inert solvent such as dimethylformamide at a temperature of from room temperature to 1200C. The desired product can be recovered according to known procedures such as crystallisation.
According to embodiment (f) of the process, an acid of formula Ic can be converted into the corresponding ester by known procedures. For example, an alkali metal salt of such an acid (e.g. the sodium salt) can be reacted with an appropriate substituted or unsubstituted alkyl halide under known reaction conditions: for example, in an inert solvent such as dimethylformamide at a temperature of from room temperature to the reflux temperature of the reaction mixture.
According to embodiment (g) of the process, an acid of formula Ic can be converted into the corresponding amide by known procedures. For example, an acid of formula Ic is treated with thionyl chloride to give the corresponding acid chloride which is then treated with an appropriate amine (e.g. ammonia, dimethylamine and 3-diethylaminopropylamine) in the presence of a solvent such as tetrahydrofuran. The desired amide is then recovered according to known procedures such as crystallisation.
According to embodiment (h) of the process, a halopyridine derivative of formula V is condensed with an anthranilic acid or ester of formula II at a temperature of from about 100 C to about 200"C in the presence or absence of a solvent. The condensation is preferably carried out in the presence of a catalytic amount of an alkali metal iodide such as sodium iodide, potassium iodide and caesium iodide. Solvents which may be used in the condensation are high boiling solvents such as acetic acid, diglyme and triglyme. The condensation is conveniently carried out at atmospheric pressure. The condensation product can be recovered according to known procedures such as crystallisation.
The compounds of formula I in which A represents a hydroxy group form pharmaceutically acceptable salts with bases. Examples of such bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide. sodium alkoxides such as sodium ethanolate and potassium ethanolate and organic bases such as piperidine, diethylamine and N-methylglucamine.
The compounds of formula I also form pharmaceutically acceptable salts with acids. Examples of such acids are organic and inorganic acids such as methanesulphonic acid, paratoluenesulphonic acid, hydrochloric acid, hydrobromic acid and sulphuric acid.
The halopyridine derivatives of formula V hereinbefore are known or can be prepared according to known methods. Thus, for example, a hydroxy-(lower alkyl)substituted 2-halopyridine is reacted with an acyl halide such as benzoyl chloride under known reaction conditions to yield the corresponding acyloxy-(lower alkyl)substituted halopyridine which is converted into the corresponding N-oxide of formula V with a peroxidising agent such as m-chloroperbenzoic acid in the presence of an inert solvent (e.g. a halogenated hydrocarbon such as methylene chloride). the resulting mixture is neutralised with an alkali metal hydroxide such as sodium hydroxide and thereafter the resulting N-oxide is recovered.
The compounds of formula I and their pharmaceutically acceptable salts inhibit cutaneous anaphylaxis in rats and are therefore useful in the prevention of allergic reactions. For example, they are useful in the prophylactic treatment of bronchial asthma. The anti-anaphylactic activity can be demonstrated by the passive cutaneous anaphylaxis assay (PCA) test in the rat. This test involves passive local sensitisation 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- blquinazoline derivative is administered intraperitoneally followed after 5 minutes by an intravenous injection of reagen and Evans blue dye. The events associated with localised antigen-antibody reaction lead to the formation of skin weals, the sizes of which are measured. The ability of the test compound to decrease the size of the weals compared to controls is taken as a measure of its activity.
When a compound provided by the present invention such as 2-methoxy-l 1 oxo-llH-pyrido[2,1-b]quinazoline - 8 - carboxylic acid is used as the - test compound at a dosage of 16 mg/kg intraperitoneally, the reduction in the weal size is 63?'o. When the sodium salt of 2 - methoxy - 11 - oxo - IIH - pvrido[2,1-b]- quinazoline - 8 - carboxylic acid is used as the test compound at a dosage of 16 mg/kg intraperitoneally, the reduction in the weal size is 86%.
The anti-allergic activity of the compounds of formula I can also be demonstrated in the actively sensitised guinea pig (IgG). In this test, the guinea pig is sensitised intraperitoneally with horse serum on day 1 and then the guinea pig is challenged intravenously on days 11-14 with antigen (horse serum) which immediately initiates the immediate-type hypersensitive reaction (IHR bronchospasm). When an anti-allergic compound is administered intravenously prior to the antigen, the IHR is blocked and thereby prevents bronchospasm.
When 2 - methoxy - 11 - oxo - 1 1H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid is used in the foregoing test at an oral dosage of 200 mg/kg, the percentage inhibition of bronchospasm is 65?o'. When the foregoing compound is administered intravenously at a dosage of 20 mg/kg, the percentage inhibition of bronchospasm is 54%.
The anti-allergic activity can also be demonstrated in the passively sensitised rat (IgE). In this test, a rat is administered anti-sera intravenously 18 hours prior to the intravenous antigen (egg albumin) challenge. The antigen challenge originates the IHR. When an anti-allergic compound is administered intravenously prior to the antigen challenge, it inhibits 111k and prevents bronchospasm.
When 2 - methoxy - 11 - oxo - 11H - - pyrido[2,1-b]quinazoline - 8 - carboxylic acid is used in the foregoing test at an oral dosage of 10 mg/kg, the percentage inhibition of bronchospasm is 59%. When the foregoing compound is aministered intravenously at a dosage of 10 mg/kg, the percentage 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, for example in the prophylactic treatment of bronchial asthma, with dosage adjusted to individual requirements. They can be administered therapeutically (e.g. orally or parenterally) by incorporating a therapeutic dosage in a conventional dosage form such as a tablet, capsule, elixir or suspension solution. They can be administered in admixture with conventional pharmaceutical carriers or excipients such as, for example, corn starch, calcium stearate, magnesium carbonate, calcium silicate, dicalcium phosphate, talc and lactose. Moreover, they can be administered in the presence of buffers or agents used to adjust to isotonicity, and the pharmaceutical dosage forms can, if desired, be subjected to conventional pharmaceutical operations such as, for example, sterilisation. As stated earlier, the dosage can be adjusted to individual requirements. The pharmaceutical dosage forms can also contain other therapeutically valuable substances.
The quantity of active ingredient which is present in any of the aforementioned dosage forms can be varied. It is preferred, however, to provide capsules or tablets containing from 10 mg to 20 mg of a compound of formula I or an equivalent amount of a medicinally acceptable salt thereof.
The frequency with which any of the aforementioned dosage forms will be administered to a patient will vary depending upon the quantity of active ingredient present therein and the needs and requirements of the patient. Under ordinary circumstances, however, up to 20 mg/kg of a compound of formula I can be administered daily in several dosages. It will be appreciated, however, that the dosages set forth herein are given by way of example only.
The following Examples illustrate both the process provided by the present invention and the preparation of starting materials used therein: Example 1 Preparation of 6-chloro-3-(Ndiethylaminoethylcarbamoyl)pyridine hydrochloride A solution of 5.0 g of 6-chloronicotinic acid and 8.56 ml of diphenylphosphorylazide in 25 ml of dimethylformamide was cooled in an ice-bath and 4.27 ml of N,N-diethylethylenediamine were added dropwise. After completion of the addition, the mixture was left to stand at room temperature overnight and was then poured into 500 ml of water. The aqueous solution was extracted with three 500 ml portions of dichloromethane and the combined organic layers were washed with water, dried over potassium carbonate and evaporated to give an oil which was dissolved in 15 ml of ethanol and carefully acidified with hydrochloric acid in tetrahydrofuran. After cooling, 5.62 g (61%) of 6 - chloro - 3 - (N - diethylaminoethylcarbamoyl)pyridine hydrochloride of melting point 182"-- 1840C were obtained. The filtrate yielded an additional 1.74 g (19 ,) of 6 - chloro 3 - (N - diethylaminoethylcarbamoyl)pyridine hydrochloride; melting point 171"--181"C.
Example 2 Preparation of N-(2-diethylaminoethyl)-2-methoxy-l l-oxo-l lH- pyrido[2, 1 -biquinazoline-8-carboxamide hydrochloride A suspension of 4.4 g of 6- chloro - 3 - (N - diethylaminoethyl carbamoyl)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"C under a stream of argon for 5 hours. After cooling, the mixture was triturated with ether and filtered to give a yellow solid which was recrystallised from ethanol/ether to give 3.47 g (57%) of N - (2 diethylaminoethyl) - 2 - methoxy - 11 - oxo - I lH - pyrido[2,1-b]quinazoline 8 - carboxamide hydrochloride of melting point 2490--251"C.
Example 3 Preparation of 2-methoxy-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8 carboxamide A suspension of 10.24 g of 2-chloro - 5 - carbamoylpyridine, 14.26 g of 5methoxyanthranilic acid and 300 mg of potassium iodide in 30 ml of triglyme was heated to a bath temperature of 155"C 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 - 1111 - pyrido[2,l-b)qui TABLE
Method Melting Recrystalof pre- Yield point lisation Product Starting material paration % C solventa 2-Ethoxy-11-oxo-11H-pyrido- 5-Ethoxyanthranilic acid B 42 295-300 DMF [2,1-b]quinazoline-8 -carboxylic acid 11-Oxo-2-propoxy-11H-pyrido- 5-Propoxyanthanilic acid B 30 275-277 DMF [2,1-b]quinazoline-8- hydrochloride -carboxylic acid 2-Isopropoxy-11-oxo-11H- 5-Isopropoxyanthranilic B 32 278-279 Pr/DMEAc -pyrido[2,1-b]quinazoline-8- acid hydrochloride -carboxylic acid 2-Butoxy-11-oxo-11H-pyrido 5-Butoxyanthranilic acid B 33 254-256 DMF [2,1-b]quinazoline-8- hydrochloride -carboxylic acid 2-Amyloxy-11-oxo-11H-pyrido 5-Amyloxyanthranilic acid B 22 237-240 DMF [2,1-b]quinazoline-8- hydrochloride carboxylic acid 2-Methylthio-11-oxo-11H- 5-Methylthioanthranilic C 48 337b Pr/DMEAc pyrido[2,1-b]quinazoline-8- acid methyl ester hydrochloride carboxylic acid TABLE (cont.).
Method Melting Recrystalof pre- Yield point lisation Product Starting material paration % C solventa 2,4-Dimethoxy-11-oxo-11H- 3,5-Dimethoxyanthranilic C 13 353b Pr/DMEAc pyrido[2,1-b]quinazoline-8- acid methyl ester carboxylic acid 2-Isopropyl-11-oxo-11H- 5-Isopropylanthranilic B 11.8 318-320 DMF pyrido[2,1-b]quinazoline-8- acid carboxylic acid 11-Oxo-11H-2,3,4-trimethoxy 3,4,5-Trimethoxy- C 9 288-289 Pr/DMEAc pyrido[2,1-b]quinazoline-8- anthranilic acid methyl carboxylic acid hydrate ester 3-Methoxy-11-oxo-11H-pyrido- 4-Methoxyanthranilic acid C 51 304-306 Pr/DMEAc [2,1-b]quinazoline-8- methyl ester carboxylic acid 4-Methoxy-11-oxo-11H-pyrido- 3-Methoxyanthranilic acid B 7 304-306 Pr/DMEAc [2,1-b]quinazoline-8- hydrochloride carboxylic acid hydrate 4-Chloro-11-oxo-11H-pyrido- 3-Chloroanthranilic acid A 34 367b DMF/HOAc [2,1-b]quinazoline-8carboxylic acid aDMF=dimethylformamide; HOAc=acetic acid; Pr=isopropyl alcohol; DMEA=N,N-dimethylethanolamine. bMelting point was determined on a Dupont Instruments Model 900 thermal analyser. cCompounds recrystallised from this solvent were obtained as the free acids by precipitation from water with acetic acid.
Example 6 Preparation of 2-methoxy-11-oo-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 C overnight and an additional 2.24 g of sodium azide and 1.87 g of ammonium chloride were added. After a further 6 hours, the mixture was allowed to cool and was filtered. The yellow solid collected was recrystallised 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 of melting point 286 C (decomposition). The filtrate deposited a second crop of 2.28 g (29%) of melting point 285 C (decomposition).
Example 7 Preparation of methyl 2-methoxy-11-oxo-llH-pyrido[2,I-b]- quinazoline-8-carboxylate hydrochloride A) A suspension of 6.10 g of 2-methoxy-l 1 -oxo-l 1 H-pyrido[2,1 -biquinazoline- 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 were added. After a further 48 hours, the 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[2,1b]quinazoline-8-carboxylate of melting 205 -208 C. A second crop amounted to 0.43 g (7%) of melting point l950-2000C. A portion of this material was crystallised from methanol/ether/hydrochloric acid to give the hydrochloride salt of melting point 235 -238 C.
B) A suspension of 2.40 g of 2-methoxy-11-oxo-11H-pyrido[2,1b]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 48 hours. The resluting mixture was diluted with 75 ml of water and the yellow precipitate was collected, there being obtained 2.36 g (94%) of melting point 188 195 C. Recrystallisation from methanol/hydrochloric acid/acetic acid gave 2.24 g (79%) of methyl 2 - methoxy - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 carboxylate hydrochloride of melting point 2280-2310C.
Example 8 Preparation of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline 8-carboxylic acid (2-diethylaminoethyl) ester hydrochloride 12.5 g of diethylaminoethyl chloride hydrochloride were partitioned between 50 ml of 1-N sodium hydroxide and 60 ml of ether. The combined ether layers were washed with water and brine, dried over potassium carbonate and evaporated in the 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 for 2 hours. After cooling, the solids were collected and recrystallised from methanol/ether to give 5.72 g (76% of 2-methoxy-11-oxo-11H-pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2-diethylaminoethyl) ester hydrochloride of melting point 250 -253 C. A further crystallisation from dimethylformamide/acetic acid raised the melting point to 2550-2580C.
Example 9 Preparation of 8-(N,N-dimethylcarbamoyl)-2-methoxy- 11 -oxo- 11 H pyrido[2, 1-biquinazoline A solution of 6.0 g of 2 - methoxy - 11 - oxo - 11H - pyrido[2,1- b]quinazoline - 8 - carboxylic acid in 100 ml of thionyl chloride was refluxed for 3 hours. The 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 colour had changed from yellow to green-yellow, and the solids were collected. The solids were dissolved in methanol and the solution was filtered and evaporated to dryness. The residue was recrystallised from 500 ml of ethyl acetate to give 4.0 g (61%) of 8-(N,N-dimethylcarbamoyl)-2-methoxy-11-oxo-11Hpyrido[2,1-b]quinazoline of melting point 190 -196 C. Recrystallisation from ethyl acetate/hexane and then from ethyl acetate raised the melting point to l970-l990C.
Example 10 Preparation of 6-chloro-3-pyridinemethanol benzoate To an ice-cold solution of 24.41 g of 2-chloro-5-hydroxy-methylpyridine in 250 ml of dry methylene chloride and 27.0 ml of dry triethylamine were added dropwise 23.0 ml of benzoyl chloride. The resulting mixture was stirred at 0 C for 1 hour and at room temperature for 2 hours. It was next diluted with 500 ml of methylene chloride and washed with 100 ml portions of water, saturated sodium bicarbonate solution and saturated sodium chloride solution. Drying over potassium carbonate and evaporation gave 45.4 g of a yellow semi-solid which was distilled through a short-path apparatus to give 41.51 g (98 ,') of crude 6 - chloro - 3pyridinemethanol benzoate of boiling point 1500-1600C/0.l-0.2 mm.
Recrystallisation from ether/ligroin gave, after filtration to remove some insoluble material, 33.42 g (79%) of the desired benzoate of melting point 580-600C. An analytical sample was obtained from ether/hexane and melted at 590-620C.
Example 11 Preparation of 6-chloro-3-pyridinemethanol benzoate N-oxide A solution of 33.42 g of 6-chloro-3-pyridinemethanol benzoate and 75 g of mchloroperbenzoic acid in 1800 ml of methylene chloride was stirred at room temperature for 5 days, washed with two 500 ml portions of l-N sodium hydroxide, two 500 ml portions of water and 500 ml of brine and then dried over potassium carbonate. Evaporation gave a yellow solid which, after crystallisation from ethyl acetate/hexane gave 25.85 g (73%) of 6 - chloro - 3 - pyridinemethanol benzoate N-oxide of melting point 116 -121 C. An analytical sample was obtained from ethyl acetate and melted at 120 -123 C.
Example 12 Preparation of 8-hydroxymethyl-2-methoxy-11H-pyrido[2,1-b] quinazolin-11-one benzoate A suspension of 5.00 g of 5-methoxyanthranilic acid and 3.90 of 6 - chloro 3 - pyridinemethanol benzoate N-oxide in 9 ml of triglyme was heated to a bath temperature of 120 C overnight. After cooling, the mixture was triturated with 15 ml of ethynol and filtered to give 3.79 g (71%) of crude 8 - hydroxymethyl - 2 methoxy - 11H - pyrido[2,1-b]quinazolin - 11 - one benzoate of melting point of 206 -219 C. Trituration with boiling methanol gave 1.75 g (33%) of the desired benzoate of melting point 226 -229 C. Two recrystallisations from aqueous acetic acid gave a sample of melting point 2280-2300C.
Example 13 Preparation of 8-hydroxymethyl-2-methoxy-1 11-pyrido [2,1-b]- quinazolin-11-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 of melting point 248 -251 C (decomposition) separated and the filtrate yielded an additional 0.72 g (51%) of melting point 244 -248 C. An analytical sample obtained from methanolic hydrochloric acid/ether and melted at 253 -255 C (decomposition).
Example 14 Preparation of 2-nitro-5-methylthiobenzoic acid To a solution of 50 ml of methylmercaptan in 200 ml of dimethylformamide were added portionwise at 400C 48 g of sodium hydride. After completion of the reaction, 100.0 g of 5-chloro - 2 - nitrobenzoic acid were added. The temperature was allowed to rise to -10 C, again reduced to -40 C and the excess reagent was quenched with 1-N hydrochloric acid. After stirring for 2 hours at room temperature, the product was collected, there being obtained 102.3 g (97 o) of melting point l650-l690C. Recrystallisation from methanol/ethyl acetate gave 52.14 g of melting point l730-l740C. An analytical sample was obtained from ethyl acetate; melting point l740-l750C.
Example 15 Preparation of methyl 2-amino-5-methylthiobenzoate To an ice-cold solution of 52.1 g of 2-nitro-5-methyl-thiobenzoic acid in 250 ml of methanol was added an ethereal solution of diazomethane until thin-layer chromatography indicated that the reaction was complete. The resulting solution was evaporated to dryness and used as such. In one case, the crude product was crystallised from methanol to give yellow needles of methyl 2-nitro-5methylthiobenzoate of melting point 530--54"C.
The crude product from the foregoing paragraph (55.5 g) was suspended, together with 55.5 g of iron powder, in 280 ml of glacial acetic acid. The bath temperature was raised to 1250C over a period of 30 minutes, the resulting grey suspension was left to cool and was filtered through Celite (registered Trade Mark).
Evaporation gave a dark oily residue. This was triturated with methanolic hydrochloric acid to give a white solid which was crystallised from methanoVether to give 33.32 g (58%) of methyl 2-amino-5-methylthiobenzoate hydrochloride of melting point l93C1940C. A second crop of 7.35 g (13%) of melting point19l0- 192"C was obtained from the filtrate. An analytical sample was obtained from methanol/ether; melting point 196"--197"C.
Example 16 Preparation of crude 2-methoxy-l l-oxo-1 lH-pyrido[2,l-b] quinazoline-8-carboxylic acid hydrochloride A 1.0 litre three-necked flask was equipped with a mechanical stirrer, argon inlet, short-path condenser and receiver, oil-bath, hot plate, thermowatch, temperature controller and bath thermometer. The flask was flushed with argon and charged with 135 g of 5-methoxyanthranilic acid, 135 g of 6-chloronicotinic acid, 2.0 g of potassium iodide and 400 ml of triethylene glycol dimethyl ether (triglyme). This mixture was stirred and heated under a low stream of argon. When the bath temperature had reached about 140"C most of the solid had dissolved.
Upon continued heating, the product slowly precipitated as a yellow solid. The bath temperature was maintained at 1500C overnight and a slow stream of argon was maintained over the stirred mixture. The thick mixture which resulted was cooled to less than 50"C and was 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 600C under a high vacuum to yield 326 g of crude product, 2 - methoxy - 11 - oxo - IIH - pyrido[2,1-b]quinazoline - 8 carboxylic acid hydrochloride.
Example 17 Purification of 2-methoxy-11-oxo-llH-pyrido[2,I-b]quinazoline- 8-carboxylic acid hydrochloride via the ethylenediamine salt 326 g of the crude hydrochloride prepared as described in Example 16 were dissolved in 6.2 litres of pyridine (25 ml/g assuming 100% theoretical yield) and heated to reflux in a 12 litre three-necked flask. To the stirred and refluxing solution were added 81.1 ml of distilled ethylenediamine over a period of 5 minutes and the resulting slurry was refluxed for 10 minutes. The heating mantle was then removed and the stirred mixture was allowed to cool (about 4 hours) to room temperature. The crystals were collected by vacuum filtration, washed with three 250 ml portions of pyridine, pressed dry and dried to constant weight in vacuo at 60"C overnight to yield 189.8 g of the ethylenediamine salt of the product as a yellow solid. This solid was recrystallised by dissolving it in 500 ml of hot water. The hot aqueous solution was added to a 12 litre three-necked flask containing 500 ml of refluxing pyridine and then 5.2 litres of pyridine were added slowly to the refluxing solution. After completion of the addition, an atmospheric distillation of the pyridine/water azeotrope was commenced. During the distillation an additional 1.0 litre of pyridine was added slowly (over a 1 hour period) to the stirred mixture and product began to separate. Distillation was continued until the head temperature had reached 110 C and was then stopped (approximately 2.7 litres of distillate were collected) and the mixture was allowed to cool to below reflux temperature. 27 ml of distilled ethylenediamine were 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 rapidly.
The product (about 200 g) was used directly or stored in vacuo.
Example 18 Regeneration of purified 2-methoxy- 11 -oxo- 11 H-pyrido[2, 1-b] quinazoline-8-carboxylic acid 200 g of the entire recrystallised ethylenediamine salt of the aforementioned quinazoline were dissolved in 1.0 litre of water and stirred at room temperature while a solution of 300 ml of glacial acetic acid dissolved in 1.5 litres of water was added dropwise over a period of 2 hours. The final pH of the mixture was about 4 by Accutint paper (range No. 70). The resulting crystals were collected, washed with two 1.0 litre portions of water and dried overnight at 100"C in vacuo to yield 95 g of a yellow solid melting at 3220 C. This solid was crystallised by dissolving it in 1.25 litres of refluxing pyridine. The hot solution was quickly vacuum filtered through a steam-jacketed Buchner funnel. The filter and flask were washed with 300 ml of boiling pyridine. The filtrate was transferred to a 2 litre wide-mouth Erlenmeyer flask and heated to redissolve all the solids. The resulting solution was allowed to cool slowly to room temperature and the slurry was then thoroughly chilled to 00C for 2 hours. The crystals were filtered off, washed with 200 ml of cold pyridine, pressed dry and dried in vacuo at 1 150C overnight under a slow stream of nitrogen to yield 87.6 g of product of melting point 3250C.
Example 19 Preparation of 2-methoxy-11-oxo-1 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid sodium salt monohydrate 27.023 g of 2-methoxy - 11 - oxo - 11H - pyrido[2,l-b]quinazoline - 8 carboxylic acid were stirred in 50 ml of water at room temperature while 100 ml of 1.0-N sodium hydroxide solution were 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 litre three-necked flask together with 1.0 litre of pyridine. The resulting slurry was heated to reflux, at which temperature all of the solids dissolved. Atmospheric distillation of solvent was commenced while an additional 1.0 litre of pyridine was slowly added. The quinazoline product began to separate, but distillation was continued until a head temperature of 100"C was achieved (approximately 1 litre of distillate). The slurry was then cooled to room temperature for 3 hours, filtered, washed with two 100 ml portions of pyridine and dried in vacuo at 950C overnight under a slight stream of nitrogen. This gave 30.2 g (97.0 ) of the aforementioned monohydrated sodium salt as a light yellow solid.
Example 20 Preparation of 2-methoxy- 11 -oxo- 11 H-pyrido[2, 1 -b]quinazoline 7-carboxylic acid A suspension of 2.80 g of 5-methoxyanthranilic acid, 2.65 g of 2chloroisonicotinic acid and 0.135 g of potassium iodide in 13 ml of triglyme was stirred and heated at a bath temperature of 1500C for 21 hours under a stream of argon. After cooling, 40 ml of methanol were added and the yellow solid was removed by filtration. The crude product was purified by recrystallisation of the ethylenediamine salt from pyridine, reconversion into the free acid by treatment with acetic acid and recrystallisation from acetic acid to give 0.42 g (9%) of pure 2 methoxy-ll-oxo-ll H-pyrido[2, l-blquinazoline-7-carboxylic acid of melting point 3230-3270C.
Example 21 Preparation of 2-methoxy- 11 -oxo- 11 H-pyrido[2, 1 -b]quinazoline 6-carboxylic acid A suspension of 1.05 g of 5-methoxyanthranilic acid, 0.99 g of 2chloronicotinic acid and 0.050 g of potassium iodide in 5 ml of triglyme was stirred and heated at a bath temperature of 150"C for 17 hours under a stream of argon.
After cooling, 15 ml of methanol were added and the yellow solid was removed by filtration. The crude material was purified by recrystallisation from dimethylformamide/acetic acid to give 0.67 g (40%) of pure 2-methoxy-l 1-oxo- llH-pyrido[2,1-b]quinazoline-6-carboxylic acid of melting point 2720-273.50C.
Example 22 Preparation of pivaloylmethyl 2-methoxy-ll-oxo-ll H-pyrido[l,l-bl- quinazoline-8-carboxylate To 0.40 g of 2-methoxy-l l-oxo-l IH-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"C for 19 hours. An additional 0.3 ml of chloromethyl pivalate was added and heating was continued at 100"C for 4.5 hours. The solvent was removed on an 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% ethyl acetate/benzene. Recrystallisation from methanol/water gave 0.37 g (65%) of pure pivaloylmethyl 2-methoxy-l 1-oxo- I lH-pyrido[2,1-b]quinazoline - 8 - carboxylate of melting point l290-l3l0C.
Example 23 Preparation of 2-methoxy-8-acetyl-11-oxo-1 lH-pyrido[2,1-b]quinazoline A suspension of 0.526 g of 5-methoxyanthanilic acid, 0.490 g of 2-chloro-5acetylpyridine and 0.030 g of potassium iodide in 2.5 ml of triglyme was stirred and heated at a bath temperaure of 150 C for 21 hours under a stream of argon. After cooling, 8 ml of methanol were 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 recrystallised from methylene chloride/ether to give 0.13 g (14%) of pure 2-methoxy-8-acetyl-1 I- oxo-11H-pyrido[2,1-b]quinazoline of melting point 194 196 C.
Example 24 Preparation of 2-methoxy-11-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-chloropyridine5-acetic acid and 15 mg of potassium iodide was stirred and heated at a bath temperature of 1500C under argon for 1.25 hours. After cooling, the solid mass was triturated with isopropyl alcohol and the yellow solid was filtered off. The crude product was purified by recrystallisation of the ethylenediamine salt from pyridine and reconversion into the free acid by treatment with acetic acid to give 0.054 g (3.8%) of pure 2-methoxy-l 1-oxo-11H-pyrido[2,1-m]quinazoline - 8 - acetic acid of melting piont 28l0-2820C.
Example 25 Preparation of 2-(n-butyl) - 11 - oxo - 11H - pyrido[2,1-b]quinazoline 8-carboxylic acid A suspension of 11.6 g of 5 - (n-butyl)anthranilic 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 1500C overnight under a stream of argon. After cooling, the mixture was triturated with ethanol and water and filtered to give 7.6 g of a dark yellow solid of melting point 2650-2920C. Formation of the ethylenediamine salt in hot pyridine produced a pure water-soluble salt. This salt was dissolved in water and the pure acid was precipitated with dilute acetic acid and recrystallised 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 of melting point 250 -253 C.
Example 26 Preparation of 2-ethyl-11-oxo-1 H-pyrido[2,1-b]quinazioline-8- carboxylic acid This acid was prepared according to the procedure described in Example 25; yield 26.4 , melting point 3l30-3l50C.
Example 27 Preparation of 2-isopropoxy- 1-oxo-1 lH-pyrido[2,l-b]quinazoline- 8-carboxylic acid (2-diethylaminoethyl) ester hydrochloride 9.2 g of diethylaminoethyl chloride hydrochloride were partitioned between 50 ml of 4-N sodium hydroxide and 100 ml of ether. The combined ether layers were washed with water and saturated brine, dried over potassium carbonate and evaporated to give a light coloured oil. To this oil were added 100 ml of dry isopropanol and 4.0 g of pure 2-isopropoxy-11-oxo-1 IH - pyrido[2,1- b]quinazoline - 8 - carboxylic acid. The mixture was heated to reflux for 3 hours and cooled. The solids were collected and recrystallised from methanol to give 3.22 g (57.5%) of 2 - isopropoxy - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 carboxylic acid (2 - diethylaminoethyl)ester hydrochloride of melting point 208 209 C.
Example 28 Preparation of 8-cyano-2-isopropoxy- Il-oxo-ll H-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"C overnight under a stream of argon. 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 recrystallisations of this solid from dimethylformamide/acetic acid/water gave pure 8-cyano-2-isopropoxy-l l-oxo 1 lH-pyrido[2,l-b]quinazoline of melting point 2340-2360C.
Example 29 Preparation of 8-hydroxymethyl-2-isopropoxy-1 H-pyrido [2,1-b] quinazolin-l l-one benzoate A suspension of 1.0 g of 5-isopropoxyanthranilic acid, 1.1 g of 6-chloro-3pyridinemethanol benzoate and 0.01 g of potassium iodide in 10 ml of triglyme was heated to 1500C overnight under a stream of argon. After cooling, the mixture was dissolved in hot methanol, filtered and evaporated to give an orange oil.
Chromatographic separation and recrystallisation from hexane/dichloromethane yielded 8 - hydroxymethyl - 2 - isopropoxy - 1 1H - pyrido[2,1-biquinazoline 11 - one benzoate of melting point 1230-l260C.
Example 30 Preparation of 2-bromo-4-isopropylacetanilide 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 450C and the dropwise addition of 60 g of bromine was commenced. The addition was continued at such a rate so as to maintain the temperature of the solution below 55"C. After completion of the addition, the mixture was left to stir for 1 hour. The dark liquid was then poured on to 2 litres of crushed ice while stirring. The resulting suspension was left to stir for 10 minutes while 5.0 g of sodium bisulphite were added. This suspension was stirred until the bromine colour had been discharged. The solid was then filtered off, washed with water and dried in air overnight. The damp solid (115 g) was recrystallised from 1.0 litre of 50% aqueous ethanol to give 64.4 g (68.2%) of 2-bromo-4-isopropylacetanilide of melting point l220-l260C.
Example 31 Preparation of 2-cyano-4-isopropylacetanilide A solution of 1.0075 g of 2 - bromo - 4 - isopropylacetanilide and 0.7308 g of cuprous cyanide in 10 ml of N-methylpyrrolidone was heated and stirred at 1 800C for 7 hours. The 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 and water, dried over magnesium sulphate and concentrated in vacuo to give an oil. Residual N-methylpyrrolidinone was removed by distillation (boiling point 330-370C/0.l mm) and the viscous residue crystallised on coolin eluted with 40% ethyl acetate/toluene. The combined pure fractions were concentrated in vacuo to yield 11.22 g of pure 2-bromo-4-cyclo-propylacetanilide of melting point 108.5 -110 C.
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 8.96 g of cuprous cyanide was stirred and refluxed for 3 hours. After cooling to 250C, 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 sulphate and concentrated in vacuo to give a solid. Crystallisation from ethyl acetate/hexane gave 6.45 g of pure 2-cyano-4-cyclopropylacetanilide of melting point l400-14l0C.
Example 35 Preparation of 5-cyclopropylanthranilic acid To a solution of 6.30 g of 2 - cyano - 4 - cyclopropylacetanilide in 60 ml of ethyleneglycol and 60 ml of water were added 8.86 g of potassium hydroxide. The mixture was stirred and refluxed for 19 hours. After cooling, 1 litre of water was added. The solid which precipitated was removed by filtration and the filtrate was extracted several times with ethyl acetate. The basic aqueous layer was acidified to a pH of 3 with acetic acid and extracted with ethyl acetate. The extract was dried over sodium sulphate and concentrated in vacuo to give a solid. Crystallisation from ether/hexane gave 2.31 g of pure 5-cyclopropylanthranilic acid of melting point l57.50-l58.50C.
Example 36 Preparation of 2-isopropyl-l I-oxo-l 1H-pyrido[2,1-b]quinazoline- 8-carboxylic acid A suspension of 6.0 g of 5- isopropylanthranilic acid, 5.4 g of 6chloronicotinic acid and 0.05 g of potassium iodide in 10 ml of triglyme was heated overnight (bath temperature 150 C) under a stream of argon. After cooling, the mixture was triturated with ethanol and argon. After cooling, the mixture was triturated with ethanol and water and filtered to give 5.89 g of crude product of melting point 280"--287"C. This crude product 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. Recrystallisation from dimethylformamide/acetic acid/water gave 2.5 g (26.6 4) of 2-isopropyl - 11 - oxo - 11H - pyrido[2, I-b]quinazoline - 8 carboxylic acid of melting point 3l40-3l60C.
Example 37 Preparation of 2-isopropyl-11-oxo-1 IH-pyrido[2,1-b]quinazoline- 8-carboxylic acid (2-diethylaminoethyl) ester hydrochloride 5.8 g of diethylaminoethyl chloride hydrochloride were partitioned between 100 ml of 2-N sodium hydroxide and 100 ml of ether. The ether layer was separated, washed with water and saturated brine, dried over potassium carbonate and evaporated to give a light coloured oil. To this oil were added 200 ml of isopropanol and 2.4 g of pure 2-isopropyl-l l-oxo-l IH-pyrido[2,1-b]quinazoline - 8 - carboxylic acid. The mixture was refluxed for 3 hours and cooled. The solids were collected and recrystallised from methanol to give 1.87 g (53.4%) of 2-isopropyl - 11 - oxo I 1H - pyrido[2,1 -b]quinazoline - 8 -carboxylic acid (2-diethylaminoethyl) ester of hydrochloride of melting point 220"--222"C.
Example 38 Preparation of 5-hydroxy-2-nitrobenzoic acid A mixture of 5.0 litres of water, 800 g of sodium hydroxide and 504 g of 5chloro-2-nitrobenzoic acid was refluxed for 24 hours. The solution was cooled and acidified with 1.75 litres of concentrated hydrochloric acid. The acidic-aqueous mixture was extracted three times with 1.5 litres of ether. The combined ether extracts were dried over anhydrous magnesium sulphate, filtered through Celite and evaporated to give a light yellow solid (473 g). This solid was recrysallised from ether/petroleum ether to yield 298 g (65.2%) of 5-hydroxy-2-nitrobenzoic acid of melting point l670-l690C.
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 were then added and the mixture was stirred and heated to 1000C for 5 hours. The mixture was then cooled and diluted with ice-water. The pH of the mixture was adjusted to ca 8 with 4-N sodium hydroxide solution. The mixture was then extracted three times 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 give a yellow oil which crystallised on cooling to yield 74.0 g (91.7 ,) of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester of melting point 450-500C.
This product may be distilled under a high vacuum to give pure ester of melting point 510-520C.
Example 40 Preparation of 5-isopropoxyanthanilic acid 74.0 g of 5-isopropoxy - 2 - nitrobenzoic acid isopropyl ester were dissolved in 650 ml of ethanol and 145 ml of 4-N sodium hydroxide solution. This solution was left to stir at room temperature for 16 hours. The mixture was diluted with 2.0 litres of water and washed three times with I litre of dichloromethane. The aqueous layer was then acidified to a pH of below 2 with concentrated hydrochloric acid and extracted three times with 1.0 litre of ether. The combined ether extracts were washed with 1.0 litre of saturated brine, dried over anhydrous sodium sulphate, filtered through Celite and evaporated to give 65.9 g of an orange oil which solidified on cooling; melting point 129--1310C. The solid was dissolved in 1.0 litre of ethyl acetate and hydrogenated using 3.1 g of 10% palladium-on-carbon as the catalyst. When hydrogen uptake had ceased, the catalyst was removed by filtration and the filtrate was evaporated to give 49.5 g of a yellow solid of melting point 120"-- l220C.
Example 41 Preparation of 2-isopropoxy-11-oxo-1 lH-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 1500C under a constant stream of argon for 16 hours. The mixture was cooled, diluted with about 50 ml of ethanol and filtered to give 18.9 g of crude product of melting point 256"-- 2670 C. This crude product was dissolved in about 50 ml of hot pyridine. To the boiling solution were added 4.8 ml of ethylenediamine. This mixture was left to cool and the crystals which had precipitated were filtered off, 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 which precipitated were collected, washed with water, ethanol and ether and dried to yield 9.8 g of 2-isopropoxy - 11 - oxo - 11H - pyrido[2,1-b]quinazoline-8- carboxylic acid of melting point 2780-2800C.
Example 42 Preparation of 2-methylthio- 11 -oxo- 11 H-pyrido[2, 1 -b]quinazoline 8-carboxylic acid A stirred intimate mixture of 50 g of methyl 5-methylmercaptoanthranilate hydrochloride, 34.7 g of 6-chloronicotinic acid and 0.1 g of potassium iodide was immersed in an oil-bath pre-heated to 1500C. 40 ml of triglyme were carefully added to the mixture. The mixture was heated to 175"C for 16 hours under a slow stream of argon. The mixture 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 yield 31.3 g (51 ,,) of 2methylthio - 11 - oxo - IIH - pyrido[2,1-b]quinazoline - 8 - carboxylic acid of melting point 3030-3200C.
The crude material (10 g) was dissolved in 150 ml of hot pyridine. To this hot solution were added about 1.25 ml of ethylenediamine. The resulting mixture was stirred while it cooled. 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 off and dried to yield 1.7 g of purified product of melting point 337"C.
Example 43 Preparation of 2-methylthio-l l-oxo-l IH-pyrido[2,1-b]quinazoline- 8-carboxylic acid (2-diethylaminoethyl) ester hydrochloride 2.5 g of diethylaminoethyl chloride hydrochloride were partitioned between 50 ml of ether and 50 ml of 2-N 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 brine. The organic phase was then dried over anhydrous potassium carbonate, filtered through Celite and evaporated to give 1.61 g of a light coloured oil. This oil was dissolved in 35 ml of isopropanol and to this stirred solution were added 1.15 g of purified 2-methylthio-11-oxo-llH- pyrido[2,1-b]quinazoline-8-carboxylic acid. The resulting mixture was refluxed for 4 hours and cooled. The crystalline product was collected by filtration and recrystallised from methanol to yield 1.16 g (92%) of the desired 2-methylthio 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2diethylaminoethyl) ester hydrochloride of melting point 2360--2380C.
Example 44 Preparation of 2cyclopropyl-ll -oxo-11H-pyrido[2,1 -b]quinazoline- 8-carboxylic acid A solution of 2.12 g of 5-cyclopropylanthranilic acid and 1.89 g of 6chloronicotinic acid in 20 ml of toluene was boiled to remove the toluene. The resulting solid mixture was heated at 1 500C for 25 minutes. After cooling, the solid residue was triturated with ether and filtered. The resulting solid was crystallised from acetic acid and then from ethanol to give 0.275 g of pure 2-cyclopropyl - 11 oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid of melting point 316 318"C.
The foregoing acid was reacted with 2-diethylaminoethyl chloride in isopropanol in the manner described in Example 37 to give 2-cyclopropyl-l 1-oxo- 11 H-pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2-diethylaminoethyl) ester hydrochloride.
Example 45 Preparation of 8-acetyl-2-bromo-11-oxo-llH-pyrido [2,1 -b]quinazoline A suspension of 15.50 g of 5-bromoanthranilic acid, 11.9 g of 2-chloro-5acetylpyridine and 0.50 g of potassium iodide in 20 ml of triglyme was heated at a bath temperature of 1500C under an atmosphere of argon for 7 hours. 40 ml of methanol were 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 crystrallised and recrystallised from methylene chloride/ether to give 5.10 g of pure 8 - acetyl - 2 - bromo - 11 - oxo - IIH pyrido[2,1-b]quinazoline of melting point 22l0-2240C.
Example 46 Preparation of 4-isopropylisonitrosoacetanilide To a stirred solution of 1480 g of sodium sulphate decahydrate dissolved in 1.8 litres of water 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 litres of 90% aqueous ethanol and 162 g of hydroxylamine hydrochloride dissolved in 700 ml of water. This mixture was refluxed for 12 hours, cooled to room temperature and extracted with 1.8 litres of dichloromethane. The organic layer was separated and evaporated to give a dark oil. This oil was partitioned between 1.0 litre of 10% sodium hydroxide solution and 500 ml of ether. The aqueous layer was separated and washed with two 500 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 sulphate, filtered through Celite and evaporated to dryness to give 160 g of 4-isopropylisoisonitrosoacetanilide. This crude product was recrystallised from 250 ml of benzene to yield 46.6 g of product of melting point l260-l300C.
Example 47 Preparation of 5-isopropylanthranilic acid 460 ml of concentrated sulphuric acid were stirred and heated to 70"C. 46.6 g of 4-isopropylisonitrosoacetanilide were then added at such a rate so as to maintain the temperature of the mixture between 70"--80"C. Water cooling was applied as necessary. After completion of the addition, the temperature of the mixture was maintained at 805C for 30 minutes. The mixture was cooled to room temperature and poured on to 4 litres of crushed ice. The resulting suspension was stirred for 15 minutes and the precipitated 5-isopropylisatin was filtered off. The solid was washed with water, collected and dissolved in 460 ml of l-N sodium hydroxide solution. This mixture was filtered to remove insolubles and the filtrate was treated with 30% peroxide until a positive starch iodide test was obtained. The mixture was cooled in an ice-bath and acidified with 6-N hydrochloric acid until a pH of approximately 4 was obtained. The precipitated product was collected and dried to give 28.0 g of 5-isopropylanthranilic acid of melting point 900--96"C. This product was of sufficient purity for further use. The following examplesillustrate pharmaceutical preparations containing the pyrido[2,1-b3quinazoline derivatives provided by the present invention: Example A Capsule Formulation
mg/capsule Ingredient 10 mg 20 mg Active ingredient of formula I 10.0 20.0 Lactose 215.0 205.0 Corn starch 60.0 60.0 Magnesium stearate 3.0 3.0 Talc 12.0 12.0 Total 300 mg 300 mg Procedure: Mix the active ingredient of formula I, the lactose and the corn starch in a suitable mixer. Mill through a suitable mill. Mix with the magnesium stearate and the talc and fill on a capsule filling machine.
Example B Tablet Formulation
mg/tablet Ingredient 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 Corn starch 30.0 30.0 Magnesium stearate 3.0 3.0 Total 300 mg 300 mg Procedure: Mix the active ingredient of formula I, the lactose, the microcrystalline cellulose, the modified starch and the corn starch in a suitable mixer for 1 to 15 minutes. Then, add the magensium stearate and mix for 5 minutes. Compress on a suitable press.
Example C Wet Granulation Tablet Formulation
mg/tablet Ingredient 10 mg | 20 mg Active ingredient of formula I 10.0 20.0 Lactose 264.0 254.0 Pregelatinised starch 17.5 17.5 Corn starch 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, the lactose and the pregelatinised starch in a suitable mixer. Mill through a suitable mill. Mix with the modified starch and the magnesium stearate and fill on a capsule filling machine.

Claims (29)

WHAT WE CLAIM IS:
1. Compound of the general formula
wherein R1, R2and R3 each independently represent a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkythio, cyclopropyl, cyclobutyl or hydroxy group and R4 represents a cyano, 5-tetrazolyl, hydroxy-(lower alkyl) or acyloxy (lower alkyl) group or a group of the formula
in which A represents a lower alkyl, hydroxy, lower alkoxy, di(C1-C7 alkyl)amino-(C2-C7 alkoxy) or pivaloyloxymethyl group or a group of the formula
in which R5 and R6 each independently represent a hydrogen atom or a lower alkyl or di(C1-C7 alkyl)amino-(C2-C7 alkyl) group, Y represents a hydrogen atom or a methyl group and n stands for zero or 1, with the proviso that at least one of R1,R2 and R3 represents other than a hydrogen atom and with the proviso that at least one of R1, R2 and R3 represents a lower alkylthio, cyclopropyl or cyclobutyl group and/or R4 represents an acyloxy-(lower alkyl) group or a group of the formula
in which A, Y and n have the significance given above, except that, in the case where n stands for zero, A cannot represent a hydroxy or lower alkoxy group or the group of the formula
said provisos not acting to exclude compounds of general formula I wherein (a) R4 represents a carboxy group in the 8-position and either (aa) R1 represents ethyl, isopropyl, butyl, ethoxy, propoxy, isopropoxy, butoxy or amyloxy and R2 and R3 represent hydrogen or (ab) R1 represents hydrogen and either one of R2 and R3 represents methoxy and the other represents hydrogen or R2 represents hydrogen and R3 represents chlorine or (ac) R1 and R3 represent methoxy and R2 represents hydrogen or methoxy; (b) Rl represents methoxy, R2 and R3 represents hydrogen and R4 represents (ba) a carboxy group in the 6- or 7-position, or (bb) 5-tetrazolyl, hydroxymethyl, cyano or the group -COA in the 8-position, wherein A represents diethylaminoethylamino, amino, dimethylamino, methoxy or pivaloyloxymethyl, and (c) R1 represents isopropoxy, R2 and R3 represent hydrogen and R4 represents cyano in the 8-position; pharmaceutically acceptable acid addition salts thereof and, when A represents a hydroxy group, pharmaceutically acceptable salts thereof with a base.
2. Compounds as claimed in claim 1 of the general formula
wherein R'" R'2 and R'3 each independently represent a hydrogen or halogen atom or a lower alkyl, lower alkoxy, lower alkylthio or hydroxy group and R4 has the significance given in claim 1, with the proviso that at least one of R'" R'2 and R'3 represents other than a hydrogen atom and with the proviso that at least one of R'1, R'2 and R'3 represents a lower alkylthio group and/or R4 represents an acyloxy (lower alkyl) group or a group of the formula
in which A, Y and n have the significance given above, except that in the case where n stands for zero, A cannot represent a -hydroxy or lower alkoxy group or the group of the formula
3. Compounds as claimed in claim 1, wherein R2 and R3 each represent a hydrogen atom and R4 represents a group of the formula
in which A represents a di(C1-C7 alkyl)amino-(C2-C7 alkoxy) group.
4. Compounds as claimed in claim 1, wherein at least one of R1, R2 and Rs represents a lower alkyl, lower alkoxy or lower alkylthio group and R4 represents a substituent in the 8-position.
5. Compounds as claimed in claim 1, wherein R2 represents a hydrogen atom, R, and/or R3 represents other than a hydrogen atom and R4 represents a substituent in the 8-position.
6. Compounds as claimed in claim 1, wherein R2 represents a hydrogen atom, R, and/or R3 each independently represents a lower alkyl, lower alkoxy or lower alkylthio group and R4 represents a hydroxy-(lower alkyl) or 5-tetrazolyl group or a group of the formula
in which A represents a hydroxy or di(C1-C7)amino-(C2-C7 alkoxy) group.
7.2 - Methylthio - 11 - oxo - 1111 - pyrido[2,1-b]quinazoline - 8 - carboxylic acid.
8. 2 - Isopropyl - 11 - oxo - 1111 - pyrido[2,1-b]quinazoline - 8 - carboxylic acid.
9. 2 - Cyclopropyl - 11 - oxo - 11H - pyrido[2,l-b]quinazoline - 8 carboxylic acid.
10. 2 - 1sopropyl - 11 - oxo - 1 IR - pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2-diethylaminoethyl) ester.
11.2 - Methoxy - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2 - diethylaminoethyl) ester.
12. 2 - Methoxy - 11 - oxo - 1111 - pyrido[2,1-b]quinazoline - 8 - acetic acid.
13. 2 - Cyclopropyl - 11 - oxo - 11H - pyrido[2,1-b]quinazoline - 2carboxylic acid (2-diethylaminoethyl) ester.
14. A process for the manufacture of the pyrido[2,1-b]quinazoline der1vatives claimed in claim 1, which process comprises (a) for the manufacture of a compound of formula I in whch R4 represents a cyano or acyloxy-(lower alkyl) group or a group of the formula
wherein A represents a lower alkyl, hydroxy or lower alkoxy group or a group of the formula -N(R5) (R6) and R1, R2, R3, R5, R6, Y and n have the significance given in claim 1, treating an anthranilic acid or ester of the general formula
wherein K represents a hydrogen atom or a lower alkyl group and R1, R2 and R3 have the significance given in claim 1, with a halopyridine derivative of the general formula
wherein R'4 represents a cyano or acyloxy-(lower alkyl) group or a group of the formula
wherein A represents a lower alkyl, hydroxy or lower alkoxy group or a group of the formula -N(R5)(R6), Y represents a hydrogen atom or a methyl group and n stands for zero or 1, R5 and R6 each independently represent a hydrogen atom or a lower alkyl or di(C1-C7 alkyl)amino-(C2-C7 alkyl) group and X represents a halogen atom, or (b) for the manufacture of a compound of formula I in which R4 represents a 5tetrazolyl group and R1, R2 and R3 have the significance given in claim 1, treating a compound of the general formula
wherein R1, R2 and R3 have the significance given in claim 1, with an alkali metal azide, or (c) for the manufacture of a compound of formula I in which R4 represents a hydroxy-(lower alkyl) group and Rl, R2 and R3 have the significance given in claim 1, hydrolysing a compound of the general formula
wherein R7 represents an acyloxy-(lower alkyl) group and R1, R2 and R3 have the significance given in claim 1, or (d) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a di(C1-C7 alkyl)amino-(C2-C7 alkoxy) group and R1, R2, R5, Y and n have the significance given in claim 1, treating a compound of the general formula
wherein R1, R2, R5, Y and n have the significance given in claim I, with a di(C1-C7 alkyl)amino-(C2-C7 alkyl) halide or subjecting an acid chloride of a compound of formula Ic to alcoholysis with a di(C1-C7 alkyl)amino-(C2-C7 alkanol), or (e) for the manufacture of a compound of formula 1 in which R4 represents a group of the formula
wherein A represents a pivaloyloxymethoxy group and R1, R2, R3, Y and n have the significance given in claim I, treating a compound of formula Ic with a tertiary organic base and chloromethyl pivalate, bromomethyl pivalate or iodomethyl pivalate, or (f) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a lower alkoxy group and R1, R2, R3, Y and n have the significance given in claim 1, esterifying a compound of formula Ic, or (g) for the manufacture of a compound of formula I in which R4 represents a group of the formula
wherein A represents a group of the formula -N (R5)(R6) and R1, R2, R3, R5, R6 Y and n have the significance given in claim 1, subjecting a compound of formula Ic to ammonolysis with a compound of the general formula HN(Rs)(R5) (IV) wherein R5 and R6 have the significance given in claim 1, or (h) for the manufacture of a comopund of formula Ib, condensing an anthranilic acid or ester thereof of formula II with a halopyridine derivative of the general formula
wherein R7 and X have the significance given earlier in this claim, and (i) if desired, converting a compound obtained into a pharmaceutically acceptable salt.
15. A process as claimed in claim 14, wherein a compound according to claim 2 is manufactured.
16. A process as claimed in claim 14, wherein there is manufactured a product according to claim 3.
17. A process as claimed in claim 14, wherein there is manufactured a compound according to claim 4.
18. A process as claimed in claim 14, wherein there is manufactured a compound according to claim 5.
19. A process as claimed in claim 14, wherein there is manufactured a compound according to claim 6.
20. A process as claimed in claim 14, wherein 2 - methylthio - 11 - oxo IIH - pyrido[2,1-b]quinazoline - 8 - carboxylic acid is manufactured.
21. A process as claimed in claim 14, wherein 2 - isopropyl - 11 - oxo - 11H pyrido[2,1-b]quinazoline - 8 - carboxylic acid is manufactured.
22. A process as claimed in claim 14, wherein 2 - cyclopropyl - 11 - oxo IIH - pyrido[2,1-b]quinazoline - 8 - carboxylic acid is manufactured.
23. A process as claimed in claim 14, wherein 2 - isopropyl - 11 - oxo - 11H pyrido[2,l-b]quinazoline - 8 - carboxylic acid (2-diethylaminoethyl) ester is manufactured.
24. A process as claimed in claim 14, wherein 2-methoxy - 11 - oxo - 11H pyrido[2,1-b]quinazoline - 8 - carboxylic acid (2 - diethylaminoethyl) ester is manufactured.
25. A process as claimed in claim 14, wherein 2 - methoxy - 11 - oxo - 11 H pyrido[2,1-b]quinazolin - 8 - acetic acid is manufactured.
26. A process as claimed in claim 14, wherein 2 - cyclopropyl - 11 - oxo 11H - pyrido[2,1-b]quinazoline - 2 - carboxylic acid (2-diethylaminoethyl) ester is manufactured.
27. A process for the manufacture of the pyrido[2,l-b]quinazoline derivatives claimed in claim 1, substantially as hereinbefore described with reference to the Examples.
28. Pyrido[2,1-b]quinazoline derivatives as set forth in claim 1, when manufactured by the process claimed in any one of claims 14 to 27 inclusive.
29. A pharmaceutical preparation containing a pyrido [2,1-b] quinazoline derivative set forth in claim 1 in association with a compatible pharmaceutical carrier material.
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DE2845766A1 (en) * 1978-10-18 1980-04-30 Schering Ag PYRIDO ANGLE CLAMP ON 2,1-B ANGLE CLAMP ON -CHINAZOLINONE DERIVATIVES, THEIR PRODUCTION AND USE
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ES8306729A1 (en) * 1982-04-30 1983-06-01 Lafarquim "PROCEDURE FOR OBTAINING 2-ISOPROPIL PIRIDO (2-1-B) QUINAZOLINAS AND ITS NON-TOXIC SALTS WITH ANTIANAPHILACTIC ACTIVITY".
US4551460A (en) * 1982-05-10 1985-11-05 Hoffmann-La Roche Inc. Pyrido[2,1-b]quinazoline derivatives useful as agents for treatment of allergic conditions and vascular disorders involving thrombosis
DE3300477A1 (en) * 1983-01-08 1984-07-12 Boehringer Ingelheim KG, 6507 Ingelheim NEW HETEROCYCLIC COMPOUNDS, THEIR PRODUCTION AND USE
JPS62238264A (en) * 1986-04-04 1987-10-19 Nippon Tokushu Noyaku Seizo Kk 2-halo-5-acetylpyridine

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US4033961A (en) * 1975-10-07 1977-07-05 Warner-Lambert Company Pyrido[2-1-b]quinazolin-ones and their methods of preparation

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JPS53119897A (en) 1978-10-19
IT1095493B (en) 1985-08-10
PT67821A (en) 1978-04-01
IE46505B1 (en) 1983-06-29
AU3447478A (en) 1979-09-27
AR218480A1 (en) 1980-06-13
NL7803122A (en) 1978-09-26
DK128878A (en) 1978-09-25
ES478325A1 (en) 1979-11-01
IT7821578A0 (en) 1978-03-23
FI780918A7 (en) 1978-09-25
FI780917A7 (en) 1978-09-25
NO781051L (en) 1978-09-26
ES478327A1 (en) 1979-11-01
AT367051B (en) 1982-05-25
ATA210478A (en) 1981-10-15
ES478332A1 (en) 1979-11-16
IT7821655A0 (en) 1978-03-24
FR2384771B1 (en) 1980-04-04
ES468127A1 (en) 1979-09-16
FR2384771A1 (en) 1978-10-20
ES478323A1 (en) 1979-11-01
FR2384770A1 (en) 1978-10-20
AU521096B2 (en) 1982-03-18
ES478333A1 (en) 1979-11-16
AT367050B (en) 1982-05-25
PT67820A (en) 1978-04-01
ES478328A1 (en) 1979-11-01
IL54326A0 (en) 1978-06-15
IE780582L (en) 1978-09-24
NL7803112A (en) 1978-09-26
AU521352B2 (en) 1982-04-01
ES478324A1 (en) 1979-11-01
GR73170B (en) 1983-02-14
GB1601991A (en) 1981-11-04
IL54326A (en) 1982-04-30
LU79290A1 (en) 1979-05-25
IL54328A0 (en) 1978-06-15
SE7803419L (en) 1978-09-25
SE7803418L (en) 1978-09-25
PH14130A (en) 1981-02-26
HU180782B (en) 1983-04-29
LU79293A1 (en) 1979-05-25
MC1185A1 (en) 1978-12-22
ATA210278A (en) 1981-10-15
MC1186A1 (en) 1978-12-22
PH13915A (en) 1980-11-04
NZ186759A (en) 1981-03-16
AR218060A1 (en) 1980-05-15
AU3447578A (en) 1979-09-27
IT1093710B (en) 1985-07-26
DK132778A (en) 1978-09-25
DE2812585A1 (en) 1978-09-28
IL54328A (en) 1982-03-31
DE2812586A1 (en) 1978-09-28
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ES478329A1 (en) 1979-11-01
FR2384770B1 (en) 1980-10-24
NZ186760A (en) 1981-03-16
JPS53119896A (en) 1978-10-19
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PT67821B (en) 1980-03-04
ES478331A1 (en) 1979-11-16
ES468126A1 (en) 1979-09-01
AR225415A1 (en) 1982-03-31
GR72948B (en) 1984-01-17

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