CA1053674A - Fused pyridine-4-(3h)-ones and preparation thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Fused heterocyclic ring systems in which a quinoline or pyridine component is "fused" to a pyrimidine having a 2-methyl, 2-ethyl, or 2-acetyl group and a 4-keto group, and to similar ring systems in which a quinoline, a naphthalene or a pyridine component is "fused" to a pyrimidine having a 2-carboxy group and a 4-keto group, derivatives, and pharmaceutically-acceptable cationic salts thereof, and their use as antiallergy agents, and intermediates therefor.

Description

10~3~7~

This invention relates to fused pyridine-4-(3H)-ones and preparation thereof.
This application is related to our copending appli-cation, Serial No. 197461 (5468(A)), filed April 11, 1974.
This invention relates to fused heterocyclic ring systems in which a quinoline, a naphthalene or a pyridine ring system is fused to a 2-methyl, 2-ethyl~ or 2-acetyl pyrimi~ine-4 (3H)-one or to a pyrimidine-2-carboxylic acid 4(3H)-one or a derivative thereof, and their use as anti-allergy agents.
More particularly, it relates to 2-alkyl-pyrimido[4,5-b]-quinolin-4(3H)-ones, 2-alkylpyrido[4,5-b]-pyrimidon-4(3H)-ones wherein alkyl is methyl or ethyl, and the corresponding 2-acetyl derivatives, pyrimido[4,5-b]-quinolin-4(3H)-ones-2-carboxylic acids, benzo[g]quinazolin-4(3H)-one-2-carboxylic acids, and pyrido-[2,3-d]pyrimidin-4(3H)-one-2-carboxylic acids; esters, amides, and pharmaceutically-acceptable salts thereof which are useful as inhibitors of allergic reactions, and especially of allergic bronchial asthma.
Similar compounds of this type are more fully described in the above application which sets out the nature of the art.
It has now been found in addition to ~he type of com-pound illustrated and claimed in the above identified appli-cation the following fused pyrimidines having the formulae:

-2- ~

~ OS3674 N-~
~ N ~ N ~ COR
and the pharmaceutically-acceptable cationic salts thereof al~o exert potent allergy effect~ in mammals, including man, by an Intal-like mechanism ("Intal" is a Trademark). In contrast to Intal, many of these compounds are effective via intraperitioneal and oral administration, as well as by lnhalation and intravenous administration.
In the abovo Fromulaes 1~ R is selectod from the group consisting of hydroxy, al~oxy of 1-4 carbon atoms, hydroxyalkoxy, amino, hydroxyamino;

-3-each of R3 and R4, is selected from the group consisting of ~a~ hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halo benzyloxy methylthio, methylsulfinyl and (b) hydroxy, thiol, alkanoyloxy of 1-4 carbon atoms, benzpyloxy, benzylthio and benzylsulfinyl;
providing that at least one of R3 and R4 is selected from group ~b).
The terms "alkyl," "alkanoyloxy" and'alkoxy" as used herein include alkyl, alkanoyloxy and alkoxy groups of from 1 up to, and including, 4 carbon atoms; the term "hydroxyalkoxy" includes hydroxyalkoxy groups having from 2 up to, and including, 4 carbon; and the term "carbalkoxy" including, 4 carbon atoms; and the term "carbalkoxy" includes carbalkoxy groups having from 2 up to, and including, 5 carbon atoms. The term "halo"
includes chloro, bromo, fluoro, and iodo.
By the term "pharmaceutically-acceptable cationic salts" is intended salts such as the alkali metal salts, e.g., sodium and potassium; alkaline earth metal salts such as calcium and magne~ium; aluminum salts; ammonium sal~s;
and salts with organic bases, e.g., amines such as triethyl-amine, tri-n-butylamine, piperidine, triethanolamine, di-ethylaminoethylamine, N,N'-dibenzylethylenediamine and pyrrolidine.
The following compounds are of particular interest to this invention:
Formula I: R is alkoxy or hydroxy; and R3 and R4 are hydrogen, hydroxy, or alkoxy; provided that when one of R3 or R4 is hydroxy, the other is alkoxy.
Special interest exists in the following compounds o~ Formula I:

-4--~;

R R3 4_ alkoxy OC~3 OH
Compounds of Formula I, wherein R is alkoxy are also valuable intermediates for production of compounds wherein the 2-substituent is carboxy or carbamyl.
Compound~ wherein either of R3 and R4 is benzyloxy, benzylthio or methylthio, serve as intermediates for compounds whereln the R group is hydroxy, alkanoyloxy thiol, methyl-sulfinyl, or benzylsulfinyl.
The antiallergy property of the compounds of thisinvention i8 evaluated by the passive cutaneous anaphylaxis ~CA~ test ~Ovary, J. Immun. 81, 355, 1958). In the PCA test, normal animals are injected intradermally (i.d.) with anti-bodies contained in ~erum obtained from actively sensitizedanimal~. The animals are then challenged intravenously with antigen mixed with a dye such as Evans' Blue. The increased capillary permeability caused by the an$igen-antibody reaction cause~ the dye to leak from the site of the antibody injection.
Tho test animals aro then asphyxiated and the intensity of the reaction determined by measuring the diameter and intensity of the blue coloration on the inner surface of the animals skin.

10536~4 Compounds of Formula I and the pharmaceutically acceptable cationic salts thereof wherein;
each of R3 and R4 are as hereinbefore defined may be obtained by reacting a compound of the Formula:

R3 _ =~ COR I

~' with a reagent A-Z
A) wherein when R' i6 NH2 and R iB COR then A-Z i~
(a) a dialkyl oxoalate;
(b~ a monoacid halide (chloride, bromide) of a half-alkyl oxalic acid ester;
~c~ an alkyl cyanoformate;
~d) a dialkyl ester of monoiminooxalic acid ~a carbalkoxy formimidate);
~e~ an alkyl ester of oxamidic acid;
~f) l-cyanoformamide;
~g) cyanogen; and ~h~ l-carbalkoxyformamidine; or B) wherein when Rl is an ester moiety then A-Z
is a l-carbalkoxyformamidine;
and when R in Formulae I or III is alkyl and at Rl, R2, R3, R4 and R5 is other than hydrogen, then A-Z i5 an alkanoic acid anhydride or triethyl ortho-acet~te or triethyl orthopropionate;
and whon R i~ acetyl by oxidation of the compound :l~S3~74 wherein R i8 ethyl;
and when A-Z contains a cyano group hydrolyzing the thus produced cyano derivative;
and when R is alkoxy, reacting the ester with hydroxylamine to convert R to hydroxyamino;
and when Y is other than hydrogen by reaction of the compound where Y is hydrogen with an appropriate reactant;
and when any of R2-R5 is benzyloxy or benzylthio debenzylating the benzyl ether or benzylthio ether, if desired;
and when any of R2-R5 is benzylthio, oxidizing it to benzylsulfinyl, if desired.
The compounds of this invention can be prepared by a variety of methods.
It will be appreciated that since the compounds of this invention are similar to those of the earlier application tochnlcal data appearing in that application is applicable to the practicability in chemical terms for the preparation of the fused compounds though otherwise the specific compounds of the present invention and the properties thereof are not nece~sarily practicable from data in that application.
Compounds of Formula I can be prepared by methods in which u~e iB made of the intact carbocyclic ring and the quinoline and pyrimidine systems built up in many ways.
These methods have, as a common gr~und, the construction of the -2-aminoquinoline-3-carboxamide, or 3-J

lOS367~carboxy acid or ester thereof, from the intact carbocyclic ring and subsequent use of the quinoline system as a basis for building up the pyrimidine ring. The general scope of these methods is summarized in the se~uence below wherein R' represents hydroxy, alkoxy and amino:
CN~ROUTE A) R4 ~ C O CH3> R3 ~ \ ~ ~COR' R3 ~ N-H 3 ~ ~ sOR' R4 ~ ~ ~ COR~ R4 ~ ~ NH2 ~ROUTE B~ ~

R3 ~ + 1~ V

R' The preferred process on the basis of yield and quality of the final product of Formula I is illustrated by Route A. Alternate methods, e.g., Route B, can also be used a~ i6 discu~sed below.
In each of Routes A and B, the condensation involves the carbocyclic aldehyde or ketone with an active methylene nucleoph$1e, The requisite carbocyclic aldehydes or ketone 1053~74 reactants are known materials or are prepared by methods described in the art. By "active methylene" nucleophile i~ meant a compound having a.relatively acidic methylene group; that is, a methylene group linked to one, and preferably two, electron-withdrawing groups such as -CN, -COCl, -C(NH)NH2, COR' -C(NH~C-alkyl and CO-alkyl.
The condensation is conducted in the presence of a reaction-inert solvent; that is, a solvent which is not changed as a result of the reaction even though it m~y partcipate in the reaction in the role of a cataly~t or in salt formation with a reactant or product.
Suitable solvents are alkanols, such as methanol, ethanol, isopropanol, n-butanol and n-hexanol; chlorinated solvents such as methylene chloride, ethylene chloride, chloroform and carbon tetrachloride; pyridine; aromatic hydrocarbons such as benzene, toluene, xylene; hexane; and N,N'-dimethylformamide. Other solvents are found by simple experimentation. Methanol is a preferred solvent, especial-ly when using piperidine as catalyst, because, of the satisfactory yields, ease of separation and purity of products. A solvent system of piperidine and pyridine is frequently a useful system.
A catalyst is often used to facilitate the con-densation even when the nucleophiles possess two activating groups as do derivatives of cyanoacetic acid. Suitable catalysts are ammonia, primary, secondary, and tertiary amines, such as n-butylamine, diethylamine, triethylamine, pyridine, piperidine, pyrrolidine, alkali metal alkoxides and fluorides, stannous fluoride, and basic ion-exchange resins of the amine type, e.g., Amberlite IR-45 (a weakly 1~53~i7~
basic polystyrene with polyamine groups, available from Rohm & Haas Co. ~Amberlite" is a trademark)and De-Acidite G ~poly-styrene resin with diethylamino groups; available from the Permutit Co., Ltd., London "De-Acidite" is a trademark).
The amount of catalyst used is not critical but can vary over a wide range, i.e., from about 0.1~ to about 100% b~
weight based upon the carbocyclic aldehyde reactant. The favored range of catalyst i8 from about 10~ to about 30% by weight of the carbocyclic aldehyde reactant.
The reaction is conducted at a temperature of from about 0C. to about 50C. and generally at about ambient tem-perature for periods of from about one-fourth to five hours.
The products generally separate from the reaction mixture as solids and are recovered by filtration. Those which do not separate as solids are recovered by evaporation of the solvent or by pouring into a large volume of a non-solvent for the product.
The use of an o-nitrobenzaldehyde or an Rl-(2-nitro-phenyl) ketone as the reactant (Route A) produces an ~-cyano-~-(2-nitrophenyl)-acrylamide derivative, e.g., an amide when R' of the active methylene reactant is NH2, which must subsequently be reduced and cyclized to provide the desired 2-aminoquinoline-3-carboxylic acid derivative. Reduction tof the nitro group to an amino group) i~ accomplished by a variety of reagents. In brief, any reagent which will selectively or preferentially reduce the nitro group to an amino group can be used. Rep-resentative of such reagents are metal-acid combinations such as iron-acetic acid, iron-hydrochloric acid, tin or stannous chloride-hydrochloric acid, zinc-hydrochloric acid, zinc dust-alkali; and catalytic hydrogenation using catalysts such as lOS;~674 platnum, palladium and Raney nickel.
The reduced product appears to cyclize immediately, or almost immediately, to provide the 2-aminoquinoline-3-carboxylic acid derivative.
When using an o-aminobenzaldehyde as reactant (Route B) the condensation product with the cyanoacetic acid derivative cyclizes at a very rapid rate to the 2-aminoquino-line-3-carboxylic acid derivative as noted above for the reac-tion product of Route A.
Formation of the fused pyrimidine ring with its 2-carboxylic acid derivative (ester or amide) substituent can be accomplished by a number of methods. For convenience, these methods are considered on the basis of the structure of reactant W-Z which contributes the one-carbon fragment to complete the pyrimidine ring system upon the appropriate 2-aminoquinoline-3-carboxylic acid derivative:
(1) Reaction of a 2-amino~uinoline-3-carboxamide ~Formula V, R'=NH2) with:
(a) a dialkyl oxalate;
(b) a monoacid halide (chloride, bromide) of a half-alkyl oxalic acid ester;
(c) an alkyl cyanoformate;
(d) a dialkyl ester of moniminooxalic acid (a carbalkoxy formimidate);
(e) an alkyl ester of oxamidic acid;
(f) l-cyanoformamide;
(g) cyanogen; and (h) l-carbalkoxyformamidine; or (2) Reaction of an alkyl 2-aminoquinoline-3-carboxylate with:

(a) a l-carbalkoxyformamidine.
Reactant W-Z (an oxalic acid derivative) of the step common to Routes A and B provides the one-carbon frag-ment needed to complete the fused pyrimidine ring. It may, depending upon choice of reactants, also provide the -NH group.
It represents cyanogen and W-COR whrein W is -COCl, -CN, -COR , -CO-alkyl, -C(NH)NH2 and -C(NH)O-alkyl. When W-Z
is an alkyl ester of oxamidic acid, e.g., HsC2OOC-CONH2, the cycl~zation reaction occurs 80 as to produce the amide (R=COL~H2) of Formula I.
It is evident that one of the two reactants in the final step of Routes A and B above must provide the -NH moiety. When the reactant upon which the fused pyrimidine ring i8 to be formed containq a carboxamide group (e.g.
formula V wherein -COR' is -CONH2), reactant W-Z can be any of the substances enumerated above; i.e., cyanogen or ~-COR.
However, when the reactant upon which the fused pyrimidine ring is to be formed does not contain a carboxamide group;
that i9, when -COR' is carboxy or carbalkoxy, or haloformyl, reactant W-Z must provide the -NH group.
The favored process comprises using the appropriate 2-amino-3-carboxamide (Formula V wherein R'~,~H2) as reaatant which is condensed with the W-Z reactant to provide only the one-carbon fragment to complete the pyrimidine ring.
Reaction of the 2-aminoquinoline-3-carboxylic acid derivative with reactant W-Z is carried out in a reaction-inert sclvent and desirably, when W is -COR or C(NH)-O-alkyl, one which will permit removal of by-product alcohol and water by distillation. Representative solvents for this cyclization are aromatic hydrocarbons such as xylene, toluene, benzene;

an excess of the chosen dialkyloxalate reactant; tetralin and decalin.
Suitable solvents are readily determined by ex-perimentation. A favored solvent when W-Z i8 a dialkyl oxalate i9 an excess of the dialkyl oxalate because of its ability to ~olubili2e the reactants and to permit slmplo removal of by-product alcohol and water. Although the reac-tion temperature is not critical, the reaction i8 generally run at an elevated temperature to facilitate removal of alcohol and water. Temperatures of from about 150C. to about 185C. are useful when a dialkyl oxalate i8 used as solvent. Lower temperatures can be employed with the more reactive oxalic acid derivatives (W-Z) 6uch as ethyl oxalyl-chloride. A final fusion or heating period is sometimes beneficial to achieving maximum cyclization and yield of the desired pyrimido~,5-b7quinolin-4(3H)-one-2-carboxylic acid derivative. The addition of a ~mall amount of a base, ~uch as sodium hydride and alkali metal alkoxides, i8 frequently useful in promoting cyclization, expecially in making com-pounds of Formula II.
When reactant W-Z reqults in production of the 2-cyano derivative rather than a 2-COR derivative, the ~yano group is converted to the corre~ponding 2-carboxamide by acid hydrolysis. When W-Z is a monoacid halide of a half-alkyl oxalic acid ester, an acid acceptor; i.e., an organic or inorganic base, such as triethylamine, pyridine, sodium methoxide, sodium hydroxide, is used to neutralize the by-product acid formed.
When reactant W-Z represents an alkyl ester of 0 glycolic acid, the fused pyrimidine~ of Formulae I-III pro-duced bear the hydroxymethyl group at the 2-position. Such compounds serve as precursors for corresponding aldehydes.
The conversion is accomplished by oxidation using chromic anhydride in pyridine (Sarett reagent) or chromic anhydride-pyridine-water (Cornforth reagent). The latter reagent is preferred because of its ease of preparation and handling relative to the Sarett reagent. Further oxidation of the 2-carboxaldehyde leads by, for example, chromic anhydride-sulfuric acid at about 30C-50C. produces the 2-carboxylic acid.
Alternatively, the appropriate alkyl benzyloxy acetate; e.g., ethyl benzyloxyacetate, is used as reagent W-Z to produce compounds of Formulaes I-III wherein the substituent is a 2-benzyloxymethyl group. The benzyl groups of the 2-benzyloxymethyl derivatives thus-produced are removed by reaction with strong acids such as trifluoroacetic acid in the manner described below.
The 5-substituted compounds of Formula I are also prepared from the appropriate 4-substituted 2-aminoquinoline-3-carboxamide which, in turn, is prepared by the reaction of malononitrile with the appropriate Rl-(2-aminophenyl) ketone, e.g., 2-aminobenzophenone (Rl-phenyl) and aminoacetophenone (Rl=CH3). The 2-amino-3-cyano-4-substituted quinoline thus produced is hydrolyzed to the corresponding 4-substituted-2-aminoquinoline-3-carboxamide by heating with 95% sulfuric acid, followed by aqueous work-up. The process is that described by Campaigne et al., J. Hetero. Chem. 8, 111-120 (1971).
A further method comprises condensation of an appropriate o-nitrobenzaldehyde with a dialkylmalonate to 0 produce an alkyl -carbalkoxy-~-(2-nitrophenyl)acrylate which ~053674 is subsequently reduced to the corresponding alkyl a-carbalkoxy-~-(2-aminophenyl)acrylate according to procedures described above. The reduced product spontaneously cyclizes to an alkyl 2-oxo-quinoline-3-carboxylate. The 2-oxo deriva-tive is heated directly with l-carbalkoxy formamidine in ethanol using sodium ethoxide to give compound~ of Formula I.
Or, the 2-oxo derivative is chlorinated with a suitable chlorinating agent such as phosphorous trichloride, phospho-rous pentachloride, phosphorous oxychloride in a reaction-inert solvent such as an aromatic hydrocarbon or a halogenatedaliphatic or aromatic hydrocarbon (benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, chloro-benzene) at a temperature of from about 50C. to 100C.
The alkyl 2-chloroquinoline-3-carboxylate thus produced is reacted with an alkyl l-guanylformate to provide the corre~ponding alkyl pyrimido-~,5-b7quinolin-4(3H)-one-2-carboxylate. This cyclization is carried out according to known methods.
Still a further method comprises construction of the central pyridine ring. It involves condensation of the appropriate o-nitrobenzaldehyde with an ester, e.g., an alkyl ester of 4,6-dioxo(3H,SH)-tetrahydropyrimidine-2-carboxylic acid, in the presence of a base to produce the corresponding 4,6-dioxo(3H,5H)-5-(2-nitrobenzylidene)tetrahydropyrimidine-2-carboxylic acid ester which, upon subsequent reduction in the manner described above, spontaneously cyclizes to a com-pound of Formula I. A variation on this method involves çon-densation of the o-nitrobenzaldehyde malondiamide, followed by reaction of the product with a dialkyl oxalate to form the above nitrobenzylidene compound.

Compounds of Formula II (R = COR) are prepared by methods similar to those described above for compounds of Formula I but using, of course, in place of a 2-aminoquinoline-3-carboxamide, a 2-aminonaphthalene-3-carboxamide. The reac-tion conditions for achieving construction of the pyrimidinering are substantially the same as those described for com-pounds of Formula I.
The compounds of Formula III (R = COR) are similar-ly prepared from appropriate 2-aminonicotinamide or precursors thereto, e.g., 2-aminonicotinic acid, 2-nitropyridine-3-carboxamides or 3-carboxylic acids, 2-nitro or 2-aminopyridine-3-carboxaldehydes. In preparing compounds of Formulae II and III, the favored routes comprise reacting W-Z with the appropriate 2-amino-3-carboxamide reactant.
lS The amide and hydroxamic acid derivatives of Formulae I,II, and III (R =NH2,NHOH) are prepared by methods described above from W-CONH2, W-CONHOH or by reaction of the precursor alkyl ester of Formulae I, II, and III with ammonia or hydroxylamine. The usual procedure which o~prises reacting the appropriate ester with ammonia or with hydroxylamine hydro-chloride, usually in excess, in the presence of an acid acceptor such as triethylamine. The reaction is facilitated by heating under pressure, i.e., the reaction is carried out in a bomb, in a solvent such as ethanol for from about ~ to about 20 hours and the product then recovered by suitable means.
The 2-methyl and 2-ethyl analogs of Formulae I and III are prepared by cyclization of the appropriate 2-amino-quinoline-3-carboxamide or 2-aminonicotinamide with the appro-0 priate alkanoic acid anhydride e.g., acetic or propionic-17-anhydride; or with triethyl orthoacetate or triethyl orthopro-pionate in the presence of sulfuric acid. Treatment of the product with dilute alkali followed by reacidification provides the 2-methyl or ethyl analogs. The preparation of 2-methylpyrimido/4,5-b7quinolin-4(3H)-one by this procedure i8 reported by Taylor et al., J. Am. Chem. Soc. 78, 5108-15 (1956) as previously noted. The 2-ethyl analogs, new compounds are primarily of value as intermediates for preparation of the corresponding 2-acetyl derivatives of Formulae I and III.
The 2-acetyl derivatives of Formulae I and III
are prepared by oxidation of the corresponding 2-,ethyl derivatives with selenium dioxide and water in a suitable solvent medium, for example, dioxane. In the usual procedure the 2-ethyl derivative and selenium dioxide are used in about a 2:1 molar ratio at an elevated temperature, e.g. from about 50 to about 100C. Additional selenium dioxide beyond the 2:1 molar ratio can be used to expedite the oxidation.
The 2-methyl analogs of Formulae I and III are useful intermediates for preparation of corresponding 2-carboxaldehydes and 2-carboxylic acids, and from them, of corresponding esters of the acids.
A useful procedure for preparing 2-carboxylic acids comprises refluxing the appropriate 2-methyl derivatives in a solvent such as ethanol with a slight excess of benzal-dehyde in the presence of sodium ethoxide or piperidine, or other base, to form the benzylidine adduct. The amount of base used is not critical but can vary from a catalytic amount (<1%) up to an equivalent amount. The benzylidene adduct is isolated by removal of the solvent and is then oxidized to the acid by excess cold potassium permanganate in aqueous acetone, or by ozonolysis. Alternatively, the methyl group is converted to the corresponding 2-bromomethyl compound by reaction with N-bromosuccinimide in chloroform. The succinimide by product is removed by concentration of the reaction mix-ture and filtration. The filtrate is taken to dryness andthe residue dissolved in aqueous sulfuric acid and treated with chromium trioxide to provide the acid.
Conversion of the 2-methyl groups to 2-carboxal-dehyde groups is achieved by oxidation with selenium dioxide and water in the manner described above for conversion of 2-ethyl to 2-acetyl groups. Alternatively, the 2-methyl group is transformed to the 2-bromomethyl group according to the procedure mentioned above which is then hydrolyzed to the corresponding 2-hydroxymethyl group.
lS The alkylene glycol esters of Formu]ae I-III
(R=COR wherein R is hydroxyalkoxy) are conveniently prepared by a base catalyzed transesterification process.
The process comprises treating a compound of Formulae I-III
wherein R is alkoxy with an alkylene glycol, preferably in the presence of a catalytic amount of a base (i.e., from about 5% to about 20% by weight based upon the alkylene glycol used), such as triethylamine or calcium hydroxide, in air at a temperature of from about 20C. to about 50C. Higher temperatures can be used but appear to offer na advantage.
Compounds of Fromula I wherein Y is other than hydrogen are prepared by alkylation of Formula I compounds wherein Y is hydrogen. The procedure comprises formation of the sodium salt by reaction of the appropriate Formula I
compound with sodium hydride in a suitable solvent e.g., N, N-dimethylformamide. Reaction of the sodium salt with I-Y, ~OS3674 Br-Y (or Cl-Y) affords the alkylated derivatlve. When using Cl-Y as alkylating agent, the presence of a small amount of sodium or potassium iodide ~from about 10% to 20% by weight of C1-Y) serves to accelerate the reaction.
Compounds of Formulae I-III wherein any of R2, R3, R4, or R5 is benzyl or methylsulfinyl are readily prepared from the corresponding thioether compounds by oxidation with an appropriate oxidizing agent such as hydrogen peroxide or a per acid such as m-chlorperbenzoic acid accord to methods known to those skilled in the art.
The methylthio compounds are, in turn, readily prepared by the reaction of the corresponding chloro com-pound of Formula IV; i.e., an ~-cyano-~-(2-nitro-chlorophenyl) acrylamide, with sodium methyl mercaptide. Modifications of this method are obvious to those skilled in the art. For example, the methylthio ether of Formula IV can be made by in situ formation of the methyl mercaptide salt. Similarly, benzyloxy, benzylthio, and alkoxy compounds are prepared by reacting the corresponding chloro compound of Formula IV with sodium benzyloxide, sodium benzylmercaptide, or a sodium alkoxide.
Compounds of Formulae I-III wherein any of R2-R5 is benzyloxy or benzylthio serve as intermediates for the corresponding hydroxy and thiol compounds and acyl derivatives thereof. Debenzylation is conveniently accomplished by treat-ing the benzyl ether or benzylthio ether with trifluoroacetic acid. The debenzylated products are obtained as their tri-fluoroacetate salts. The hydroxy and thiol compounds, in turn, are intermediates for preparation of corresponding alkanoyloxy, and benzoyloxy derivatives by acylation using -lOS3674 the appropriate acid anhydride e.g. acetic anhydride. A
catalytic amount of p-toluenesulfonic acid is generally used to expedite the reaction.
The products of this invention and the pharmaceuti-S cally-acceptable cationic salts thereof, are useful for the control (prophylactic and therapeutic treatment) of allergic symptoms and reactions in mammals and can be administered either as individual therapeutic agents or as mixtures of therapeutic agents, for example, with theophylline or sympathomimetic amines, by the oral, parenteral or inhalation routes. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
Typical methods of administration and butylene com-positions are described in greater detail in the aforesaid patent application.
It is necessary that the active ingredient form a proportion of the composition such that a suitable dosage form will be obtained. Obviously, several dosage unit forms can be administered at about the same time. Although com-positions with less than 0.005~ by weight of active ingredient might be used in certain instances, it is preferred to use compositions containing not less than 0.005% of the active ~ngredient; otherwise, the amount of carrier becomes exces-sively large. Activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75, 95 or an even higher peLcentage by weight of the active ingredient.
The PCA reaction test procedure employed to evalu-ate the compounds of the present invention demonstrates an excellent correlation between activity for compounds in this test and their utility in the treatment of allergic asthma.
The ability of agents to interfere with PCA reactions is measured in male Charles River Wistar rats, 170-210 g. Re-aginic antisera is prepared according to Mota, Immunology, 7. 681 (1964) using hen egg albumin and B. pertussis. Hyper-immune antisera to hen egg albumin is prepared according to Orange, et al., J. Exptl. Med., 127, 767 (1968). Forty-eight hours prior to antigen challenge the reaginic antisera is injected intradermally (i.d.) into the shaved skin of a normal rat's back; five hours before challenge the hyperimmune antisera is similarly injected; five hours later, at a third site, 60 meg. histamine dihydrochloride is injected (i.d.) as a check for antihistaminic and unspecific types of blockage;
the compounds of the instant invention or saline are then ad-ministered i.v. and immediately followed by 2.5 mg. Evan's blue dye and 5 mg. egg albumin in saline. In the case of oral administration Evan's blue dye and egg albumin are given five minutes after administration of the drug. Thirty minutes later the animals are asphyxiated using chloroform and the skin of the back removed and reversed for observa-tion. A score is assigned each injection site equal to the product of the diameter of the site in mm. and a grade of 0.1, 0.5, 1, 2, 3 or 4 proportional to intensity of dye coloration. The scores for a given injection site are summed for each group of 8 animals and compared to the saline treat-ed controls. The difference is expressed as per cent blockage due to the compound employed.
Compounds representative of those in the present ~053674 invention are tested by the aforementioned procedure and the resulting activities are reported as the degree (%) of pro-tection.

R~ i~ J

TABLE I

Antiallergy Activity of Pyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylic Acid Derivatives (Formula I).

I.V.* Oral*
R Rl R2 R3 R4 R5 mg/kg. ~ mg/kg. %
.

0C2H5 H H OH OCH3 H 0. 03 97 30 6 0.01 98 0.003 94 0.0003 38 a)OH H H OH CCH3 H 3 100 0.01 86 .003 90 C00-(n-C4Hg~ H H OH OCH3 H 3 100 10 672 .003 52 OX~(n-C4Hg~ H H CH3COOOCH3 H 3 100 10 36 COCC2H H H OH H H0.3 92 10 13 0.Q3 21 3 4 0.03 91 .003 4 Cooc2H H H CCH3 OH H0.003 0 0.3 100 3.0 100 *The superscripts indicate a particular value is an average of two or more determinations.

It is considered that an effective daily oral dosage of the compounds of the present invention in humans of from about 1(~53~74 10 to about 1,500 mg. per day, with a pre erred range of about 10 to about 600 mg. per day in single or divided doses, or at about 0.2 to about 12 mg./kg. of body weight will ef-fectively alleviate broncho-constriction in human subjects.
These values are illustrative and there may, of course, be individual cases where higher or lower dose ranges are merited.
When administered intravenously or by inhalation, the effective daily dose is from about 0.5 to about 400 mg.
per day and preferably from about 0.25 to 200 mg. per day, or at about 0.005 to 4 mg./kg. of body weight in single or divided doses.
EXAMPLE I
Ethvl-9-benzyloxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carb-oxylate.
A) 2-Amino-8-benzyloxy quinoline-3-carboxamide.
Cyanoacetamide (19.4 g., 0.23 mole) is added to a solution of sodium ethoxide (6.65 g., 0.29 mole) in absolute ethanol (460 ml.) maintained at 50C. The mixture is stirred and 2-amino-3-benzyloxybenzaldehyde (52.3 g., 0.23 mole) in absolute ethanol (100 ml.) added. After fifteen minutes stirring at 50C., the reaction mixture is cooled in an ice bath, filtered and dried to give the product.
B) Ethyl-9-benzyloxy Pyrimido[4,5-b]quinoline-4(3H)-one-2-carbox~late.
A mixture of 2-amino-8-benzyloxyquinoline-3-carbox-amide (41.7 g., 0.134 mole) and dibutyl oxalate (500 ml.) is heated to reflux for 4 hours while distilling off the butanol-water formed. The reacticn mixture is then cooled to room temperature, the solid product filtered off, washed with di-ethyl oxalate and air dried. It is purified by recrystal--24~

lization, with decolorization, from hot chloroform.
EXAMPLE II
Ethyl-7-benzyloxy-8-methoxy pyrimido[4,5-b]quinolin-4~3H)-one-2-carboxylate.
A~ ~-cyano-B-(2-Nitro-4-methoxv-5-benzyloxvphen acrylamide.
Piperidine (2.1 g., 0.0237 mole) and 2-~yano-acetamide (22.0 g., 0.263 mole) are added to a slurry of 3-benzyloxy-4-methoxy-6-nitroben2aldehyde (0.237 mole) in methanol (500 ml.). The mixture is heated to r~flux for t~o hour~ and then cooled in an ice bath and filtored. The bright yellow filter cake is washed with cold isopropanol ~300 ml.) and then air dried. Yield - 45 g.~; m.p. 157-158-C.
Following the procedure of preparations above, but using the appropriate alkoxy substituted nitrobenzaldehyde reactant, the compounds listed below are prepared:

R3~CONH2 R4 ~ 2 CN

R2 R3 R4 R5 m.p.(C) Yield H OC2H5 OC7H7 H 167-167.5 (dec.) 73 B) 6-Benzyloxy-7-methoxy-2-aminoquinoline-3-carbox-amide.
Iron powder (65.2 g., 1.22 mole~) is added over a period of one-half hour to a slurry of the product of proce-dure A ~0.271 molç) in a 50% solution of acetic acid-N,N-di-1~53674dimethylformamide (750 ml.) at 75C. When addition of the iron powder is complete, the mixture is hea~ed to 90C., for four hours and then filtered while hot. The filter cake is washed with hot acetic acid (150 ml.). The dark red filtrate is gradually added to lN hydrochloric acid (1,500 ml.) and the pink precipitate recovered by filtration and rQcrystal-lized from an excess (10%) of aqueous sodium hydroxide. The solid is filtered, washed with cold isopropanol and dried to give the title product as yellow crystals. Yield ~ 80%;
m.p. 264-266C.
Upon repetition of procedure B above but using the appropriate a-cyano-~-(2-nitrophenyl)acrylamide from proce-dure A, the following compounds are prepared:

~, ~ ~ ~2 R2 R3 R4 R5 m-p. (C.) % Yield H OC2H5 OC7H7 H 279-80 (dec.) 73 H OCH3 OC7H7 H 282-3 (dec.) 95 C) Ethyl-7-benzyloxy-8-methoxy pyrimido[4,5-b]guinolin-4(3H)-one-2-carboxylate.
To a round-bottomed flask equipped with stirrer, reflux condenser and Dean-Stark apparatus and containing a mixture of diethyl oxalate (50 ml.) and xylene (80 ml.) at reflux is added the product of procedure B (0.012 mole). The xylene, water and ethanol are distilled off and collected over a four hour period. When all the xylene is removed, the 1053674reaction mixture is brought to 185C., cooled to about 100C.
and then slowly poured into chloroform (300 ml.). The chloro--form solution is cooled and the brown precipitate which forms removed by filtration. The filtrate is decolorized with charcoal, concentrated and chilled to give a crystalline mass.
The crystals are taken up in hot chloroform, the ~olution charcoaled, filtered and concentrated to give pale yellow crystals 25%; m.p. 274-275C.
Still further, a mixture of 6,7-dimethoxy-2-amino-quinoline-3-carboxamide (0.5 g., 2 millimoles), ethyl cyano-formate (0.43 g., 44 millimoles) and benzene (30 ml.) is refluxed for three days. The mixture is then cooled, filter-ed and the solid extracted with chloroform. Concentration of the chloroform extract affords the product which is recrystal-lized from chloroform.
Following the procedure of C above, but using theappropriate alkoxy substituted 2-aminoquinoline-3-carboxamide reactant from B above and the appropriate ester of oxalic acid, the compounds listed below are prepared:

R 1 ~ ~ ~ ~ ~H

R ~2 R3 R4 R5 m-p- (C.) ~ Yield OC2H5 H OC2H5 OC7H7 H 241-2 (dec.) 41 OC2H5 H OCH3 OC7H7 H 254-5 (dec.) 8 O-n-C4Hg H OC7H7 OCH3 H 261-2 ~dec.) 13 C2H5 H OC7H7 H H 255-7 (dec.) 32 1~)53674 D) 7-Benzvloxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acid.
Ethyl 7-benzyloxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)- one-2-carboxylate (7.4 mM) in 5~ aqueou~ sodiumhydroxlde (37.5 ml.) i~ stirred at room temperature for twenty hours.
The e~ter dissolves within ten minutes and is followed by the gradual appearance of a light colored precipitate. The reaction mixture is acidified by the 8Iow addition of 10% aqueous hydro-chloric acid (13 ml.). The light colored precipitate di~solves and a yellow precipitate forms. The acid mixture is stirred for 45 minutes and then filtered. The filter cake is washed-with water and then dried in vacuo.
The remaining products of Example II-C are hydrolyzed according to procedure D to afford the corresponding acids.
EXAMPLE III
EthYl-7-benzYloxv-8-ethoxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate.
A) ~-Cyano-~-(2-nitro-4-benzyloxy-5-ethoxyphenyl)-acrylamide.
A mixture of 3-ethoxy-4-benzyloxy-6-nitni~ eoldehyde (0,0592 mole), 2-cyanoacetamide (5.24 g. , 0.0622 mole), piperidine (0.37 g., 4.36 millimole) and ethanol (92 ml.) i8 heated to reflux on a steam bath for two hours. It is then cooled in an ice-bath whereupon the product precipitates and is recovered by filtration, washed with cold ethanol and dried.
I~ is of sufficient purity for use in the succeeding step.
B) 6-Ethoxy-7-benzyloxy-2-aminoquinoline-3-carboxamide.
Iron powdes (8.52 g., 0.152 mole) is gradually added over a forty-minute period to a slurry of the product of ~OS3679t Procedure A (0.034 mole) in acetic acid (100 ml.) at 85C.
When addition of the iron powder is complete, the mixture is heated to 95-100~., for 1.5 hours and then filtered hot through diatomaceous earth. The filtra~e is cooled in an ice bath and then filtered to give a tan crystalline solid. The solid is partitioned between ethyl acetate and water, the organic phase separated, dried over anhydrous sodium sulfate and concentrated to yield the title amide as yellow crystals.
C) Ethyl-7-benzyloxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate.
A mixture of diethyl oxalate (57.2 g., 0.392 mole) and the product of procedure B (0.0261 mole) is heated for eighteen hours at 160C., under a nitrogen atmosphere and then allowed to cool to room temperature. Hexane (300 ml.) is added, the mixture stirred and filtered to provide the desired product. It is washed with hexane and dried.
EXAMPLE IV
7-Benzyloxy-8-methoxy pyrimidol4~s-~lquinolin-4(3H)-one-2 carboxamide.
Anhydrous ammonia is bubbled into a mixture of ethyl 7-benzyloxy-8-methoxy pyrimido[4,s_b]quinolin-4(3H)-one-2-carboxylate (9.00 millimoles) in absolute ethanol (75 ml.) for fifteen minutes. A clear solution formed followed after a few minutes by ormation of a precipitate. The reaction mixture is transferred to a pressure bomb (Monel, "Monel" is a trademark)and heated in a 95C., oil bath overnight. The bomb is then cooled to room temperature and the contents removed. The bomb is washed with ethanol and the combin~
reaction mixture plus wash filtered to recover the product.
The filter cake is washed with ethanol and then dried in air.

.

EXAMPLE V
7-Methoxy-8-benzyloxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxamide.
A mixture of 2-amino~6-methoxy-7-benzyloxyquinoline-3-carboxamide (1.15 millimoles), ethyl oxamate (2.71 g., 23.1 millimoles), ethylene glycol (10 ml.) and Qodium methox-ide (10 mg.) is heated at 170C., for one hour. The product is precipitated by 510w addition of ice cold methanol (50 ml.) to the hot reaction mixture followed by chilling in an ice bath. It is filtered off, washed with cold methanol and dried ln vacuo.
EXA~PLE VI
7-Methoxv-8-benzYloxv PYrimido~4,5-b]quinolin-4(3H)-one-2-hYdroxamic acid.
Ethyl 7-methoxy-8-benzyloxy pyrimido[4,5-b]quinolin-4~3H)-one-2-carboxylate (6.08 millimoles) is added to a solu-tion of hydroxylamine hydrochloride (69 mg., 100 millimoles) and triethylamine (100 mg., 100 millimoles) in absolute ethanol ~50 ml.). The mixture is heated at 95C., overnight in a bomb and then cooled. The insoluble yellow solid is filtered off, washed with hot ethanol and dried to provide the product.
EXAMPLE VII
Ethyl 7-hydroxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate trifluoroacetate.
A 301ution of ethyl 7-benzyloxy-8-methoxy pyrimido-14,5-b]quinolin-4(3H)-one-2-carboxylate (~50 mg., 0.618 mmole) in trifluoroacetic acid (5 ml.) is refluxed for 2.5 hours. (Alternatively the mixture is sti~red at room tem-perature for three days). The reaction mixture is then poured ~053674 into ether (25 ml.) and the resulting bright yellow precipi-tate of the trifluoroacetate salt recovered by filtration, washed with ether and dried.
Yield - 194 mg., 72~; m.p. 279C.
Analysis:

C~lcd- for C15H13N35CF3CH 1/2 H2O: C, 46-58; H 5 N, 9.58%
Found: C, 46.81; H, 3.41;
N, 9.21%.
Repetition of the above procedure but using the corresponding n-butyl ester (862 mg., 0.199 mmole) in place of the ethyl ester, 8 ml. trifluoroacetic acid and a reflux period of 3.5 hours affords n-butyl 7-hydroxy-8-methoxy-pyrimido[4,5-b]quinolin-4~3H)-one-2-carboxylate trifluoro-acetate (0.67 g., 74%); m.p. 240C. (dec.) Analysis:

Calcd- for C17H17Os~3CF3COOH: C, 49.89; H, 3.96; N, 9.18;
F, 12.46%
Found: C, 49.93; H, 3.97; N, 8.79;
F, 11.17%.
Similarly, ethyl 7-benzyloxypyrimido[4,5-b]-quinolin-4(3H)-one-2-carboxylate is debenzylated to give a 74~ yield of ethyl 7-hydroxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate hemitrifluoroacetate; m.p. 274-275C.
(dec.) Analysis:

Calcd- for C14H114N3 1/2 CF3COOH: C, 57.43; H, 3.6 N, 13.39%
Found: C, 57.75; H, 4.05;
N, 13.65~.

EXAMPLE VIII
7-Hydroxy-8-methoxypyrimido[4,5-b]quinolin-4 (3E-I) -one-2-carboxylic acid.
The trifluoroacetate-hemihydrate salt of ethyl 7-hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3X)-one-2-carboxyl-ate (200 mg., 0.456 mmole) is slurried in O.lN sodium hydrox-ide (5 ml.~ and 15% sodium hydroxide added dropwise with stirring until solution is complete. The mixture is stirred at room temperature for 18 hours and is then made strongly acid by addition of trifluoroacetic acid. The precipitate which forms is separated by filtration, washed with water and then with isopropyl alcohol and air-dried. Yield -114 mg.; m.p. 281C. (dec.).
Analysis-Calcd. for C13HgOsN32H2O: C, 48.29; H, 4.02; N, 13.00%
Found: C, 47.3; H, 3.32; N, 12.73%.
In like manner, ethyl 7-hydroxypyrimido[4,5-b]-quinolin-4(3H)-one-2-carboxylate hemitrifluoroacetate (210 mg.) is converted to 7-hydroxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acid. Yield = 191 mg., 91% m.p. 340C.
(dec.).
EXAMPLE IX
Ethyl-7-methoxy-8-hydr-oxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate.
A solution of ethyl 7-methoxy-8-benzyloxypyrimido-~4,5-b~quinolin-4(3H)-one-2-carboxylate (198 mg., 0.488 mmole) in trifluoroacetic acid (4 ml.) is stirred at room temperature for 8 days. Ether (15 ml.) is added and the yellow precipi-tate which forms separated by filtration. It is taken up in chloroform and the solution filtered through diatomaceous earth to remove a small amount of insoluble material. The filtrate is decolorized with charcoal and concentrated under reduced pressure to small volume. The solid which forms is filtered and dried; 9 mg., 6% yield; m.p. 265-266C. (dec.).

EXAMPLE X
The compounds below are prepared from appropriate reactants by the procedures of the preceding examples.

R3 ~ -H

~ N ~ N ~ COR

Method R R2 - R4 R5 f Ex O-n-C3H7 H H OC7H7 H II

C2H5 OC7H7 Br H Br II

OCH3 H OCH3 OC7H7 Br II

OC2H5 H Br H OC7H7 O-n-C3H7 C2H5 H OC7H7 H III

O-n-C3H7 C2H5 OC7H7 H H III

OC2H5 H Br OC7H7 H II

OCH3 H Cl OC7H7 H IV

Method R R2 R3 R4 R5 f Exp _ NHOH H Cl OC7H7 H VI

The benzyl ethers and benzylthio ethers tabulated above are converted ts the corresponding hydroxy and thiol compounds by the procedure of Example VII.
20The thus-produced hydroxy and thiol substituted 2-carboxylic acid e~ters are hydrolyzed to the corresponding 2-carboxylic acid derivatives by the procedure of Example VIII.
EXAMPLE XI
25Ethyl 7-acetoxy-8-methoxy pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate p-toluenesulfonate.
A mixture of acetic anhydride (4 ml.), ethyl 7-hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate trifluoroacetate hemihydrate (250 mg., 0.572 mmole) and p-toluenesulfonic acid monohydrate (100 mg., 0.572 mmole) is heated at 100C., for 24 hours. The acetic anhydride is then stripped from the reaction mixture ln vacuo. The solid residue is dissolved in hot chloroform and the solution decolorized with activated charcoal. Benzene (4 volumes) is added to the decolorized solution which is then ahilled in ice. The crystals which separate are recover-ed by filtration and air dried. Yield = 174 mg., 58%;
m.p. 215-217C.
AnalysiS: Calcd- for Cl7Hl5o6N3c7H8o3 N, 7.98%
Found: C, 53.74; H, 4.28;
N, 7.24%.
The above procedure is repeated but using the corresponding n-butyl ester trifluoroacetate salt (200 mg., 0.437 mmole) in place of the ethyl ester trifluoroacetate salt. The product is recovered by concentration of the chloroform solution to 1/3 volume and filtration of the solid which precipitates rather than by precipitation with benzene.
Yield = 30 mg., 18%; m.p. 260-261C. (dec.).
The above procedure is repeated but using the ap-propriate acid anhydride and in place of acetic anhydride and the appropriate hydroxy or thiol Formula I compound as reac-tant to give the following compounds:

R J ~ l ¦ N H

R4~J~N NlR

Rl R2 R3 R4 ~5 R

H H C3H7cOO OCH3 H COOC2H5 H H OCH3 CH3COO H COOC~H5 H H OCH3 HCOO H COOC2Hs H H HCOO OCH3 H ~X~n-C4Hg H H CH3COO OCH3 H COO-n-C~Hg C6H5 H HCOO H H CH~

H H H HCOO H COO-n-C3H7 H H H CH3COO H COO-n-C3H7 H H OCH3 CH3COO Br COOCH3 n-C4Hg H C6H5C OCH3 H C2H5 H C3H7cOO OCH3 H H COOCH3 H H Br H CH3COO COOC2H5 H H H H HCOO OX~n-C4Hg H H H H C3H7COO ~X~n-C4Hg n-C4Hg C2H5 CH3COO H H C~H5 Rl R2 R3 R4 R5 R
-H H Cl CH3COO H COOCH3 c2H5 H F 3 7 H COOC2H5 C2 5 HCOO H H COO-n-C3H7 H CH3COO H H COO~n-C3H
H H C3H7COO H H COO-n-C3H7 CH3 ~ C6H5C OCH3 H COOC2H5 H H Cl C6H5C H COOC2H5 EXAMPLE XII

2-HydroxYethyl-7-benzyloxy-8-methoxy pyrimidin[4,5-b]-quinolin-4-(3H)-one-2-carboxylate.
Triethylamine (1 ml.) is added to a slurry of ethyl 7-benzyloxy-8-methoxy pyrimidin[4,5-b]quinoline-4(3H)-one-2-carboxylate (500 mg.) in ethylene glycol (5 ml.). The mix-ture i8 stirred for 6 hours and is then diluted with water (30 ml.). The resulting clear yellow solution i~ acidified with acetic acid and the precipitate which forms filtered off.

It is recrystallized while still damp from N,N-dimethylform-amide (20 ml.).

In like manner, the alkyl esters of Example II, XI, XIII-XV and XIX-XXII are transesterified to the corresponding 2-hydroxyethyl esters. Replacement of ethylene glycol by propylene glycol, butylene glycol or 1,4-dihydroxybutane affords the corresponding hydroxyalkoxy e~ters.

EXAMPLE XIII
Ethyl 7-benzylthio pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate.
A) -CYano-~-(2-nitro-5-benzylthiophenyl)acrylamide A solution of the sodium salt of benzylmercaptan (2.78 g., 0.0398 mole) in N,N-dimethylformamide (50 ml.) is prepared by adding benzylmercaptan to a mixture of sodium hydride (1.67 g. of 57% NaH) in N,N-dimethylformamide (50 ml.).
The reaction mixture is cooled by means of an ice-bath until the reaction is complete.
The sodium benzylmercaptide solution is then added dropwlse to a mixture of a-cyano-~-(2-nitro-5-chlorophenyl)-acrylamide (10 g., 0.0398 mole) in N,N-dimethylformamide (35 ml.) cooled in an ice-bath. The mixture is stirred for one hour and then removed from the ice-bath and stirred for an additional two hours. The reaction mixture is poured into water (600 ml.) and the resulting mixture thoroughly stirred.
Ether (30 ml.) is added and the precipitate filtered off, washed with ether and dried.
B) 6-BenzYlthio-2-aminoquinoline-3-carboxamide A mixture of a-cyano-~-(2-nitro-5-benzylthiophenyl)-acrylamide (0.032 mole) in acetic acid - N,N-dimethylformamide (110 ml. of 1:1) is heated in a 75C., bath. Iron powder (2.0 g.) is added and the mixture stirred until the internal temperature rose to 95C. Additional iron powder (6.16 g.
total iron added = 0.146 mole) is added in small portions over a fifteen-minute period. The reaction mixture is stirred for one hour following completion of addition and then filtered hot. The iron residue is washed with hot acetic acid and the combined filtrate and wash solution pou`red into .

LN hydrochloric acid (200 ml.). The hydrochloride salt which separates is filtered off and dissolved in hot dilute aqueous oodium hydroxide. The yellow solid which separates on cooling is filtered off, washed with isopropyl alcohol and air dried.
It is used in Step C without further purification.
C) EthYl-7-benzylthio Pyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate.
A round-bottom flask equipped with stirrer, con-denser, thermometer and Dean-Stark trap and containing a mixture of 6-benzylthio-2-aminoquinoline-3-carboxamide (4.3 millimoles), diethyl oxalate (20 ml.) and xylene (15 ml.) is immersed in an oil-bath heated to 200C. Xylene, water and ethanol are distilled from the reaction mixture until the internal temperature of the mixture reaches 165C. The mixture is stirred at 165C., for three hours and is then poured into chloroform (40 ml.). After cooling to room temperature the mixture is filtered. The brown filter cake is air-dried and then slurried in hot chloroform (100 ml.) to which activated charcoal is added. The slurry is filtered hot and the filtrate evaporated to half-volume and chilled in ice. The yellow solid which precipitates is filtered and dried in air.
EXAMPLE XIV
EthYl-7-benzylsulfinyl pyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate .

A solution of ethyl 7-benzylthio pyrimido[4,5-b]-quinoline-4(3H)-one-2-carboxylate (1 millimole) in trifluoro-acetic acid (2 ml.) is heated in an oil bath tc 55C. Hydro-gen peroxide (113 mg. of 30% H2O2, 1 millimole~ is added and the solution stirred for ten minutes. After cooling to room temperature, absolute ethanol (6 ml.) is added. The resulting yellow precipitate is filtered off, washed with ether and air-dried. Recrystallization from absolute ethanol gives S the product.
The thiobenzyl compounds of Example X are oxidized to the corresponding sulfinyl~enzyl compounds by this procedure.
EXA~PLE XV

Repetition of the procedures of Examples XIII A-C
and XIV, but using the appropriate chloro substituted 2-nitro-benzaldehyde as reactants, affords the following compounds:

ll R ~ ~ N-H

R~N~J--COOC2H5 EXAMPLE XVI

2-MethYl-7-hydroxv-8-methoxy pyrimido[4,5-b]quinolin-4( 3H)-one.
A) 7-Benzyl ether of title compound:
A mixture of 6-benzyloxy-7-methoxy-2-amino-quinoline-3-carboxamide (1. 50 g.), concentrated sulfuric acid (0.05 ml.) and acetic anhydride (20 ml.) is heated at 85C., for 15 minutes. The mixture is then cooled and ice chips added to the reaction mixture. The yellow solid which pre-cipitates is filtered, washed with water and then with iso-propyl alcohol-ether (1:1) and air-dried. Yield = 1.60 g.
(99~); m.p. 202-203C. (dec.).
B) Debenzylation of 7-benzyl ether:
The 7-benzyl ether from preparation A above is treated with trifluoroacetic acid according to the procedure of Example VII to give the title compound in 95~ yield;
m.p. 135C. (dec.).
EXAMPLE XVII
2-Methyl-7-methox~-8-benzyloxy pyrimido[4,5-b]quinolin-4(3H)-one.
Concentrated sulfuric acid (1.5 ml.) is added to a slurry of 2-amino-6-methoxy-7-benzyloxyquinoline-3-carboxamide (0.02 mole) and acetic anhydride (40 ml.). The slurry dis-solves to give a dark orange solution from which a heavy yellow precipitate separates. Acetic anhydride (10 ml.) is added to facilitate stirring and heating continued for an additional 75 minutes. The mixture is cooled, water (50 ml.) added and the resulting solution made alkaline with 5N ~odium hydroxide (225 ml.). It i8 chilled, the precipitate collected by filtration and air-dried. The yellow solid is recryqtallized from ethanol.
In like manner, the following compounds are prepared from appropriate reactants:

3 ~ ~-H
R4 ~-- CH3 Rl R2 R3 R4 R5 H OC7H7 Br H Br H H OCH3 OC7H7 Br ~5 H H OC2H5 SC7H7 H
H H Br SC7H7 H
H H Cl OC7H7 H

C6H5 H Cl OC7H7 H

n~C3H7 H OC7H7 OCH3 H
30 n-C4Hg H OC7H7 OCH3 H

lOS3674 Rl R2 R3 R4 R5 _ n C4H7 C2H5 SC7H7 H H
n-C4Hg OC7H7 OCH3 OCH3 H
The benzyl ethers and benzylthio ethers enumerated above are debenzylated by treatment with trifluoroacetic acid as is described in Example VII.
EXAMPLE XVIII
2-Ethyl-7-ethoxy-8-benzyloxy pyrimidin[4,5-b]quinolin-4(3H)-one.
To a stirred mixture of 6-ethoxy-7-benzyloxy-2-aminoquinoline-3-carboxamide (0.002 mole) in propionic anhydride (10 ml.) at 60C., is added concentrated sulfuric acid (0.5 ml.). The reaction mixture is stirred for one hour and is then cooled to room temperature and added to water (25 ml.). The aqueous mixture is stirred and made basic with 6N sodium hydroxide. It is stirred overnight and then acidified to pH 5.0 with 10% hydrochloric acid. The yellow precipitate which forms is filtered off and recrystallized from ethanol.
The following compounds are prepared in li~e manner from appropriate reactants:

4 ~rJ ~i C H

Rl R2 R3 R4 R5 H H OCH3 OC7~i7 Rl R2 R3 R4 R5 H H Cl OC7H7 H

C6H5 OC7H7 Br H Br CH3 H OCH3 OC7H7 Br n C3H7 H C2H7 C2H5 H
i C3H7 H OC7H7 C2H5 H
n-C4Hg H OC7H7 H H
n-C4Hg C2H5 OC7H7 H H
n~C4Hg H OC7H7 OCH3 H

Debenzylation of the benzyl ethers cited above by reaction with trifluoroacetic acid according to the procedure of Example VII affords the corresponding hydroxy compounds.
EXAMPLE XIX
2-Acetyl-7-ethoxy-8-benzyloxy pyrimido[4,5-~.
To a solution of selenium dioxide (24.5 mg., 2.2 millimoles) in dioxane water ~11 ml. of 10:1) is added 2-ethyl-7-ethoxy-7-benzyloxy pyrimido[4,5-b]quinolin-4(3H)--4~-one (125 mg., 4.4 millimoles~. The mixture is heated to reflux for 48 hours after which more selenium dioxide (24.5 mg.) is added and refluxing continued for an additional 24 hours. The mixture is cooled, the selenium filtered off and the filtrate concentrated to dryness. The residue is taken up in ethanol/chloroform (1:99) and chromatographed on a column of silica using the same solvent as eluant (250 ml.) followed by ethanol/chloroform (2:98). Concentration of the second eluate (625 ml.) gives a yellow solid.
Similarly, the remaining 2-ethyl derivatives of Example XVIII are oxidized to their corresponding 2-acetyl derivatives.
EX~LE XX
Ethyl 3-methyl-7-benzyloxy-8-methoxy Pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate.
Sodium hydride (470 mg. of 50~ in oil, 0.011 mole) i~ added to a slurry of ethyl 7-benzyloxy-8-methoxy pyrimido-[4,5-b]quinolin-4(3H)-one-2-carboxylate (3.3 g., ~.01 mole) in N,N-dimethylformamide (75 ml.). The mixture is stirred and heated on a steambath for ten minutes and then at room temperature for a half hour. It is cooled in an ice-bath and iodometane (2.1 g., 0.015 mole) added dropwise over a 30 minute period. Following completion of addition, the mixture is stirred for an additional 15 minutes in an ice-bath and then for a half-hour at room temperature. The reaction mix-ture is poured into ice-water (200 ml.) and the resulting solid filtered off, air-dried and recrystallized from ethanol to give yellow crystals.
In like manner, but using the appropriate compound of Formula I (Y=H) and the appropriate alkyl iodide, the pro-ducts of the preceding examples are converted ~o their corresponding 3-methyl, 3-ethyl, 3-n-propyl, 3-isopropyl and 3-n-butyl derivatives.
Compounds wherein one of R2, R3, R4 or R5 i~ thiol or hydroxy are obtained by debenzylation of the corresponding benzylthio ethers or benzylethers by reaction with tri-fluoroacetic acid according to the procedure of Example VII.
EXAMPLE XXI
Ethyl 3-carbethoxYmethyl-7-ethoxy-8-benzYloxy pvrimido[4,5-b~-quinolin-4(3H)-one-2-carboxylate.
To a slurry of ethyl 7-ethoxy-8-benzyloxy pyrimido-t4~5-b]quinolin-4(3H)-one-2-carboxylate (1.6 g., 5.0 milli-moles) in N,N-dimethylformamide (30 ml.) is added sod~um hydride (235 mg., 5.5 millimoles of 56% in oil). The 31urry i8 heated on a steambath for ten minutes and then cooled to room temperature. Ethyl bromoacetate (968 mg., 5.8 milli-mOle8) i9 added and the reaction mixture heated on a steam-bath for one hour. After standing o~ernight at room tempera-ture the mixture is diluted with water (75 ml.) and the re-sulting yellow solid filtered off ~1.4 g.). It i3 purifi~d by chromatography on a column of silica gel using chloroform as solvent and eluant. The eluant is evaporated to give a yellow ~olid. It is recrystallized from hot ethanol ~S0 ml.) containing sufficient chloroform to achieve solution.
EXAMP~E XXII
Pyrimido[4,5-b]quinolin-4(3H)-one compounds of Examples I-XIX are alkylated substantially according to the procedure of Example XXI but using the appropriate alkyl bromoalkanoate or alkylating agent. The products are re-crystallized from suitable solvents such as ethanol or ~053674 benzene: hexane (1:1).

R ~ ~ ~ ~ Y

(CH2~2COOc2H5 COO-n-C4Hg H H OC7H7 OCH3 H
CH2COo-n-c4H9 COOC2H5 H H OC7H7 H H
(CH2~3COOC2H5 COOC2H5 H H OCH3 OC7H7 H
CH2COOC2H5 COOCH3 H H OC7H7 OC7H~ H
(CH2~4COOCH3 COOC2H5 H OC7H7 OCH3 OCH3 H
(CH2)2COO-n-C4Hg COO-n-C4Hg H H H H OC7H
CH2COO-n-C3H7 COO-n-C3H7 H C2H5 OC7H7 H H
CH2COOC2H5 COOC2H5 H H Br OC7H7 H
CH2COOC2H5 COOCH3 H H Cl CC7H7 H
lS CH2COOCH3 COOCH2CH20H H H OC7H7 OCH3 H

(CH2)2COOC2H5 COO(CH2)40H H H OC7H7 H H
CH2COO-n-C4Hg COO~CH2)30H H H F OC7H7 H
CH2COOC2H5 CH3 H H OC7H7 O~H3 H

CH2COOC2H5 C2H5 H H OCH3 OC7H7 Br CH2COOC2H5 C2H5 H H Br 0~7H7 H
CH2COOC2H5 ~OCH3 H H OC7~7 ~CH3 Y R Rl R2 R3 R4 R5 CH2oXX~3 CH3 C6H5 H Oc7H7 OCH3 H
(CH2)3COCC2H5 C2H5 C2H5 OC7H7 OCH3 H
(CH2)2~x~n-c4H9 CH3 n-C4Hg C2H5 OC7H7 H H

(CH2)4ccOc2H5 COOC2H5 H H H H SC7H7 (CH2)2oX~n-C4H9 COOC2H5 H H H SC7H7 H
CH2OXX~3 COOC2H5 H SC7H7 H H SC7H7 (CH2)3COO-i-C3H7 COOC2H5 H SOC7H7 C2H5 H

(CH2)4COOC2H5 COOC2H5 H H OCH3 C6H5COO H
The benzyl ethers and benzylthio ethers tabulated above are converted to the corresponding hydroxy and thiol compounds by reaction with trifluoroacetic acid according to the procedure of Example VII.
EXAMPLE XXIII
Eth~l 3-acetoxyethyl-7-ethoxy-8-benzyloxy pyrimidin[4,5-b]-quinolin-4(3H)-one-2-carboxylate.
The procedure of Example XXI is repeated but using bromoethyl acetate (969 mg., 5.8 millimoles) as alkylating agent. The solid product which separates upon dilution of the reaction mixture with water is filtered off, dried and recrystalli~ed from ethanol (20 ml.) containing sufficient acetonitrile to achieve solution.
In like manner, the following compounds are prepared from the appropriate pyrimidin[4,5~b]quinolin~4(3H)-one com-pounds of the preceding example and the appropriate bromo-alkanoate or bromoalkyl benzoate:

R3 ~ ~ ~ ~

Y R Rl R2 R3 R4 R5 (CH2)30COCH3 COOC2H5 H H C2H5 C7H7 H
CH2CH2000c6H5 H H OC2H5 OC7H7 H
CH2CH2oX~6H5 CC2H5 H H OC7H7 OCH3 H
CH2cH2ococ6H5 COO n C4Hg H H C7H7 CH3 H
CH2cH2ococH3 COOC2H5 H H OCH3 OC7H7 H
~CH2)40COC3H7 CC2H5 H H OC7H7 H H
(CH2)30COC2Hs COOC2H5 H OC7H7 0CH3 H H

(CH2)30oOC6H5 CH3 C6H5 H OCH3 OCH3 H
CH2CH20occH3 CH3 n-C4Hg C2H5 C7H7 H
CH2cH2ococ3H7 C2II5 H H OC7H7 0C7H7 H
CH2CH20COCH3 C2H5 CH3 H OCH3 OC7H7 Br (CH2)40XC2H5 COOC2H5 H H SC7H7 C2H5 H
CH2cH2oooc6H5 CC2H5 H H H SC7H7 H
CH2CH20coc3H7 COOC2H5 H H SC7H7 H H
CH2CH20xc6Hs COOC2H5 H H H SOC7H7 H
CH2CH2oX~H3 COO-n-C4Hg H H CH3COO OCH3 H
(CH2)40QCC2Hs CC2H5 H H C3H7CC0 OCH3 H

Y R Rl R2 R3 _ 5 _ CH2CH2o~6H5 COOCH3 H HCOO OCH3 H H

(CH2)3Oox~3 COOC2H5 H H H C2H5COS H
CH2CH2~X~3H7 COOC2H5 H C6H5C OCH3 H

(CH2)4QCcc2H5 COOC2H5 H C6H5C H H
EXAMPLE XXIV
Ethyl-7-benzyloxy benzo[q]quinazolin-4(3H)-one-2-carboxylate.
A) 5-Benzyloxybenzo-isatoic anhydride 2-amino-5-benzyloxybenzoic acid (0.133 mole) is dissolved, warming if necessary, in a mixture of water (50 ml.), concen-trated hydrochloric acid (50 ml.) and dioxane (100 ml.).
Phosgene is passed into the solution with good stirring at such a rate that bubbles of the gas escape slowly into an ammonia scrubber attached to the reaction flask. The tempera-ture is held below 50C., by regulating the rate of introduc-tion of the phosgene. After passing phosgene into the mix-ture for four hours, the residual phosgene is blown out by passing air through the mixture. The mixture is cooled and the product filtered off, washed with cold water and dried.
B) 2-Amino-6-benzyloxynaphthalene-3-carboxamide.
Ammonia is intermittently bubbled into a suspension of the product of procedure A (2.25 millimoles) and ethanol (80 ml.) for a period of two days. The bright green solid which formed is filtered from the reaction mixture, dried and then recrystallized from ethanol.
C) Ethyl-7-benzyloxybenzo[g]quinazolin-4(3H)-one-2-carboxylate.
Diethyl oxalate (2.35 g., 16.1 millimoles), sodium 0 methoxide (10 mg.) and 2-aminonaphthalene-3-carboxamide (1.50 g., 8.05 millimoles) are mixed together and heated atreflux for two days. The mixture is then cooled in an ice bath and the brown precipitate recovered by filtration.
D) The ester is hydrolyzed to the disodium salt as follows:
The ester (3.92 millimoles) is added to 15% aqueous sodium hydroxide (20 ml.) and the mixture stirred for two days. It is then acidified at room temperature with 10%
hydrochloric acid to pH 2 and evaporated to dryness under re-duced pressure. The residue is treated with methanol-water ~1:1, 50 ml.) and the suspension filtered to give 0.70 g. of yellow crystals. The crystals are added to a saturated solu-tion of aqueous sodium bicarbonate (35 ml.) and water (20 ml.). The mixture is stirred for a half-hour and the yellow solid filtered off and dried.
E) Repetition of this hydrolysis procedure but using potassium bicarbonate or ammonium bicarbonate in place of sodium bicarbonate affords the dipotassium salt and the di-ammonium salt.
EXAMPLE XXV
Alkyl Benzo[g]quinazolin-4(3H)-one-2-carboxylate.
The following alkyl benzo[g]quinazolin-4(3H)-one-2-carboxylates are prepared from the appropriate reactants by the procedure of Example XXIV.

~ NlCOR
R R2 ~`3 R4 -OC~3 H SC7H7 H

lOS3674 O-n-C3H7 SC7H7 H H

The thioethers are converted to the corre~ponding sulfinyl derivatives by oxidation with hydrogen peroxide ac-cording to the procedure of Example XIV.
Benzyl ether~ and benzylthio ethers are debenzyl-ated by reaction with trifluoroacetic acid as described inExample VII to the corresponding hydroxy and thiol compounds.
EXAMPLE XXVI
enzotg]quinazolin-4(3H~-one-2-carboxamides.
Following the procedure of Example V but using the appropriate 2-aminonaphthalene-3-carboxamide in place of 2-aminoquinolin-3-carboxamide, the amides corresponding to ~he ester products of Examples XXIV and XXV are prepared. The compounds have the formula:

R3 ~ ~2 EXAMPLE XXVII
Benzo~g]quinazolin-4(3H)-one-2-hydroxamic acids.
The ester products of Example XXIV-XXV are convert-ed to the corresponding hydroxamic acids by the procedure of Example VI. The compounds have the formula:

R4 ~ ~ CONHOH
EXAMPLE XXVIII
Repetition of the procedure of Example XVII but using the appropriate 2-aminonicotinamide in place of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide produces the follow-ing compounds:

R ~ HCH3 CH3 SOc7H7* H
CH3 SOc7H7* CH3 OC7H~ H H
*Produced by oxidation of the corresponding thioethers according to the procedure of Example XIV.
The benzyl ethers and benzylthio ethers listed above are debenzylated by treatment with trifluoroacetic acid to afford the corresponding hydroxy and thiol compounds ac-0 cording to the procedure of Example VII.EX~MPLE XXIX

2-Ethylpyridot2,3-dl-pyrimidin-4(3H)-ones.
Concentrated sulfuric acid (0.5 ml.) is added to a mixture of 2-aminonicotinamide ~0.24 g., 0.002 mole) in propionic anhydride (10 ml.) at 60~C. and the resulting mix-ture stirred for one hour. It is then cooled to room tem-perature and poured into water (25 ml.). The aqueous mix-ture i5 stirred, made basic with 6N sodium hydroxide and stirred overnight. Upon acidification to pH 5.0 with 10%
hydrochloric acid the desired product precipitates. It is filtered off and dried.
The following compounds are prepared in like manner from appropriate reactants:
l2 ~ H

~ N ~ N ~ 2H5 ~Prepared by oxidation of the corresponding thio compound according to the procedure of Example XIV.
Debenzylation of the benzyl ethers and benzylthio ethers by treatment with trifluoroacetic acid according to the procedure of Example VII affords the corresponding hydroxy and thiol compounds.
EXAMPLE XXX
2-Acetyl pyrimido[2,3-d]-pyrimidin-4~3H)-ones.
The products of Example XXIX are oxidized by selenium dioxide substantially according to the procedure of Example XIX to provide compounds of the formula:

R3~H

N ~ CO-CH3 EXAMPLE XXXI
Repetition of the procedure of Example XXV but using appropriate reactants produces the following compounds:

R2 Pl R ~ NH

4~N~\NlcoRo OCH3 CH3 SC~H7 CH3 - ~ OC2H5 CH3 SC7H7* H

*Prepared by oxidation according to the procedure of Example XIV.
Hydrolysis of the ester by the method of Example XV-D produces the acid and disodium salt derivatives. De-benzylation of benzyl ethers and benzylthio ethers in the manner of Example VII affords the corresponding hydroxy and thiol compounds.
EXAMPLE XXXII
The hydroxy and thiol compounds of Examples XXVIII-XXXI are converted to acyloxy derivatives by the procedure of Example XI. In this manner the formyloxy, acetoxy, butyryloxy and benzyloxy derivatives are prepared.

.

10536'74 EXAMPLE XXXIII
Pyrido[2,3-d] pyrimidin-4(3~)-one-2-carboxamides.
The procedure of Example V is repeated but using the appropxiate 2-aminonicotinamide as reactant in place of 2-aminonaphthalene-3-carboxamide to produce the amides corre-8ponding to the e8ters of Example XXXI.
EXAMPLE XXXIV
Pyrido[2!3-d] pyrimidin-4(3H)-one-2-hydroxamic acids.
The esters of Example XXXI are converted by the procedure of Example VI to hydroxamic acids of the formula:

~2 N ~ ONHOH
EXAMPLE XXXV
The ester products of the preceding Examples are converted to the corresponding acids by the procedure of Example II-D and to the disodium, dipotassium and diammonium ~alt8 by the procedure of Example XXIV-D and XXIV-E.
The acids are converted to the calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperidine, tri-ethanolamine, diethylaminoethylamine, N,N'-dibenzylethylene-diamine and pyrrolidine by reaction with an equivalent amountof the appropriate base (Ca(OH)2, Mg(OH)2, Al(OH)3) or amine in water or ethanol followed by filtration of the salt if insoluble or by evaporation of the solvent if the salt iS
soluble therein.

Claims (12)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing fused pyrimidines of the Formula and the pharmaceutically-acceptable cationic salts thereof wherein R° is selected from the group consisting of hydroxy, and alkoxy of 1-4 carbon atoms;
each of R3 and R4 is selected from the groups consist-ing of (a) hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, benzyloxy, methylthio and methylsulfinyl; and (b) hydroxy, thiol, alkanoyloxy of 1-4 carbon atoms, benzylthio, benzoyloxy and benzylsulfinyl with the proviso that at least one of R3 and R4 is selected from the group (b), by reacting a compound of the Formula wherein R3 and R4 are as defined above, with a reagent A-Z
(a) wherein when R' is NH2 and R is COR° then A-Z is a) a dialkyl oxalate;
b) a monoacid halide (chloride, bromide) of a half-alkyl oxalic acid ester;
c) an alkyl cyanoformate;
d) a dialkyl ester of monoiminooxalic acid (a carbalkoxy formimdate);

e) 1-cyanoformamide;
f) cyanogen; and g) 1-carbalkoxyformamidine; or (b) wherein when R' is an ester moiety then A-Z is a 1-carbalkoxyformamidine;
and when A-Z contains a cyano group hydrolyzing the thus produced cyano derivative;
and when either of R3 and R4 is benzyloxy or benzylthio debenzylating the benzyl ether or benzylthio ether, if desired;
and when either of R3 and R4 is benzylthio, oxidizing it to benzylsulfinyl, if desired.

2. A process according to claim 1, wherein one of R3 or R4 is hydroxy.

3. A process according to claim 2, wherein R° is alkoxy one of R3 and R4 is hydroxy and the other alkoxy.

4. A process according to claim 2, wherein R° is hydroxy.

5. A process according to claim 3, wherein R° is n-butoxy;
R3 is hydroxy and R4 is methoxy.

6. A process according to claim 3, wherein R° is ethoxy;
and R3 is methoxy and R4 is hydroxy.

7. A fused pyrimidine when produced by the process of claim 1, or an obvious equivalent thereof.

8. A fused pyrimidine when produced by the process of claim 2, or an obvious equivalent thereof.

9. A fused pyrimidine when Produced by the process of claim 3, or an obvious equivalent thereof.

10. A fused pyrimidine when produced by the process of claim 4, or an obvious equivalent thereof.

11. A fused pyrimidine when produced by the process of claim 5, or an obvious equivalent thereof.

12. A fused pyrimidine when produced by the process of claim 6, or an obvious equivalent thereof.