IE42746B1 - Fused pyrimidine-4-(3h)-ones and preparation thereof - Google Patents

Abstract

1501438 Fused - pyrimidine - 4(3H) - ones PFIZER Inc 2 May 1975 [5 July 1974] 18583/75 Addition to 1458205 Heading C2C Novel compounds I, II and III and salts thereof in which R is Me, Et, MeCO or COR0 (where R‹ is OH, alkoxy, hydroxyalkoxy, NH 2 or NHOH); Y is H, alkyl, carbalkoxyalkyl, carboxyalkyl, -(CH 2 ) m -OCOPh or -(CH 2 ) m -OCOalkyl (where m is 2 to 4) with the proviso that when R0 is NH 2 or NHOH then Y is H; R1 is H, alkyl or Ph and R2, R3, R4 and R5 are selected from (a), H, alkyl, alkoxy, halo, benzyloxy, MeS and MeSO or (b) OH, SH, alkanoyloxy, benzoyloxy, benzylthio and benzylsulphinyl providing that at least one is selected from (b); are prepared by methods analogous to those described in the parent Specification for compounds where R is COR‹; compounds I (Y= H; R=Me, Et) are prepared oyclizing the appropriate 2 - amino - quinoline - 3 - carboxamide or 2-aminonicotinamide either with Ac 2 O or (EtCO) 2 O or with (EtO) 3 Me or (EtO) 3 Et in the presence of H 2 SO 4 ; compounds I (R= MeCO) are prepared by oxidation of the corresponding compound (R=Et) using SeO 2 ; compounds I where Y Is other than H are prepared by alkylation of such compounds where Y=H using an appropriate alkylating agent. Compounds where R‹ is hydroxyalkyl are prepared by transesterification of compounds where R‹ is alkoxy. Compounds where any one of R 2 , R 3 , R 4 or R 5 is MeSO or B 3 SO are prepared by oxidation of corresponding MeS or B 3 S compound. Compounds where R 2 , R 3 , R 4 or R 5 are B 3 O or B 3 S are debenzylated to give the corresponding OH or SH compounds and these compounds may in turn be acylated to give compounds containing an alkanoyloxy or benzyloxy substituent. Compounds I, II and III have anti-allergy activity and form with a carrier a pharmaceutical composition which may be administered orally, parenterally or by inhalation.

Description

This invention relates to fused pyrimidin-4(3H)-one and preparation thereof.

This application is a Patent of Addition to Patent Specification No. 41673 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-acetyi pyrimidin-4(3H)-one or to a 4(3H)-oxopyrimidine- 2-carboxylie acid or a derivative thereof, and their use as antiallergy agents. More particularly, it relates to 2-alkylpyrimldo[4,5-b]quinolin-4(3H)-ones and 2-alkylpyrido [2,3-d]-pyrimidin-4(3H)-ones wherein alkyl is methyl or ethyl, and the corresponding 2-acetyl derivatives, 4.( 3H)-oxo-pyrimido[4,5-b]-quinoline-215 carboxylic acid, 4(3H)-oxo-benzo]g]quinazoline-2-car~ boxylic acids, and 4(3H)-oxo-pyrido-[2,3-d]pyrimidine2-carboxylic acids; esters, amides, and pharmaceuticallyacceptable salts thereof which are useful as inhibitors of allergic reactions, and especially of allergic bron20 chial 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 the type 25 of oompound illustrated and claimed in the above identified application the following fused pyrimidines having the formulae: 43746 and the pharmaceutically-acceptable cationic salts thereof also exert potent allergy effects in mammals, including man, by an Intal-like mechanism (Intal is a Registered Trade Mark). In contrast to Intal, many of these compounds are effective via intraperitioneal and oral administration, as well as by inhalation and intravenous administration.

In the above Formulae: R is methyl, ethyl, acetyl, or COR* wherein R* is hydroxy, alkoxy, hydroxyalkoxy, amino or hydro.-y amino; Y is hydrogen or alkyl, carbalkoxyalkyl. carboxyalkyl, - (CH2)m-0-C0~CgH5 or-(CHj)m-O-CO-alkyl; with the proviso that when R° is amino ->r hydroxyamino, Y is hydrogen; m is an integer from 2 up to, and including, 4; is hydrogen, alkyl or phenyl; each of R., R,, R. and Rc is selected from 2 3 4 -5 (a) hydrogen, alkyl, alkoxy, halo, benzyloxy, methylthio and methylsulfinyl or (b) hydroxy, thiol, alkanoyloxy, benzoyloxy, benzylthio and benzylsulfinyl; providing that at least one of r2, r3, r4 and R5 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 -3hydroxyalkoxy includes hydroxyalkoxy groups having from 2 up to, and 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 magnesium; aluminum salts; ammonium salts; and salts with organic bases, e.g. amines such as triethylamine, tri-n-butylamine, piperidine, triethanolamine, diethylaminoethylamine, N,Ndibenzylethylenediamine and pyrrolidine.

The following compounds are of particular interest to this invention: Formula I: R is CHg or COR° wherein R° is alkoxy or hydroxy; each of R^, Rg, and Rg is hydrogen; and one of Rg and R^ is hydroxy, and the other is alkoxy.

Special interest exists in the following compounds of Formula I: COR° R° = OH, OH OCH, OCH, OH a1koxv (prerered ethoxy] or n-butoxy> Compounds of Formulae I, and III wherein R is carbalkoxy are also valuable intermediates for production of compounds wherein R is carboxy or carbamoyl, This is especially true of also analogous compounding Formula II since those wherein the substituent in the 2-position is carbalkoxy appear of marginal interest as antiallergy agents.

Compounds wherein any of Rg-Rg !3εηζΥΐ°χ1Γι benzylthio or methylthio, serve as intermediates for compounds wherein this group is hydroxy, alkanoyloxy, thiol, methylsulfinyl, or benzylsulfinyl. -4The antiallergy property of tbe compounds of this invention is evaluated by the passive cutaneous anaphylaxis (PCA) test (Ovary, J. Immun. 81, 355, 1958). In the PCA test, normal animals are injected intra5 dermally (i.d.) with antibodies contained in serum obtained from actively sensitized animals. The animals are then challenged intravenously with antigen mixed with a dye such as Evans' Blue. The increased capillary permeability caused by the antigen-antibody reaction causes the the dye to leak from the site of the antibody injection. The test animals are 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.

The compounds of this invention can be prepared by a variety of methods. Since structures I, II and III have in common the fused pyrimidine* ring, the same reactions can be used to complete this portion of each structure. Simularly, the fused pyridine rings of struc20 tures I and III can be obtained by the same type of reaction using, of course the appropriate precursor in each instance.

The general technique for preparing fused compounds described in Patent Specification No. 41673 are also applicable to the production of the compounds of the present invention.

Compounds of Formula I (R = COR°) can be prepared by methods in which use is made of the intact carbocyclic ring and the quinoline and pyrimidine systems built up in many ways. These methods have, as a common ground, the construction of the 2-arainoquinoline-3-carboxamide, or 3-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 sequence below wherein R' represents hydroxy, alkoxy and aminos by Route A. Alternate methods, e.g., Route B, can also be used as is discussed below. ΐη each of Route A and B, the condensation involves the carbocyclic aldehyde or ketone with an active methylene nucleophile. The requiste carbocyclic aldehydes or ketone reactants are known materials or are prepared by methods described in the art. By active methylene nucleophile is 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,COC1, -C(NH)NH2, COR', -C(NH)-O-alkyl and CO-alkyl.

The condensation is conducted in the presenoe 43746 -6of a reaction-inert solvent; that is, a solvent which is not changed as a result of the reaction even though it may participate in the reaction in the role of a catalyst 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 oarbon tetrachloride; pyridine; aromatic hydrocarbons such as benzene, toluene, xylene; hexane; and Ν,Ν'-dimethylformamide. Other solvents are found by simple experimentation. Methanol is a preferred solvent, especially 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 condensation even when the nucleophiles possess two activating groups as do derivatives of cyanoaoetic 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 (Amberlite is a Registered Trade Mark) (a weakly basic polystyrene with polyamine groups, available from Rohm 6 Haas Co.) and De-Acidite G (polystyrene resin with diethylamino groups; De-Acidite is a Trade Mark. The product is available from the Permutit Co., Ltd., London).

The amount of catalyst used is not critical but can vary over a wide range, i.e., from 0.1* to 100* by weight based upon the carbocyclic aldehyde or Ketone reactant. The favored range of catalyst is from 10% to 30% by weight of the carbocyclic aldehyde or Ketone reactant.

The reaction is conducted at a temperature of from 0eC. to 50°C. and generally at about ambient temperature for periods of frcm one-fourth to five hours.

The products generally separate from the reaction mixture -7as 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 R^-{2nitrophenyl) ketone as the reactant (Route A) produces an ct-cyano-β-(2-nitrophenyl)acrylamide derivative, e.g., an amide when R* of the active methylene reactant is NH2, whioh must subsequently be reduced and cyclized to provide the desired 2-aminoquinoline-3-carboxylie acid derivative. Reduction (of the nitro group to an amino group) is 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. Representative of such reagents are metal-acid combinations such as iron-acetic acid, iron-hydrochloric acid, tin or stannous chloride-hydrochloric aoid, zinchydrochloric acid, zine dust-alkali; and catalytic hydrogenation using catalysts such as 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 25 (Route B) the condensation product with the cyahoacetic acid derivative cyclizes at a very rapid rate to the 2aminoquinoline-3-carboxylic acid derivative as noted above for the reaction product of Route A.

Formation of the fused pyrimidine ring with 30 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 contributes the one-carbon fragment to complete the pyrimidine ring system Upon the appropriate 2-amihoquinoline-3-carboxylic acid derivative: (1) Reaction of a 2-aminoquinoline-3-car42746 -8boxamide (Formula V, R’-NHj) with: (a) a dialkyl oxalate? (b) a monoacid halide (chloride, bromide) of an oxalic acid monoalkyl ester; (c) an alkyl cyanoformate; (d) a dialkyl ester of moniminooxalic acid (a carbalkoxy forminidate); (e) an alkyl ester of oxamidic acid; (f) 1-oyanoformamide; (g) cyanogen; or (h) 1-carbalkoxyformamidine? or (2) Reaction of an alkyl 2~aminoquinoline-3carboxylate with: (a) a 1-carbalkoxyformamidine.

Reactant W-z (an oxalic acid derivative) of the step common to Routes A and B provides the one-carbon fragment needed to complete the fused pyrimidine ring.

Xt may, depending upon choice of reactants, also provide the -NH group. It represents cyanogen and W-COR° wherein W is -COCI, -CN, -COR, -C(NH)NH2 and -C(NH)O-alkyl.

When W-z is an alkyl ester of oxamidic acid, e.g., H5C2OOCCONH2, the cyclization reaction occurs so as to produce the amide (R=OONH2) 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 is to be formed contains a carboxamide group (e.g. Formula V wherein -COR' is -CONHj), reactant W-z can be any of the substances enumerated above; i.e., cyanogen or W-COR°. However, when the reactant upon which the fused pyrimidine ring is to be formed does not contain a carboxamide group; that ia, when -COR' is carboxy or carbalkoxy, reactant W-Z must provide the -NH group.

The favored process comprises using the appropriate 2-amino-3-oarboxamide (Formula V wherein R'=NH2> as reactant which is condensed with the W-Z reactant to -9provide only the single carbon atoms required to complete the pyrimidine ring.

Reaction of the 2-aminoquinoline-3-carboxylic aoid derivative with reactant w-z is carried out in a reaction-inert solvent and desirably, when w is -COR° or C(NH)-O-alkyl, one which will permit removal of byproduct 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 experimentation. A favored solvent when W-Z is a dialkyl oxalate is an excess of the dialkyl oxalate because of its ability to solubilize the reactants and to permit simple removal of by-product alcohol and water. Although the reaction temperature is not critical, the reaction is generally run at an elevated temperature to facilitate removal of alcohol and water. Temperatures of from 150°C. to 135°C. are useful when a dialkyl oxalate is used as solvent. Lower temperatures can be employed with the more reactive oxalic acid derivatives (W-Z) such as ethyl oxalylchloride. A final fusion or heating period is sometimes beneficial to achieving maximum cyclization and yield of the desired 4(3H)-oxo- pyrimido[4,5-bj quinoline-2-carboxylio acid derivative. The addition of a small amount of a base, such as sodium hydride and alkali metal alkoxides, is frequently useful in promoting cyclization, .expecially in making compounds of Formula II.

When feactant W-Z results in production of the 2-cyano derivative rather than a 2-COR0 derivative, the cyano.group is converted to the corresponding 2-oarboxamide 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.

Replacing th® required W-Z with an alkyl ester 43746 -10of glycolic acid yields fused pyrimidines having a hydroxy methyl 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 anhydridepyridine-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, for example by chromic anhydridesuluric acid at 30°C-50°C. produces the 2-carboxylic acid.

Alternatively, the appropriate alkyl benzyloxy acetate; e.g., ethyl benzyloxyacetate, is used instead of reagent w-z to produce fused pyrimidines wherein the 2-eubstituent is a benzyloxymethyl group. Benzyl groups of 2-benzyloxymethyl derivatives are removed e.g. 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-caxboxamide which, in turn, is prepared by the reaction of malononitrile with the appropriate R^(2-aminophenyl) ketone, e.g., 2-aminobenzophenone diphenyl) and aminoacetophenone (R^»>CH3,. The 2-amino-3~ cyano-4-substituted quinoline thus produced is hydrolyzed to the corresponding 4-substituted-2-aminoquinoline-3carboxamide by heating with 954 sulfuric acid, followed by aqueous work-up. The process is that described by Campaigns et al., J. Hetero. Chem. 3, 111-120 (1971).

A further method comprises condensation of an appropriate o-nitrobenzaldehyde with a dialkylmalonate to produce an alkyl a-carbalkoxy-0-(2-nitrophenyl) acrylate which is subsequently reduced to the corresponding alkyl a-carbalkoxy-5-(2-aminopbenyl)acrylate according to procedures described above. The reduced product spontaneously cyclizes to an alkyl 2-oxo-quinoline-3-carboxylate. The 2-oxo derivative is heated -11direotly with 1-oarbalkoxy formamidine in ethanol using sodium ethoxide to give compounds of Formula I. Or, the 2- oxo derivative is chlorinated with a suitable chlorinating agent such as phosphorous trichloride, phospho5 rous pentachloride, phosphorous oxychloride in a reaction inert solvent such as an aromatic hydrocarbon or a halogenated aliphatic or aromatic hydrocarbon (benzene, toluene, xylene, methylene chloride, ethylene chloride, chloroform, chlorobenzene) at a temperature of from 50°C. to 100 °C.

Th’e alkyl 2-chloroquinoline-3-carboxylate thus produced is reacted with an alkyl 1-quanylormate to provide the corresponding alkyl 4(3H)-oxo-pyrimido-[4,5-b) quinoline-2-carboxylate. This cyclization is carried out according to known methods.

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,5H)-tetrahydropyrimidine-220 carboxylic acid, in the presence of a base to produce the corresponding 4,6-dioxo(3H,5H)-5-(2-nitrobenzylidene) tetrahydropyrimidine-2-carboxylie acid ester which, upon subsequent reduction in the manner described above, spontaneously cyclizes to a compound of Formula I. A variation on this method involves condensation of an o-nitrobenzaldehyde with malondiamide, followed by reaction Of the product with a dialkyl oxalate to form a 4,6-dioxO-(3H,5H)-5-(2-nitrobenzylidene)tetrahydropyrimidine -2-carboxylic acid ester.

Compound of Formula II are prepared by methods similar to those described above for oompounds of Formula I but using, of course, in place of a 2-aminoquinoline3- oarboxamide, a 2-aminonaphthalene-3-carboxamide. The reaction conditions for achieving construction of the pyrimidine ring are substantially the same as those described for oompounds of Formula I.

The compounds of Formula III (R = C0Re) are -12eimilarly prepared from appropriate 2-aminonicotinamides or precursors thereto, e.g., 2-aminonicotihie acid, 2nitropyridine-3-carboxamides or 3-carboxylic acids, 2nitro or 2-aminopyridine-3-carboxaldehydes. In preparing compounds of Formulae II and 1X1, the favored routes comprise reacting W-Z with the appropriate 2-amino-3carboxamide reactant.

The amide and hydroxamic acid derivatives of Formulae I, II, and III (R° = NH2,NHOH) are prepared by methods described above from W-C0NH2, or by reaction of the precursor alkyl ester of Formulae I, II, and III with ammonia or hydroxylamine. The usual procedure which comprises reacting the appropriate aster with ammonia or with hydroxylamine hydrochloride, 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 4 to 20 hours and the product then recovered by suitable means.

The 2-methyl and 2-ethyl compounds of Formulae I and III are prepared by cylization of the appropriate 2-aminoquinoline-3-carboxamide or 2-aminonieotinamlde with the appropriate alkanoic acid anhydride e.g. acetic or propionic anhydride; or with triethyl orthoacetate or triethyl orthopropionate in the presence of sulfuric acid. Treatment of the product with dilute alkali followed by reacidification provides the 2-methyl or ethyl derivatives. The preparation of 2-methyIpyrimido [4,5-b]quinolin-4(3H)-one by this procedure is reported by Taylor et al., J. Am. Chem. Soc. 78., 5108-15 (1956) as previously noted. The 2-ethyl derivatives 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 pro-13cedure the 2-ethyl derivative and selenium dioxide are used in about a 2:1 molar ratio at an elevated temperature, e.g. from 50° to about 100°c. Additional selenium dioxide beyond the 2:1 molar ratio can be used to expedite the oxidation.

The 2-methyl derivatives of Formulae I and III are useful intermediates for the preparation of corresponding 2-carboxaldehydes and 2-carboxylic acids, and from them the 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 benzaldehyde 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%5 up to an equivalent amount. The benzylidene adduct is Isolated by removal of the solvent and is then oxidized to the aoid by excess cold potassium permanganate in aqueous acetone, or by qzpnolysis. 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 mixture and filtration. The filtrate is taken.to dryness and the residue dissolved in aqueous sulfuric acid and treated with.chromium trioxide to provide the acid.

Conversion of the 2-methyl groups to 2-oarboxal· dehyde groups is achieved by oxidation with selenium dioxide and water in the manner described above for eon30 version of 2-ethyl to 2-acetyl groups.

The alkylene glycol esters of Formulae I-III (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 5% to 20% by weight based upon the alkylene glycol -14used), such as triethylamine or calcium hydroxide, in air at a temperature of from 20°C. to 50°C. Higher temperatures can be used but appear to offer no advantage.

Compounds of Formula X 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 slat with I-Y, Br-Y or Cl-Y affords the alkylated derivative. When using Cl-Y as alkylating agent, the presence of a small amount of sodium or potassium iodide (from 10% to 20% by weight of Cl-Y) serves to accelerate the reaction.

Compounds of Formulae I-II1 wherein any of Rg, Rg, r^, or Rs 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-chlorparbenzoic 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 compound of Formula IV; i.e., an a-cyano-β-(2-nitrochlorophenyl) 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 treating the benzyl ether or benzylthio ether with trifluoroacetic acid. The debenzylated pro42746 -15ducts are obtained as their trifluoroacetate salts. The hydroxy and thiol compounds, in turn, are intermediates for preparation of corresponding alkanoyloxy, and benzoyloxy derivatives by acylation using 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 pharmaceutically-acceptable cationic salts thereof, are use10 ful for the control (prophylactic and therapeutic treatment) of allergic symptoms and reactions in mammals and can be administered as pharmaceutically distinct dosage forms either as individual therapeutic agents or as mixtures of therapeutic agents, for example, with theoph15 ylline 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.

Compositions include solutions or suspensions of the reagent in water; suspensions in a liquefied propellant and mixtures of a solid antiallergy regeant and a solid diluent for example as a shaped tablet.

Typical methods of administration and com25 positions are described in greater detail in the aforesaid patent specification. .

It is necessary that the active ingredient forms a proportion of the composition such that a suitable dosage form will be obtained. Obviously, several dosage unit forms can be admihistered at about the same time. Although compositions 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 ingredient; otherwise, the amount of carrier becomes excessively large. Activity increases with the concentration of the active ingredient. The composition may contain 10, 50, 75, 95 or an even higher -16percentage by weight of the active ingredient.

The PCA reaction test procedure employed to evaluate 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 Wister rats, 170-210 g. Reaginic antisera is prepared according to Mota, Immunology, 2· 681 (1964) using hen egg albumin and B. pertussis. Hyperimmune 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 mg. histamine dihydrochloride is injected (i.d.) as a check for antihistaminic and unspecific types of blockage; the compounds of the present invention or saline are then administered 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 observation. A score is assigned to 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 treated controls. The difference is expressed as per cent blockage due to the compound employed.

Compounds representative of those in the present invention are tested by the aforementioned procedure and the resulting activities are reported as the degree (%) of protection.

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

I.V.* Oral* 5 RR1R2R3R4R5 mg/kg. % mg/kg, % cooc2h5 H H CHgCOO OCHg H 3 .003 100 S3 10 . 40 COOC2H5 H H OH OCHg H 0.03 0.01 97 98 30 6 10 0.003 94 0.0003 38 COOH H H OH OCH- H 3 1Q0 J 0.01 8 6 .003 90 15 COO-(n-C^Hg) H H OH och3 H 3 .003 100 52 10 67 COO-(n-C4Hg) H H CH-COO OCHg H 3 100 10 36 COOC„Hc H H OH H H 0.3 92 10 13 0.03 21 3 4 20 COOH H H OH H H 3 100 0.03 91 .003 4 cooc2h5 H H OCHg OH H 0.003 0.3 0 100 25 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 30 of from 10 to 1,500 mg. per day, with a preferred range of 10 to 600 mg. per day in single or divided doses, or at 0.2 to 12 mg./kg. of body weight will effectively alleviate broncho-constriction in human subjects. These values are illustrative and there may, of course, be -18individual cases where higher or lower dose ranges are merited.

When administered intravenously or by inhalation, the effective daily dose is from 0.5 to 400 mg. per day and preferably from 0.25 to 200 mg. per day, or at 0.005 to 4 mg./kg. of body weight in single or divided doses.

EXAMPLE I Ethyl 9-benzyloxy-4(3H)-oxo-pyrimido[4,5-b]quinoline-2carboxylate, 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 50“C. The mixture is stirred and 2-amino-3-benzyloxybenzaldehyde (52. g., 0,23 mole) in absolute ethanol (100 ml.) added.

After fifteen minutes stirring at 50°c., the reaction mixture is cooled in an ice bath, filtered and dried to give the product.

B) Ethyl 9- benzyloxy-4(3H)-oxo-Pyrimido[4,5-b]quinoline- 2-carboxylate.. ___________ A mixture of 2-amino-8-benzyloxyquinoline -3carboxamide (43.7 g., 0.134 mole) and diethyl oxalate (500 ml.) is heated to reflux for 4 hours while distilling off the ethanol water formed. The reaction mixture is then cooled to room temperature, the solid product filtered off, washed with diethyl oxalate and air dried. It is purified by recrystallization, with decolorization, from hot chloroform.

EXAMPLE II 7-benzyloxy-8-methoxy 4(6H)-oxo-pyrimido[4,5-b]quinoline 2-carboxyllc acid.__ A) a-Cyano-β-(2-Nitro-4-methoxy-5-benzyloxyphenyl)acrylamide.

Piperidine (2.1 g., 0.0237 mole) and 2-uyanoacetamide (22.0 g., 0.263 mole) are added to a slurry of 5-benzyloxy-4-methoxy-2-nitrobenzaldehyde (0.237 nole) in methanol (500 ml.). The mixture is heated to reflux 43746 -19for two hours and then cooled in an ice bath and filtered. 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 substituted nitrobenzaldehyde reactant, the compounds listed below are prepared: 167-167.5 (dec.) 73 182-3 52 125-6 47 H 0C2H5 OC7H7 H h och3 oc7h7 H H OC?H7 Η H B) 6-Benxyloxy-7-methoxy-2-aminoquinoline-3-carboxamide.

Iron powder (65.2 g., 1.22 moles) is added over a period of one-half hour to a slurry of the product of procedure A (0.271 mole) in a 50% solution of acetic acid-Ν,Ν-dimethylformamide (750 ml.) at 75°C. When addition of the iron powder is complete, the mixture is heated to 90 °C., for four hours and then filtered while hot. The filter cake is washed with hot acetic aoid (150 ml.). The dark red filtrate is gradually added to IN hydrochloric acid (1,500 ml.) and the pink precipitate recovered by filtration and recrystallized 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. 264-266°C.

Upon repetition of procedure B above but using the appropriate ct-cyano-β-(2-nitrophenyl)acrylamide from procedure A, the following compounds are prepared: R2 *3R4R5 m.p. (°C.) % Yield H oc2hs oc7h? H 279-80 (dec.) 73 H och3 oc?h7 H 282-3 (dec.) 95 5 H 0C?H7 H H 238-9 94 C) Ethyl 7-benzyloxy-8-methoxy-4(3H)-oxo-pyrimido [4,5-b]quinoline-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. Whan all the xylene is removed, the reaction mixture is brought to 185°C., cooled .15 to about 100°C. and then slowly poured into chlorcform (300 ml.). The chloroform solution is cooled and the brown precipitate which forms removed by filtration. The filtrate is decolorized with charcoal, concentrated and chiled to give a crystalline mass. The crystals are taken up in hot chloroform, the solution charcoaled, filtered and concentrated to give pale yellow crystals 25%; m.p. 274-275°C.

Following the procedure of C above, but using the appropriate alkoxy substituted 2-aminoquinoline-3-carbox25 amide reactant from B above and the appropriate ester of oxalic acid, the compounds listed below are prepared: -21%N-H \COR° R°R2 *3R4OC2H5 HOC2H5 OC?H70C2H5 H OCHg OC?H7 O-n-C4H9 HOC7H7 OCH3OC2H5 H OC?H7 a R5 m.p. (°C.) ft Yield H 241-2 (dee.) 41 H 254-5 (dec.) 8 H 261-2 (dec.) 13 H 256-7 (dec.) 32 D) 7-Benzyloxy-8-methoxy-4(3H)-oxo-pyrimidO[4,5-b] quinoline -2-carboxylic acid. _.

Ethyl 7-benzyloxy-S-methoxy-4(3H)-oxo-pyrimido [4,5-b]quinolino-2-carboxylate (7.4 mM) in 5ft aqueous sodium hydroxide (37.5 ml.) is stirred af room temperature for twenty hours. The ester dissolves within ten minutes and is followed by the gradual appearance of a light colored precipitate. The reaction mixture is acidified by the slow addition of 10% aqueous hydrochloric acid (13 ml.). The light colored precipitate dissolves 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 yacuo.

The remaining products of Example II-C are hydrolyzed according to procedure D to afford the corresponding acids.

EXAMPLE III Ethyl-8-benzyloxy-7-ethoxy 4(3H)-oxo-pyrimido(4,5-b]quinoline -2-carboxylate. ______________ A) a-Cyano-8~(2-nitro-4-benzyloxy-5-ethoxyphenyl)acrylamide.

A mixture of 5-ethoxy-4-benzyloxy-2-nitrobenzaldehyde (0.0592 mole), 2-cyanoacetamide (5,24 g., 0.0622 mole), piperidine (0.37 g., 4.36 millimole) and ethanol (92 ml.) is heated to reflux on a steam for two hours. It is then cooled in an ice-bath whereupon the -22product precipitates and is recovered by filtration, washed with cold ethanol and dried.

It is of sufficient purity for use in the succeeding step.

B) 6-Ethoxy-7-benzyloxy-2-aminoguinoline-3-carboxamide.

Iron powder (8.52 g., 0.152 mole) is gradually added over a forty-minute period to a slurry of the product of procedure A (0.034 mole) in acetic acid (100 ml,) at 85°C. When addition of the iron powder is complete, the mixture is heated to 95e-100°C., for 1.5 hours and then filtered het through diatomaceous earth. The filtrate is cooled in an ice bath and then filtrered to give a tan crystalline solid. The solid ie 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-8-benzyloxy-7-methoxy-4(3H)-oxo-pyrimido 4,5-b)quinollne-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 160eC., 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 ie washed with hexane and dried.

EXAMPLE IV 7-Benzyloxy-8-methoxy-4-(3H)-oxo-pyrimido(4,5-b]quinoline2-carboxamide_ Anhydrous ammonia is bubbled into a mixture of ethyl 7-benzyloxy-8-methoxy-4(3H)-oxo-pyrimido[4,5-b J quinoline-2-carboxylate (9.00 millimoles) in absolute ethanol (75 ml.) for fifteen minutes. A clear solution formed followed after a few minutes by formation of a precipitate. The reaction mixture is transferred to a pressure bomb Monel (Registered Trade Mark) and heated at 95°C. in an oil bath overnight. The bomb is then cooled to room temperature and the contents removed.

The bomb is washed with ethanol and the combined reaction -23mixture plus wash filtered to recover the product. The filter cake is washed with ethanol and then dried in air, EXAMPLE V 7-Methoxy-8-benzyloxyloxy-4-(3H)-oxo-pyrimido[4,5-b]quin5 oline-2-carboxamide. _ A mixture of 2-amino-6-methoxy-7-benzyloxyquinoline-3-carboxamide (1.15 milliomoles), ethyl oxamate (2.71 g., 23.1 millimoles), ethylene glycol (10 ml.) and sodium methoxide (10 mg.) is heated at 170°C., for one hour. The product is precipitated by slow 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 in vacuo.

EXAMPLE VI 7-Methoxy-8“benzyloxy-4(3H)-oxo-pyrimido[4,5-b]quinoline2-hydroxamic acid.

Ethyl 7-methoxy-8-benzyloxy-4(3H)-oxo-pyrimido [4,5-b]quinoline-2-oarboxyiate (6.08 millimoles) is added to a solution of hydroxylamine hydrochloride (69 mg., 100 millimoles) and triethylamine (100 mg., 100 millimoles) in absolute ethanol (50 ml.). The mixture is heated at 95°C., 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-4(3H)-oxo-pyrimido[4,5-b]quinoline -2-carboxylate trifluoroacetate.

A solution of ethyl 7-benzyloxy-8-methoxy-4-(3H)oxo pyrimido-[4,5-b]quinoline-2-carbOxylate (250 mg., 0.618 mmole) in trifluoroacetic acid (5 ml.) is refluxed for 2.5 hours. (Alternatively the mixture is stirred at room temperature for three days). The reaction mixture is then poured into diethyl ether (25 ml.) and the resulting bright yellow precipitate of the trifluoroacetate salt recovered by filtration, washed with diethyl ether and dried.

Yield = 194 mg., 72%; m.p. 279°C.

Analysis: Calcd. for C15H13N3O5CP3COOH 1/2 H2O: C, 46.58; H. 3.42; 43746 -24N, 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-8methoxy-4(3H)-oxo-pyrimido[4,5-b]quinoline-2-carboxylate trifluoroacetate (0.67 g., 74); m •p. 240eC. (dec/ ) Analysis: Calcd. for C17H17O5N3CF3COOH: 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~benzyloxy-4(3H)-oxo-pyrimido (4,5-b]-quinoline-2-carboxylate is debenzylated to give a 74% yield of ethyl 7-hydroxy-4(3H)-oxo-pyrimido[4,5-b] quinoline-2-carboxylate hemitrifluoroacetate; m.p. 274°275°C. (dec.) Analysie: Calcd. for 1/2 CF3COOH: C, 57.43; H, 3.66; N, 13.39% Found: C, 57.75; H, 4.05; N, 13.65%.

EXAMPLE VIII 7-Hydroxy-8-methoxy-4(3H)-oxo-pyrimido[4,5-b]quinoline2-carboxylic acid, _,_ The trifluoroacetate-hemihydrate salt of ethyl 7-hydroxy-8-meth4)xy-4(3H)-oxo-pyrimido[4,5-b]quinoline2-carboxylate (200 mg., 0.456 mmole) is slurried in 0.1N 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. 281°C. (dec.). -25Analysis: Calcd. for C13HgO5N32H2O: C, 48.29; H, 4.02; N, 13.00% . Found: C, 47.3; H, 3.32; N, 12.73%.

In' like manner, ethyl 7-hydroxy-4(3H)-oxo5 pyrimido[4,5-b]quinoline-2-carboxylate hemitrifluoroacetate (210 mg.) is converted to 7-hydroxy-4(3H)-oxopyrimido [4, 5-b] quinoline- 2-carboxylic acid. Yield = 191 mg., 91% m.p. 340°C. (dec.).

EXAMPLE IX Ϊ0 Ethyl-7-methoxy-8-hydroxy-4(3H)-oxo-pyrimido[4,5-b]quinoline- 2-carboxylate._ A solution of ethyl 7-methoxy-8-benzyloxy-4(3H) oxo-pyrimido-[4,5-b]quinoline-2-carboxylate (198 mg., 0.483 mmole) in trifluoroacetic acid (4 ml.) is stirred at room temperature for 8 days. Diethyl ether (15 ml.) is added and the yellow precipitate 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 charcaol and concentrated under reduced pressure to small volume. The solid which forms is filtered and dried; 9 mg., 6% yield; m.p, 265°-266°C. (dec.).

EXAMPLE X , The compounds below are prepared from appropriate reactants by the procedures of the preceding examples. -26Method* R°R2R3R4R5 of Ex. oc2h5 H H oc7h? och3 II O-n-C3H? H H OC?H7 H II och3 OC7H7 OCH3 H H II oc2h5 H oc7h7 oc7h7 H II °c2h5 oc?h7 H H H II OC2H5 oc7h? Br H Br II0CH3 H OCH3 oc?h7 Br II och3 H oc7h? oc7h? H II OC2hs οο?η7 OCH3 och3 H II OC2h5 H Br Η OC7H7 I O-n-C3H7C2H5 H oc7h7 H III O-n-C3H7C2H5 OC7H7 H H IIIOC2H5 H oc?h7OC2H5 H II oc2h5 HOC2H5 oc7h7 H II oc2h5 H F OC7H7 H IIOC2H5 H Br OC?H7 H II nh2 H oc?h7 H och3 IV NHOH HOC7H7 och3 H VI NHOH OC?H7 och3 och3 H VI NHOH H oc2h5 oc7h? H VI nh2 H OC7H7 oc2h5 H IV nh2 H F OC?H7 Η IV NHOH H Cl OC7H7 Η VIOC2H5 H SC7H7 H Η II NHj H H H sc7h7 IV 0C2h5 H SC?H7C2H5 Η II 0¾ H Η SC7H7 Η II NHOH H H sc7h7 Η VI oc2h5 sc7h? H Η sc7h? II nh2 sc7h7 H H SC?H7 VI *When the method of Example Ii is used steps A to C only are employed. The benzyl ethers and benzylthio ethers tab- ulated above are converted to the corresponding hydroxy and thiol compounds by the procedure of Example VII. -27The thus-produced hydroxy and thiol substituted 2-carboxylic acid esters are hydrolyzed to the corresponding 2-carboxylic acid derivatives by the procedure of Example VIII.

EXAMPLE XI Ethyl 7-acetoxy-8-methoxy-4(3H)-oxo-pyrimido[4,5-b]quinoline-2-carboxylate p-toluenesulfonate..

A mixture of acetic anhydride (4 ml.), ethyl 7-hydroxy-8-methoxy-4(3H)-oxo-pyrimido(4,5-bI quinoline 2-carboxylate trifluoroacetate hemihydrate (250 mg., 0.572 mmole) and p-toluenesulfonic acid monohydrate (100 mg., 0.572 mmole) is heated at 100°C., for 24 hours.

The acetic anhydride is then stripped from the reaction mixture in 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 chilled in ice. The crystals which separate are recovered by filtration and air dried. Yield = 174 mg., 58%; m.p. 215°-217°C.

Analysis: Calcd. for C17H15Oe«3C7H8O3S: C, 54.43; H, 4.37; 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 trifluoroaoetate 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°261°C. (dec.).

The above procedure is repeated but using the appropriate acid anhydride in place of acetic anhydride and the appropriate hydroxy or thiol Formula I compound as reactant to give the following compounds: f2 Fi ft -28-Rr —r r R-_ J 4R5R!R2R3R4R5 R Η H C,HqCOO OCHg H COOCjHg Η H C3H?COO OCHg H COOCjHg Η H HCOO OCHg H cooc2h5 Η H OCHg CHgCOO H COOCgHg Η H OCHg C,HqCOO H COOCjHg Η H OCHg HCOO H COOCgHg Η H HCOO' OCHg H COO-n-C4Hg Η H CHgCOO OCHg H coo-n-c4HgC6H5 H HCOO H HCH3 CgH5 H CgH7COO OCHg H ch3 Η H H HCOO H COO-n-CgH7 Η H H CHgCOO H COO-n-CgH7CRH5 H H CHgCOO OCHgCH3 Η H CHgCOO CHgCOO H COOCjHg Η H HCOO HCOO H COOCjHg Η H OCHg CHgCOO Br COOCHg Η CHgCOO OCHg H HC2H5 CHg H c6h5coo OCHg HC2H5 n-cjig H CgHgCOO OCHg HC2R5CgHg H CHgCOO H HC2H5 Η CgH7COO OCHg H H COOCHg Η CHgCOO OCHg OCHg H COOCjHg Η H Br H CHgCOO COOCjHg Η H H H HCOO coo-n-c4Hg Η H H H CgH7COO C00-n-C4Hg Η CpH^ H CHgCOO H COOCjHg CH. H CHgCOO oc2h5 H CHgC2H5 H F CHgCOO HC2H5 *1R2R3 -29-R4R5 R n-C4H9C2H5 ch3coo H HC2H5 H H Cl ch3coo H COOCH3 H P c3h?coo Η COOC?H,- HC2H5 HCOO H H COO-n-C3H? H H CH3COO H H COO-n-C3H7 H H C3H7COO H H COO-n-C3H7 H H CHjCOO H H cooch3 H H C3H?COO H H cooch3 H H ch3coo ch3coo H cooch3 H H H c2h5co° H COOC,Hq ch3 H c6h5c°° och3 H COOCjHg H H och3 c6h5c°° H COOC,H,- H H Cl C>H-COO 6 5 H COOCjHg EXAMPLE XII Ethyl 7-benzylthio-4(3H)-oxo-pyrimido[4,5-b]quinoline-2carboxylate.

A) a-Cyano-6-(2-nitro-5-benzylthiophenyl)acrylamide A solution of the sodium salt of benzylmercaptan (2.78 g., 0.0398 mole) in Ν,Ν-dimethylformamide (50 ml.) is prepared by adding benzylmercaptan to a mixture of sodium hydride (1.67 g. of 57% NaH) in Ν,Ν-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 dropwise to a mixture of a-oyano-8-(2-nitro-5chlorophenyl>acrylamide (10 g., 0.0398 mole) in Ν,Νdimethylformamide (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. Diethyl ether (30 ml.) is added and the precipitate filtered off, washed with diethyl ether and dried.

B) 6-Benzylthio-2-aminoguinoline-3-carboxamide A mixture of a-cyano-8-(2-nitro-5-benzylthiophenyl)-acrylamide (0.032 mole) in acetic acid - N,N-di4 3 7 4 6 -30roethylformamide (110 ml. of 1:1) is heated in a 75®C., bath. Iron powder (2.0 g.) ie added and the mixture stirred until the internal temperature rises to 95°C. 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 poured into IN hydrochloric acid (200 ml.). The hydrochloride salt which separates is filtered off and dissolved in hot dilute aqueous sodium 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-4(3H)-oxopyrimido[4,5-)quinolines-2-carboxylate.

A round-bottom flask equipped with stirrer, condenser, 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 200°c, Xylene water and ethanol are distilled from the reaction mixture until the internal temperature of the mixture reaches 165°C. The mixture is stirred at 165®C., 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 XIII Ethyl 7-benzylsulfinyl-4(3H)-oxo-pyrimido(4,5-b]quinoline 2-carboxylate.

A solution of ethyl 7-benzylthio-4(3H)~>xopyrimido[4,5-b]-quinoline-2-carboxylate (1 millimnle) in trifluoroacetic acid (2 ml.) is heated in an oil bath to 43746 -3155°C. Hydrogen 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 diethyl ether and air-dried. Recrystallization from absolute ethanol gives the product.

The thiobenzyl compounds of Example X are oxidized to the corresponding sulfinylbenzyl compounds by this procedure.

EXAMPLE XIV Repetition of the procedures of Examples XII A-C and XIII, but using the appropriate chloro substituted 2-nitrobenzaldehyde as reactants, affords the following compounds: H H soc7h7 R3R4R5 SOC7H7C2H5 H H soc7h? H H H SOC?H7 EXAMPLE XV 2-Methyl-7-hydroxy-8-methoxy pyrimido[4,5-6]quinolin-4(3H)one.

A) 7-Benzyl ether of title compound: A mixture of 6-benzyloxy-7-methoxy-2-aminoquinoline-3-carboxamide (1.50 g.), concentrated sulfuric acid (0.05 ml.) and acetic anhydride (20 ml.) is heated at 85°C., for minutes. The mixture is then cooled and ice chips added to the reaction mixture. The yellow solid whioh precipitates is filtered, washed with water and then with isopropyl alcohol-diethyl ether (1:1) and air-dried. Yield - 1.60 g. (99%); m.p. 202°-203°C. (dec.).

B) Debenzylation of 7-benzyl ether: -32The 7-benzyl ether from preparation A above is treated with trifluoroacetic acid according to the procedure of Example Vll to give the title compound in 95% yield; m.p. 135°C, χνι General Procedure Concentrated sulfuric acid (1.5 ml.) is added to a slurry of a 2-amino quinoline-3-carboxamide (0.02 mole) and acetic anhydride (40 ml.). The slurry dissolves 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 sodium hydroxide (225 ml.). It is chilled, the precipitate collected by filtration and airdried. The yellow solid is recrystallized from ethanol.

The following compounds are prepared from appropriate reactante: R1R2R3R4R5 H H H H H H sc7h7 oc2h5 H H HOC2H5 SC7H7 H H H Br sc?h7 H ch3 H sc7h7 oc2h5 H n-C.H- 4 7C2H5 sc?h7 H H The benzylthio ethers enumerated above are debenzylated by treatment with trifluoroacetic acid as is described in Example VII. -33EXAMPLE XVII 2-Ethyl-7-ethoxy-8-benzyloxy pyrimidin[4,5-b]quinolin4(3H)-one.

To a stirred mixture of 6-ethoxy-7-benzyloxy-2 5 aminoquinoline-3-carboxamide (0.002 mole) in propionic anhydride (10 ml.) at 60°C., 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 oompounds are prepared in like manner from appropriate reactants: R1R2R3R4R5 C2Hg H P oc7h? H c2h5 H OC?H7 och3 HC2K5 oc7h? OCH3 II H n-C3H7 H oc2h7OC2H5 H i-C3H7 H OC?H7 oc2h5 H n-C4Hg K OC7H7 H H n-C4H9C2H5 oc7h7 H H n-C.Kg H oc7h7 OCH3 H H H oc2h5 oc7h7 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 XVIII 2-Acetyl-7-ethoxy-8-benzyloxy pyrimido14,5-b]quinoline4(3H)-one.__ Ίο a solution of selenium dioxide (24.5 mg.r 2.2 millimoles) in dioxane water (11 ml. of 10si) is added 2-ethyl-7-ethoxy-8-benzyloxy pyrimido[4,5-b]quinolin-4- (3H) one (125 mg,, 4.4 millimoles). The mixture is heated to feflux for 48 hours after which more selenium dioxide (24.5 mg.) is added and refluxing continued for an additional 24 hours. The mixture ie 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 XVII are oxidized to their corresponding 2acetyl derivatives.

EXAMPLE XIX Ethyl 3-methyl-7-hydroxy-8-methoxy-4(3H)-oxo-pyrimido[4,5b] quinoline-2-carboxylate. ___ Sodium hydride (470 mg. of 50% in oil, 0,011 427 46 -35mole) is added to a slurry of ethyl 7-benzyloxy-8-methoxy4(3H)-oxo pyrimidO-[4,5-b]quinoline-2-carboxylate (3.3 g., 0.01 mole) in Ν,Ν-dimethylformamide (75 ml.). The mixture is stirred and heated on a steambath for ten minutes and then at room temperature for a half hour. Xt is oooled in an ice-bath and iodiomethane (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 half10 hour at room temperature. The reaction mixture is poured into ice-water (200 ml.) and the resulting solid filtered off, air-dried and recrystallized from ethanol to give yellow crystals.

The 7-hydroxy compound is obtained by deben15 zylation of the benzyl ether by reaction with trifluoroacetic acid.

In general, compounds wherein one of Rg, R^, R^ or R5 is thiol or hyroxy are obtained by debenzylation of the corresponding benzylthio ethers or benzylethers by reaction with trifluoroacetic acid according to the procedure of Example VII.

EXAMPLE XX Ethyl 3-carbethoxymethyl-7-ethoxy-8-benzyloxy-4(3H)-oxopyrimido [4,5-bl-quinoline-4 (3H)-one-2-carboxylate._ To a slurry of ethyl 7-ethoxy-8-benzyloxy-4(3H)oxo-pyrimido-[4,5-b]quinoline-2-carboxylate (1.6 g., 5.0 millimoles) in Ν,Ν-dimethylformamide (30 ml.) is added sodium hydride (235 mg., 5.5 millimoles of 56% in oil).

The slurry is heated on a steambath for ten minutes and then cooled to room temperature. Ethyl bromoacetate (968 mg., 5.8 millimoles) is added and the reaction mixture heated on a steam-bath for one hour. After Standing overnight at room temperature the mixture is diluted with water (75 ml.) and the resulting yellow solid filtered off (1.4 g.). It is purified by chromatography on a column of silica gel using chloroform as solvent and eluant. The eluant is evaporated to give a yellow solid. -36It is recrystallized from hot ethanol (50 ml.) containing sufficient chloroform to achieve solution.

EXAMPLE XXI Pyrimido[4,5-b]quinolin-4 (3H)-one compounds 5 of, Examples I-XVIII are alkylated substantially according to the procedure of Example XX but using the appropriate alkyl bromoalkanoate or alkylating agent. The products are recrystallized from suitable solvents such as ethanol or benzene: hexane (1:1). b Fi ff '5 ΓΊ a oj a -37rSB rΟ H aaaaaaaoaaaaaaaaaaaaaa ra m Γ— Γ— O O o o tn r—- r— r— Ρ» r— p* fa a a a ma «a a ma oi r— r* r- a t— a r- p* a pooooooo o u ή o o o oooooooaoaooooa r- in r— a a m a m r- m a p- a u o o o o w ο ο ο ο o a Μ *T* h* *T* *Ύ* M 1J4 »X« - kM *-M |-H a tn Γ- a Ο OJ o a 0 a a ΓΟ o a a a alaaaaaaaaaaaaaaaaaaaaa a a a a σι σ» γ- 0 0 0 0 a a η OJ 01 Xf σ Tf M a a tn tn O in tn in 0 O tn 0 0 OJ 0 a a 1 a a m a 1 a cn 01 oj a a OI OJ β 01 oi a OJ c a 01 a a a O o O 0 r 0 0 0 O 1 1 o O 0 0 <—» O 0 0 0 0 0 O 0 o 0 O 0 0 O 0 O 0 O 0 0 0 O 0 q 0 O 0 0 O 0 o 0 0 0 0 0 O 0 0 0 O 0 u O 0 in tn tn m m m a a a a a a 01 w a XT in σι m 0 0· tn σι a a a cn 1 a a a OI OI a β m 01 tn u O 0 in 0 1 O tn m o 0 a cn 0 1 0 a 0 o I a a m cn O 1 cm a 0 β 0 010 0 β OJ 01 a a 0 β 0 O 0 | 0 0 0 0 1 0 0 O O 0 1 0 O 04 0 cn 0 <3· 01 0 0 0 O O OJ O 0 O O 0 o 0 0 O O o u O 01 0 OJ O OJ OJ O 0 0 O O OJ O OJ oj a 01 a oj a a OJ OJ OJ oi 01 04 a a 0 a O a O o a a a a a 0 a 0 o —' 0 —' 0 0 u 0 0 0 —' 0 tn in tn in in tn a a a a a a CM CN CM CM Ci CM υ υ υ υ υ o o 0 0 0 0 0 000000 υ υ u 0 0 0 CH-COO-H. COCH, Η H OC,H_ OCH tn Μ ts Μ -3843746 m rο χμμμμμμμμ ΓΜ r— υ Ώ Μ Η Μ Μ Μ ΓΜ tn Γ* Μ α ο Ο Ο 32 Μ Γin W Μ *> CM Ο «Λ Μ <μ «χοωΜΚΟΜ Ο <η ιη Μ Μ Ο ιί> Ο Ο €- t— Ο ΓΜ I— Γ- Γ- Γ- Β Μ Ο tn a Μ Μ Μ r> „f*O ΰ t- Γ- Γ- Γ- ο Ο Ρ 3 o Ο Ο Ο Ο Ο Μ 3 O Ο 03 33 0) Μ Β Β Μ 02 Ο ιη Μ Γ4 Ο Μ ΓΜ m Γ* Μ Ο CM ο υ μ Γ— Γ> χ γ*· ι— Ο Ο ο WWW ίϊ\ in m χτ Μ Μ Ο f*> Φ η» ι Μ « Ο Ο fi Ο Μ WWWWWWWW8 ιη ιη ιη ιη ιη ιη ιη ιη ιη ιη Μ Μ Β Μ Μ Μ Μ Μ Μ Μ cn <Μ CM ΓΊ CM (Μ CM CM CM CM CM Μ Μ Ο Ο U Ο Ο Ο Ο ο Ο Ο Ο ο cn Μ m Μ <μ Μ <η Ο 33 Ο Ο ο Ο Ο Ο Ο 8 8 8 X 8 Ο Ο ο ΟΟΟ Ο Ο ο υ ο υ υ Ο 0 Ο ο tΜ m υ I *·—I I Ch Μ χρ σ ρ3 σ\ Μ χ»· in ο 33 1 CM Ci υ ι 8 8 in 33 CM O cn O ό tc o ooo m CM O M1 , w o in m CM o o cm ιη ι _____ .„8 “-έ ( ουοοοοουυϋ QO «η cm Q Ο ** Q «Μ Ο ϋ 8 *Ϊμ 8 8 nl U cm 8 0 Ρϊ ΰ ϋ (Μ Ν Ν W W CM CM CMta N CN w CM CM a mmoummomossmobsssu oo — — oo — o — oo — oo — ιη Μ ρ cm ta ιη Μ η cm a O O o o -39The 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 XXII General Procedure The procedure of Example XX 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 recrystallized from ethanol (20 ml.) containing sufficient acetonitrile to achieve solution.

The following compounds are prepared from the appropriate pyrimidin[4,5-b]quinolin-4(3H)-one compounds of the preceding example and the appropriate bromoalkyl alkanoate or bromoalkyl benzoate: l5 -40in a a a a a a a a a a Γ- r* a r*. m m a U a a a CM u O υ u o a u w a cn o o a o a ro r- r* a a ο» rυ υ o O r*. o o O o a o o O o o b- m m o O m a a a 0 o a η O u> a a a o U O o O υ in Io Q u KKKKSKBWWieS «IBSXSSSSS»»® σι w >* in m in in in O μ x x a a i oi nl nl nl ni C ο ο ο ο u ι m in m a a m a a a oi a CI OJ OJ o U o U U o O o O O o O o o O o u u u o in in t- in in in r- in |>)M a Β Β «Β 33 S3 W ia* ni io m in W NiDcnEfi nl UOOUQOUUOgO ooooooooooo ouooooooooy ooooooooooo ci u· ni m m ni υ· mni m IT Κ-.ΒΒϊΒ-'-ϊϊΕu ηιΰοοο ntOUO m maj ni m m m a; ν ν n ffi KosaasKOiawwo u^-uooo — uQD·^ -41EXAMPLE XXXII Ethyl 7-benzyloxy-4(3H)-oxo-benzo[g]quinazoline-2-carboxylate.

A) 5-Benzylqxybenzo[g]isatoic anhydride 2-Amino-6-benzyloxy-3-naphthoic acid (0.133 mole) is dissolved, warming if necessary, in a mixture of water (50 ml.), concentrated 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 temperature is held below 50°C., by regulating the rate of introduction of the phosgene. After passing phosgene into the mixture for four hours, the residual phosgene is blown out by pass15 ing 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 bus20 pension 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-benzyloxy-4(3H)-oxo-benzo[g]guinazoline2-carboxylate. ________ .

Diethyl oxalate (2.35 g., 16.1 millimoles), sodium methoxide (10 mg.) and 2-amino-6-benzyloxy naphthalene-lf-carboxamide (1.50 g., 8.05 millimoles) are mixed together and heated at reflux 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 •42with 10% hydrochloric acid to pH 2 and evaporated to drynesa under reduced 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 solution 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 diammonium salt.

EXAMPLE XXIV Alkyl 4(3H)-oxo-Benzo. Eg]guinazoline-2-carboxylates.

The following alkyl 4(3H)-oxo.-benzo[giquinazoline-2-carboxylates are prepared from the appropriate reactants by the procedure of Example XXIII.

C0R° R® 0CH3 O-n-C-H-A SC7H? SC7H? H H sc7h7 The thioethers are converted to the corresponding sulfinyl derivatives by oxidation with hydrogen peroxide according to the procedure of Example XIII.

The benzylthio ethers are debenzylated by reaction with trifluoroacetic add as described in Example VII to the corresponding thiol compounds.

EXAMPLE XXV 4(3H)-Oxo-Benzo[g]quinazollne-2-carbomamides.

Following the procedure of Example V but using the appropriate 2-aminonaphthalene-3-carboxamide in place 43746 -43of 2-aminoquinolin-3-carboxamide, the amides corresponding to the ester products of Example XXIV are prepared. The compounds have the formula: EXAMPLE XXVI 4(3H)-Οχο-benzo[g]guinazoline-2-hydroxamlc acids.

The ester products of Example XXIV are converted to the corresponding hydroxamic acids by the procedure of Example VI. The compounds have the formula: N-H 'CONHOH EXAMPLE XXVIII Repetition of the procedure of Example Xvn but using the appropriate 2-aminonicotinamide in place of the 2-aminoquinoline-3-carboxamide produces the following compounds: S2R3R4 CHg SC7H? H CHg SC?H7 CH CHg SOC7H7* H CHg . SOC7H7* CH CHg OC7H? H oc7h? H H 43746 -44♦Produced by oxidation of the corresponding thioethere according to the procedure of Example XIII.

The benzyl ethers and benzylthio ethers listed above are debenzylated by treatment with trifluoroacetic acid to afford the corresponding hydroxy and thiol compounds according to the procedure of Example Vii.

EXAMPLE XXVIII Substituted-2-ethylpyrido[2,3-d]-pyrimidln-4(3H)-ones.

Thetitle compounds can be prepared using the following synthesis for 2-ethylpytide [2,3-d3pyrimidino4(3H)-one using appropriately substituted starting materials.

Concentrated suluric 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 mixture stirred for one hour. It is then cooled to room temperature and poured into water (25 ml.). The agueouB mixture is stirred, made basic with 6N sodium hydroxide and stirred overnight. Upon acidification to pH 5.0 with 10% hydrochloric aoid the desired product precipitates. It is filtered off and dried.

The following compounds are prepared from appropriate reactants; ch3 sc?h7 H CH3 SC7H7 CH3 CH3 soc?h7 h ♦Prepared by oxidation of the corresponding thio compound according to the procedure of Example XIII.

Debenzylation of the benzylthio ethera by treatment with trifluoroacetic acid according to the -45procedure of Example VII affords the corresponding thiol compounds.

EXAMPLE XXIX 2-Acetyl-pyrlmido[2,3-d]-pyrimidin-4(3H)-ones.

The products of Example XXVIII are oxidized by selenium dioxide substantially according to the procedure of Example XVIII to provide compounds of the formula: Repetition of the procedure of Example XXXV but using appropriate reactants produces the following compounds: R°R2R3R4OC2H5 ch3 sc7h? H och3 ch3SC7H7CH3 och3 ch3 °c7h7 HOC2H5 OC?H7 H H oc2h5 / ch3 soc7h7* H och3 ch3 soc7h7* ch3 ♦Prepared by oxidation according to the procedure of Example XIII.

The free acid and disodium salt derivative can be produced by the hydrolysis of the ester. Debenzylation of benzyl ethers and benzylthio ethers in the manner of Example VII affords the corresponding -46hydroxy and thiol compounds.

EXAMPLE XXXI The hydroxy and thiol compounds of Example XXVII-XXX are converted to acyloxy derivatives by the procedure of Example XI. In this manner the formyloxy, acetoxy, butyryloxy and benzyloxy derivatives are prepared.

EXAMPLE XXXII 4(3H)-Oxo-pyrido[2,3-d] pyrimidine-2-carboxamides.

The procedure of Example V is repeated but using the appropriate 2-aminonicotinamide as reactant in plaoe of 2-aminonaphthalene-3-carboxamide to produce the amides corresponding to the esters of Example XXX.

EXAMPLE XXXIII 4(3B)-0xo-pyrldo[2,3-d] pyrimidine-2-hydroxamic acids.

The esters of Example XXX are converted by the procedure of Example VI to hydroxamic acids of the formula: EXAMPLE XXXIV 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 salts by the procedure of Example XXIII-D and XXIII-E.

The acids are converted to the calcium, magnesium, aluminum, triethylamine, tri-n-butylamine, piperidine, tri25 ethanolamine, diethylaminoethylamine, Ν,Ν'-dibenzylethylenediamine and pyrrolidine salts by reaction with an equivalent amount of the appropriate base (Ca(0H)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 (20)

1. . A compound selected from those having the Formulae: and the pharmaceutically-acceptable cationic slats thereof wherein R is methyl, ethyl, acetyl or COR° wherein R° is hydroxy, alkoxy, hydroxyalkoxy, amino or hydroxyamino; Y is hydrogen,alkyl, carbalkoxyalkyl, carboxyalkyl, -(CH,) -0-C0-C,H, or -(CH_) -O-alkanoyl; with the λ in ο o a m. proviso that when R is COR° wherein R° is amiho or hydroxy amino, Y is hydrogen; m is 2 to 4; R^ is hydrogen, alkyl or phenyl; each of R 2 , R 3 , R^ and Rj is selected from (a) hydrogen, alkyl, alkoxy, halo, benzyloxy, methylthio and methylsulfinyl and (b) hydroxy, thiol, alkanoyloxy, benzyl thio, benzoyloxy and benzylsulfinyl providing at least one of KjjKy r 4 and R 5 is selected from the group (b).

2. A compound according to claim 1, wherein one of R 3 or R^ is selected from group (b).

3. A compound according to claim 2, wherein Y when 43746 -48present is hydrogen; R when present is COR® and R® is alkoxy or hydroxy.

4. , A compound according to claim 3, wherein one of R^ or R^ is hydroxy.

5. 5, A compound according to claim 4, wherein each of r , r 2 , r 5 and Y when present is hydrogen, R when present is COR® wherein R° is alkoxy; and one of R 3 and R 4 is hydroxy and the other alkoxy.

6. A compound according to claim 5, wherein R° 10 is n-butoxy; R 3 is hydroxy and R 4 is methoxy.

7. A compound according to claim 5, wherein R® is ethoxy; R 3 is methoxy and R 4 is hydroxy.

8. A compound according to claim 1, wherein one of R^, R 3 and R 4 is selected from group (b). 15

9. , a compound according to claim 8, wherein R 2 ia hydrogen; and one of R 3 and R 4 is hydroxy.

10. A fused pyrimidine according to claim 1, substantially as hereinbefore described in any of Exanpies VII co XVI, XIX, XXI, XXII and XXIV to XXXIV, 20

11. A pharmaceutical material for use as an antiallergy agent comprising a compound selected from those and the pharmaceutically-acceptable cationic salts thereof 43746 -49wherein R, Y, R°, R^y Rg, R 3 , R 4 and R g are as defined in claim 1. and a pharmaceutical carrier, said antiallergy agent being present in an amount of from 0.5% to 95% by weight of the carrier or said compound in a distinctive pharmaceutical form of unit dosage.

12. A material according to claim 11, wherein Y is hydrogen and one of Rg or R^ is alkoxy or hydroxy.

13. A material according to claim 11, wherein each of R^, Rg, Y when present and R g is hydrogen; one of R 3 and R^ is methoxy and the other hydroxy and R when present, is COR° wherein R° is butoxy.

14. A material according to claim 13, wherein each of R 3 is hydroxy acid R^ is methoxy.

15. A pharmaceutical material as claimed in claim 11, in a form suitable for administration by inhalation.

16. A pharmaceutical material as claimed in claim ll, comprising a solution or suspension of the antiallergy agent in water.

17. A pharmaceutical material as claimed in claim 11, comprising a suspension of the antiallergy agent in a liquefied propellant.

18. A pharmaceutical material as claimed in claim 11, comprising the solid antiallergy agent and a solid diluent.

19. A material according to claim 11, wherein the material is a shaped tablet.

20. A method of controlling allergic symptoms in a non-human mammalian subject which comprises administering to the subject an allergy symptom-controlling amount of a compound selected from those having the Formulae: 43746 and the pharmaceutically-acceptable cationic aalte thereof wherein R, Y, R°, R 2> R 3 , R^ and Rg are as defined in claim 1.