GB1596530A - Pyrimidoqyinoxaline derivatives process for producing the same and medicine comprising the same for allergic asthma - Google Patents

Description

(54) PYRIMIDOQUINOXALINE DERIVATIVES, PROCESS FOR PRODUCING THE SAME, AND MEDICINE COMPRISING THE SAME FOR ALLERGIC ASTHMA (71) We, MITSUBISHI YUKA PHARMACEUTICAL CO. LTD., a company organized and existing under the Laws of Japan, of 3-7 Ginza 8-chome, Chuo-ku, Tokyo-to, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates generally to pyrimidoquinoxaline derivatives and a process for producing them and, further, to pharmaceutical compositions comprising them for the treatment of allergic asthma.

It is reported by Cox, et al, (Adv. in Drug Res. 5, 115 (1970)) that sodium chromoglycate, - which has been developed in recent years, is effective for the treatment of allergic bronchial asthma. This compound is thought to exhibit its effectiveness by inhibiting the discharge of a chemical mediator from the mast cells which are formed as a result of an antigen-antibody reaction caused by a reagin antibody. However, a disadvantageous feature of this compound is that it cannot be adsorbed by oral administration, and at present it is being used as a powder inhalant.

We have sought to provide an allergic asthma remedy which can also be orally administered.

The results of our research indicate that a specific kind of new pyrimidoquinoxaline derivatives have an anti-allergic action equivalent to that of sodium chromoglycate in animal experiments and, moreover, exhibit a power effectiveness when orally administered which is comparable to that which they exhibit when intravenously injected. This suggests that these compounds may be useful as preventive medicihes for allergic asthma.

Accordingly, it is an object of this invention to provide an allergic asthma remedy which can also be orally administered.

Another object of the invention is to provide new pyrimidoquinoxaline derivatives.

Still another object of the invention is to provide a process for producing these pyrimidoquinoxaline derivatives.

According to this invention we provide substituted pyrimido - [5,6 - b] quinoxaline - 4(3H) - one - 2 - carboxylic acid compounds represented by the formula (I) set forth hereinafter, or pharmacologically acceptable salts thereof, and pharmaceutical compositions comprising these derivatives or their pharmaceutically acceptable salts.

1. Pyrimidoquinoxaline derivatives The pyrimidoquinoxaline compounds provided by this invention are substituted pyrimido[5,6 - b]quinoxaline - 4(3H)- one - 2 - carboxylic acids represented by the following formula (I), esters thereof, and pharmacologically acceptable salts thereof:

wherein: R represents hydrogen or an alkyl group having I to 4 carbon atoms, a benzyl group or a phenyl group; each of R1, R2, R3 and R4 independently represents hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having I to 4 carbon atoms, a halogen, a benzyloxy group, hydroxyl group, an alkylthio group having 1 to 4 carbon atoms, or an alkylenedioxy group having I to 4 carbon atoms and formed by the bonding of two of R', R2, R3 and R4.

For these substituents R', R2, R3 and R4, the following may be considered in addition to hydrogen: methyl, ethyl, butyl, methoxy, isopropoxy, butoxy, chloro, bromo, benzyloxy, hydroxy, methylthio and butylthio for example.

Specific examples of the compound (I) are as enumerated below. Here, [A] represents a substittient group as set forth above, and, in the case of a plurality of [A]s, they may be the same or they may be different.

(1) Non-substituted product: R1=R2=R3=R4=H (2) Monosubstituted product: a). 6-substitution: R2=R3=R4=H R1=[A] b). 7-substitution: R'=R3=R4=H R2=[A] c). 8-substitution: R1=R2=R4=H R3=[A] d). 9-substitution: R'=R2=R3=H R4=[A] (3) Disubstituted product: a). 6,9-substitution: R2=R3=H R1=[A], R4=[A] b). 7,8-substitution: R'=R4=H R2=[A], R3=[A] In the case wherein the substituent groups are vicinal as in the 7,8-substitution, R2 and R3 may be mutually bonded and form (R2-R3) methylenedioxy or ethylenedioxy, for example. c). 6,7-substitution: R3=R4=H R'=[A], R2=[A], or R'-R2=methylenedioxy or ethylenedioxy d). 6,8-substitution: R2=R4=H R'=[A], R3=[A] e). 7,9-substitution: R'=R3=H R2=[A], R4=[A] f). 8,9-substitution: R'=R2=H R3=[A], R4=[A], or R3-R4=methylenedioxy or ethylenedioxy (4) Trisubstituted product: a). 6,7,8-substitution: R'=[A], R2=[A], R3=[A], or R'-R2 or R2-R3=methylenedioxy or ethylenedioxy R4=H b). 7,8,9-substitution: Rt=H R2=[A], R3=[A], R4=[A], or R2-R3 or R3-R4=methylenedioxy or ethylenedioxy c). 6,7,9-substitution: R1=[A], R2=[A], or R'-RZ=methylenedioxy or ethylenedioxy R3=H R4=[A] d). 6,8,9-substitution: R'=[A] R2=H R3=[A], R4=[A], or R3-R4=methylenedioxy or ethylenedioxy (5) Tetrasubstituted product: R'=[A], R2=[A], R3=[A], R4=[A], or R'-R2, R2-R3, or R3-R4=methylenedioxy or ethylenedioxy.

Of these derivatives, those of 7-, 8-, and 7,8-substituted products are produced from readily available starting materials and can be easily synthesized.

Specific examples of thxse compounds are as follows: R' to R4=H (non-substituted), 6,9-dimethyl-, 6,9-dimethoxy-, 6,9-dichloro-, 6methyl-, 9-methyl-, 6,9-dibutyl-, 6-butyl-, 9-butyl-, 6,9-diisopropyl-, 6-methoxy, 9methoxy-, 6,9-dibutoxy-, 6-butoxy-, 9-butoxy-, 6,9-diisopropoxy-, 6-chloro-, 9chloro-, 6,9-dibromo-, 6-benzyloxy-9-methoxy, 6,9-dibenzyloxy-, 6-hydroxy-9methoxy-, 6,9-hydroxy-, 6,9-dimethylthio-, 6-methylthio, 6,9-dibutylthio-, 6isopropylthio-, 6-butylthio-, 7,8-dimethyl-, 7,8-dimethoxy-, 7,8-dichloro-, 7-methyl-, 8-methyl-, 7,8-dibutyl-, 7-butyl, 8-butyl, 7,8-diisopropyl-, 7-methoxy-, 8-methoxy-, 7,8-dibutoxy-, 7-butoxy-, 8-butoxy, 7,8-diisopropoxy-, 7-chloro, 8-chloro, 7,8dibromo, 7-benzyloxy-8-methoxy-, 7,8-dibenzoyloxy-, 7-hydroxy-8-methoxy, 7,8hydroxy-, 7,8-dimethylthio-, 7-methylthio-, 7,8-dibutylthio-, 7-isopropylthio, 7butylthio-, 7,8-methylenedioxy-, 7,8-ethylenedioxy-, 6,7-dimethyl-, 6,7-dimethoxy-, 6,7-dibutyl-, 6,7-diisopropyl-, 6,7-dibutoxy-, 6,7-diisopropoxy-, 6,7-dibromo-, 6,7dichloro-, 6-benzyloxy-7-methoxy-, 6,7-dibenzyloxy-, 6-hydroxy-7-methoxy-, 6,7hydroxy-, 6,7-dimethylthio-, 6,7-dibutylthio, 6,7-methylenedioxy-, 6,7diethylenedioxy-, 6,8-dimethyl-, 6,8-dimethoxy-, 6,8-dichloro-, 6,8-dibutyl-, 6,8diisopropyl-, 6,8-dibutoxy, 6,8-diisopropoxy-, 6,8-dibromo, 6-benzyloxy-8methoxy-, 6,8-dibenzyloxy, 6-hydroxy-8-methoxy-, 6,8-hydroxy-, 6,8-dimethylthio-, 6,8-dibutylthio-, 7,9-dimethyl-, 7,9-dimethoxy-, 7,9-dichloro-, 7,9-dibutyl-, 7,9diisopropyl-, 7,9-dibutoxy-, 7,9-diisopropoxy-, 7,9-dibromo-, 7-benzyloxy-9methoxy-, 7,9-dibenzylthio-, 7-hydroxy-9-methoxy-, 7,9-hydroxy-, 7,9dimethylthio, 7,9-dibutylthio-, 8,9-dimethyl-, 8,9-dimethoxy-, 8,9-dichloro-, 8,9dibutyl-, 8,9-diisopropyl-, 8,9-dibutoxy-, 8,9-diisopropyl, 8,9-dibromo-, 8,9diisopropoxy-, 8,9-dibromo-, 8-benzyloxy-9-methoxy-, 8,9-dibenzyloxy-, 8hydroxy-9-methoxy-, 8,9-hydroxy-, 8,9-dimethylthio-, 8-methylthio-, 8,9dibutylthio-, 9-isopropylthio-, 9-butylthio-, 8,9-methylenedioxy-, 8,9ethylenedioxy-, 6,7,7-trimethyl-, 6,7,8-trimethoxy-, 6,7,8-trichloro-, 6,7,8-tributyl-, 6,7,8-tributoxy-, 7,8,9-trimethyl-, 7,8,9-trimethoxy-, 7,8,9-trichloro-, 7,8,9-tributyl-, 7,8,9-tributoxy-, 6,7,8-trimethyl-, 6,7,9-trimethoxy-, 6,7,9-trichloro-, 6,7,9-tributyl-, 6,7,9-tributoxy-, 6,8,9-trimethyl-, 6,8,9-trimethoxy-, 6,8,9-trichloro-, 6,8,9-tributyl-, 6,8,9-tributoxy-, 6,7,8,9-tetramethyl-, 6,7,8,9-tetramethoxy, 6,7,8,9-tetrachloro-, 6,7,8,9-tetrabutyl-, and 6,7,8,9-tetrabutoxy.

In these cases, while R may represent any of the aforedescribed groups, a specific example thereof is H (i.e., a free acid).

Specific examples of R in the case where this substituted pyrimido[5,6 b]quinoxaline - 4(3H) - one - 2 - carboxylic acid compound is an ester are methyl, ethyl, n-propyl, isopropyl, n-butyl, benzyl, and phenyl.

In the case where this carboxylic acid compound is a pharmacologically acceptable salt, typical examples of salt-forming cations include metal ions and amine ions (inclusive of ammonium). Specific examples are Na, K, Mg, Ca, Al and Cu, and ammonia, tris(hydroxymethyl) aminomethane, N, N bis(hydroxyethyl)piperazine, 2 - amino - 2 - methyl - 1 - propanol, and mono-, di- and tri-ethanolamines.

Since this substituted pyrimido[5,6 - blquinoxaline - 4(3H)- one - 2carboxylic acid compound has basic nitrogen at the 5-position and the 10-position, salts can be made together with acids. The salts in this case, also, are within the purview of this invention provided that they are pharmacologically acceptable.

Examples of the acids in this case are hydrogen chloride, sulfuric acid, hydrogen bromide, and methanesulfonic acid.

2. Synthesis of compounds While a compound of the formula (I) can be synthesized by any appropriate process, a preferred process comprises the following steps.

2-1. Synthesis process A

R2 4 CONH2 R3 NJ\NA (Il) 4 R COX Step A-l COOR 4 a base (I;j) RI R2 CONH2 R NR4l NHCOCOOR (IV) R4 Step A-2 R1 0 R2 7N;q NH (I) R3 COOR R where: X represents a halogen; and R and R' to R4 have the same respective meanings as set forth hereinbefore.

By this process of synthesis, the compound (IV) is obtained as an intermediate, which is caused to undergo ring closure by heating. If desired, however, it is also possible to carry out the reaction under ring-closing conditions from the beginning, thereby to obtain directly the compound (I). Nevertheless, it is more advantageous first to synthesise, the- intermediate compound (IV) under relatively mild conditions, to isolate this when needed, and then to carry out the ring-closure step.

The reason for this is that the subsequent isolation and purification of the compound (I) is then vry much helped.

2-1-1. Step A-l In this synthesis process A, the 2 - aminoquinoxaline - 3 - carbox - amide compound of the general formula (II), which is a starting material, is caused to react with oxalic monohalide compound of the general formula (III), preferably a monoester monohalide, in the presence of a solvent, preferably in the presence of a base, thereby to synthesize an N - (3 - carbamoyl - quinoxaline - 2 - yl)oxamic acid compound, preferably an ester thereof.

Preferred reaction conditions of the step A-l are as follows: Temperature: -400C to 1000C, preferably -200C to 500 C.

Time: 1 hour to 7 days, preferably 5 hours to 1 day.

Base: ammonia, triethylamine, piperidine, morpholine, pyridine, and other amines, NaHCO3, Na2CO3, K2CO3, NaOH, KOH, NaH, and other alkalis.

Solvent: tetrahydrofuran, dioxane, acetone, methylethylketone, chloroform, methylene chloride, dimethylformamide, dimethylacetamide, dimethylsulfoxide, benzene, toluene, higher boiling solvents which can be used in the subsequent step A-2 which will be explained later in detail. The quantity of the solvent is 1 to 100 times, preferably 10 to 50 times, by weight of that of the compound (II).

Compound (III) (mole (mole ratio): 0.5 to 5, preferably 1 to 2.

Compound (II) Base (mole ratio): 0.5 to 5, preferably 1 to 2.

Compound (II) Upon completion of the reaction, an excess quantity of water is added to the compound (IV), and the desired substance can be isolated by filtration in the case where the crystals precipitate and by further extraction with an ordinary solvent such as chloroform or ethyl acetate which is immiscible with water and concentration in the case where the crystals do not precipitate.

2-1-2. Step A-2 By heating the compound (IV) prepared in this manner in a solvent of high boiling point thereby to dehydrate this compound and to cause it to undergo ring closure, a pyrimido[5,6 - blquinoxaline - 4(3H) - one - 2 - carboxylic acid compound, preferably an ester thereof, is obtained.

The preferred reaction conditions of this step A-2 are as follows: Temperature: 50 to 4000C, preferably 150 to 3000C.

Time: 5 minutes to 10 hours, preferably 30 minutes to 5 hours.

Solvent: a-chloronaphthalene, diphenylether, "Dowtherm" (trade mark), mineral oil, diethyl oxalate, di-n-butyl oxalate. The quantity of the solvent is 1 to 100 times, preferably 10 to 50 times, by weight of that of the compound (IV). The desired compound (I) can be obtained by transforming the R group of the compound (I) which is formed or by transformation into a pharmacologically acceptable salt thereof.

2-1-3. Step A-0 The compound (II) can be prepared by any suitable process. Specifically, for example, the process set forth in J. Chem. Soc., 1945, 622 or J. Am. Chem. Soc. 66, 1957-(1941) may be used.

In this connection, with the exception of a few di- and tetra-substituted products, a mixture of two kinds of isomers is obtained when the compound (II) is synthesized by the processes disclosed in these references. If, in this case, the separation of the isomer mixture is difficult, it can be used as it is as the starting material, in which case, a mixture of two kinds of isomers of the compound (I) will be formed.

Substituted products from which the compound (II) can be obtained as a single substance are as follows.

1). 6,7-di-substituted products R'=R4=H, R2=R3=[A] 2). 5,8-di-substituted products R2=R3=H, R1=R4=[Ai 3). 5,6,7,8-tetra-substituted product R1=R2=R3=R4=[Al Specific examples of the compound (II) correspond to those set forth as examples with respect to the aforedescribed compound (I) except that the representations of the positions of the groups R' to R4 are not 6 to 9-positions as in compound (I) but are 5 to 8-positions in compound (if).

2-2. Synthesis process B Another preferred process for synthesizing the compound (I) comprises the following steps.

Step B-l

where: RO represents an alkyl group having 1 to 4 carbon atoms, a benzyl group or a phenyl group; and R, R' to R4 have the same respective meanings as set forth hereinbefore.

In this synthesis process B, the 2-aminoquinoxaline-3-carboxamide compound represented by the formula (II) is caused to undergo a reaction under heating with the oxalic compound of the formula (VI), preferably an oxalic diester, whereupon ring closure takes place, and the compound (I) is obtained in the form of an ester.

The intermediate prior to ring closure may be synthesized first and then heated to cause it to undergo ring closure as in the case of the aforedescribed synthesis process A, but this is not necessary. The present reaction is carried out in a solventless mode although the starting material compound (VI) may be said to function as a solvent, or in a solvent of high boiling point.

The preferred reaction conditions of this step B-l are as follows: Temperature: 50 to 400"C, preferably 150 to 3000C.

Time: 30 minutes to 3 days, preferably 5 hours to I day.

Solvent: a-chloronaphthalene, diphenylether, "Dowtherm" (trade mark), mineral oil, diethyl oxalate, di-n-butyl oxalate. The solvent quantity is from 1 to 100 times, preferably 5 to 20 times (by weight) that of the compound (II).

Compound (IV) (mole ratio): 1 to 100, preferably 2 to 50.

Compound (II) Upon completion of this reaction, the compound (I) is isolated through precipitation by adding a solvent of low dissolving power such as n-hexane or petroleum benzene to the reaction liquor.

2-3. Transformation of compound (I) In the above-described synthesis processes A and B, the oxalic compounds (III) and (VI) are preferably esters (R*H), in which case, therefore, the resulting compound (I) is also obtained as an ester.

In the case where a compound (I) of a form other than an ester is required for reasons such as pharmacological effectiveness, the ester compound (I) may be transformed into the other form by an ordinary method.

Preferred reaction conditions in the case of the transformation into the free carboxylic acid by hydrolysis are as set forth below. In the case where an alkali is used for the hydrolytic agent, an alkali metal salt is formed, and, for this reason, neutralization is carried out with an acid in order to obtain free carboxylic acid. It will be obvious that this alkali metal salt can be recovered as a desired product.

Preferred hydrolysis conditions Alkali: NaOH, KOH, K2CO3, Na2CO3 and NaH, for example.

Acid: Hydrochloric acid, sulfuric acid, hydrobromic acid,p-toluenesulfonic acid and acetic acid, for example.

Temperature: 0 to 200"C, preferably 20 to 1000C.

Time: 30 minutes to 3 days, preferably I hour to 1 day.

Solvent: water, water-dioxane, water-an alcohol, benzene or toluene, for example. The quantity of the solvent relative to the compound (I) is 1 to 100 times, preferably 2 to 50 times (by weight).

3. Allergic asthma medicine While the compound (I) and salts thereof can be applied to various uses, one important use thereof is as an allergic asthma medicine.

As an allergic asthma medicine, the compound is inhaled into the bronchi in doses of I to 20 mg., 3 or 4 times daily, in the case of administration by inhalation.

In the case of intravenous injection, it is injected in a dose of I to 10 mg., 4 or 5 times daily. In the case of oral administration, it is administered in a dose of 1 to 50 mg., 3 times daily, and in the case of rectal administration, it is administered in a dose of 1 to 50 mg., 2 or 3 times daily.

The medicine may be used in any suitable form, but ordinarily, it is used in the form of a composition containing the compound (I), one or more of its salts, an ordinary pharmaceutical carrier, a vehicle, other additives and/or adjuvants.

4. Experimental Examples I. Tests of medicinal effect Evaluation of the antiallergic action of the compounds of this invention was carried out by a passive cutaneous anaphylaxis (PCA) test on rats.

Egg albumen which had been recrystallized five times and Bodetalla pertussis vaccine were intracutaneously administered into rats (DLC Wister rats), and, after 13 days, serum was extracted therefrom. The serum thus obtained contained an antibody having characteristics similar to those of human reagin and exhibited an antibody value higher than 256.

This serum was diluted 128 times and intracutaneously administered into the backs of rats, and, 48 hours later, suspensions prepared by suspending compounds of this invention in the quantities set forth in Table 1 below, in respective percent tragacanth solutions, were orally administered to respective rats. After 20 minutes, a physiological salt solution in which egg albumen and colouring matter (Evans Blue) had been dissolved was intravenously administered into each rat. 30 minutes thereafter, the dorsal skin of the rat was peeled off, and the quantity of the colouring matter which had exuded out as a result of antigen-antibody reaction was extracted by means of Na2SO4 and acetone and subjected to colorimetry at 620 m,u.

The results were as indicated in Table 1, as follows: TABLE I

Compound Dose Inhibition No. Compound (mg/kg) Rate % 1 Ethyl-7,8-dimethoxy-pyrimido[5,6-b]quinoxaline- 10 70 4(3H)-one-2-carboxylate 1 46 2 Ethyl-pyrimido[5,6-b] quinoxaline-4(3H)-one-2- 10 58 carboxylate 1 22 3 Ethyl-7,8-dimethyl-pyrimido[5,6-b]quinoxaline- 50 85 4(3H)-one-2-carboxylate 4 Ethyl-7,8-dichloro-pyrimido[5,6-b]quinoxaline- 50 58 4(3H)-one-2-carboxylate 5 Butyl-7,8-dimethoxy-pyrimido[5,6-blquinoxaline- 50 69 4(3H)-one-2-carboxylate 6 pyrimido[5,6-b]quinoxaline-4(3H)-one-2-carboxylic 50 14 acid 7 Isopropyl-7,8-dimethoxy-pyrimido[5,6-b]quinoxaline- 30 30 4(3H)-one-2-carboxylate 8 B enzyl-7,8-dimethoxy-pyrimido[5,6-b]quinoxaline- 30 45 4(3H)-one-2-carboxylate Ethyl-7-methyl-pyrimido[5,6-b]quinoxaline-4(3H)- 30 97 one-2-carboxylate 9* Ethyl-8-methyl-pyrimido[5,6-biquinoxaline-4(3H)- one-2-carboxylate Ethyl-6-methyl-pyrimido[5,6-b]quinoxaline-4(3H)- 30 62 one-2-carboxylate 10* Ethyl-9-methyl-pyrimido [5,6-blquinoxaline-4(3 H) one-2-carboxylate 11 Ethyl-7, 8-di-n-butoxy-pyrimido [5,6-b] quinoxaline- 30 68 4(3H)-one-2-carboxylate 12 Ethyl-7,8-diethyl-pyrimido[5,6-b]quinoxaline- 30 86 4(3H)-one-2-carboxylate 13 Ethyl-6,9-dimethoxy-pyrimidol5,6-b]quinoxaline- 30 23 4(3H)-one-2-carboxylate *Compounds 9 and 10 are mixtures respectively of 7-methyl and 8-methyl derivatives and 6-methyl and 9-methyl derivatives.

TABI,E I (contzd)

Compound Dose inhibition No. Compound (mg/kg) Rate "z" 14 Ethyl-7,8-methylenedioxy-pyrimido [5,6-b] - 30 91 quinoxaline-4(3H)-one-2-carboxylate 15 Ethyl-6,7,8,9-tetramethyl-pyrimido [5,6-b] 30 22 quinoxaline-4(3H)-one-2-carboxylate II. Safety of the compound of this invention The compounds 1, 2, 3, 9, 12 and 14 set forth in Table 1 are believed to have the highest effectiveness among the present compounds; the compound 1, for example, was orally administered in a dose of 3,000 mg./kg. to mice, but there were no cases of death, and no variations in the general physiological state were observed.

The degree of safety of the compounds of this invention is considered to be high, the LD 50 values being more than 3,000.

III. Examples of synthesis (1) Synthesis of ethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, the compound (I) wherein R'=R2=R3=R4=H, R=ethyl.

Process A: (a) Synthesis of ethyl N(3 - carbamoyl - quinoxaline - 2 - yl)oxamate, the compound (IV) wherein R'=R2=R3=R4=H, R=ethyl and X=CI (Step A-l).

758 mg. of triethylamine and 940 mg. of 2 - amino - quinoxaline - 3 carboxamide are added to 10 ml. of dimethyl formamide. The resulting mixture was cooled to 0 C, and 1.02 g. of ethyl oxalylchloride were added thereto. The resulting materials were agitated at OOC for 2 hours and thereafter agitated overnight at room temperature. The resulting materials were added to 75 ml. of water, and the crystals thus precipitated were separated from filtration and then dried. These crystals were then recrystalized from chloroform-n-hexane.

As a result, in one actual practical example, 800 mg. (56 percent yield) of yellow crystals of the following properties were obtained: m.p. 207 to 208"C IR 3,430 cm-' (N-H of amide) 1,735 cm-' (C=O of ester) 1,690 cm-' (C=O of amide) (b) Synthesis of ethyl pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate (Step. A-2).

720 mg. of ethyl N (3 - carbamoyl - quinoxaline - 2 - yl) oxamate were dissolved in 20 ml. of α-chloronaphthalene, and the resulting solution was heated at a temperature of 220 C to 230 C for 4 hours as the water formed was removed.

After cooling, an excess quantity of n-hexane was added, and the crystals thus precipitated were collected by filtration. These crystals were then dissolved in chloroform and treated with activated carbon. Thereafter, the solute was recrystallized from chloroform-n-hexane.

As a result, in one actual practical example, 510 mg. (76 percent yield) of yellow crystals of the following properties were obtained: m.p. 237.5 to 240"C.

IR 3,200 to 2,900 cm-' 1,705 cm-' (C=O of ester) 1,695 cm-' (C=O of 4-position) 1,295 to 1,260 cm-' (C=O of ester) M.S. m/e (%) 270 (24) M+, 198 (94), 170 (100), 143 (31) Similarly, as described above, the compounds set forth in the following Tables 2 (1) and 2 (2) were synthesized.

TABLE 2

M.S.

Compound Name Melting Point IR m/e (%) Ethyl-7,8-dimethoxy-pyrmido[5,6-b] 234~238 C 3,100~2,800 cm-1 330 (54) M+ quinoxaline-4(3H)-one-2-carboxylate 1,700 cm-1 1,500 cm-1 1,300 cm-1 1,230 cm-1 258 (100) Ethyl-7,8-dimethyl-pyrimido[5,6-b]quinoxaline- 235 C 3,200~2,800 cm-1 298 (32) M+ 4(3H)-one-2-carboxylate (decomposed) 1,700 cm-1 1,360 cm-1 226 (100) 1,300 cm-1 198 (66) Ethyl-7,8-dichloro-pyrimido[5,6-b]- 240~250 C 3,200~2,800 cm-1 340 (19) M+ quinoxaline-4(3H)-one-2-carboxylate 1,705 cm-1 1,695 cm-1 338 (27) 1,300~1,280 cm-1 268 (67) 266 (100) 240 (54) 238 (77) *Ethyl-7-methyl-pyrimido[5,6-b]quinoxaline- 3,600~3,300 cm-1 284 (41) M+ 4(3H)-one-2-carboxylate 218~230 C 3,200~2,850 cm-1 212 (100) (decomposed) 1,700 cm-1 184 (67) *Ethyl-8-methyl-pyrimido[5,6-b]quinoxaline- 1,310~1,250 cm-1 4(3H)-one-2-carboxylate **Ethyl-6-methyl-pyrimido[5,6-b]quinoxaline- 3,480 cm-1 284 (41) M+ 4(3H)-one-2-carboxylate 3,290~2,900 cm-1 212 (100) 215 ~226 C 1,700 cm-1 1,540 cm-1 184 (58) (decomposed) **Ethyl-9-methyl-pyrimido-[5,6-b]quinoxaline- 1,320~1,240 cm-1 4(3H)one-2-carboxylate Ethyl-7,8-di-n-butoxy-pyrimido[5,6-b] 212~215 C 3,620~3,300 cm-1 414 (44) M+ quinoxaline-4(3H)-one-2-carboxylate 3,000~2,800 cm-1 1,695 cm-1 287 (39) 1,500~1,420 cm-1 230 (100) 1,300 cm-1 1,200 cm-1 * A mixture of 7-methyl and 8-methyl derivatives **A mixture of 6-methyl and 9-methyl derivatives.

TABLE 2 (2)

M.S.

Compound Name Melting Point IR m/e (%) Ethyl-7,8-diethyl-pyrimidol[5,6-b]- 204~212 C 3,620~3,300 cm-1 326 (30) M+ quinoxaline-4(3H)-one-2-carboxylate 3,020~2,900 cm-1 254 (100) 1,700 cm-1, 1,460 cm-1 211 (31) 1,300 cm-1 Ethyl-6,9-dimethoxy-pyrimidol[5,6-b] 205~211 C 3,600~2,800 cm-1 330 (11) M+ quinoxaline-4(3H)-one-2-carboxylate 1,740~1,650 cm-1 243 (100) 1,640~1,560 cm-1 233 (60) 1, Process B:

188 mg. of 2 - amino - quinoxaline - 3 - carboxamide, the compound (II) wherein R'=R2=R3=R4=H, were dissolved in 5 ml. of diethyl oxalate, the compound (VI) wherein R=R =ethyl, and the resulting solution was refluxed for 24 hours as water and by-product ethanol were removed. 10 ml. of n-hexane were added to the resulting materials, and insoluble substances were removed by filtration. An excess quantity of n-hexane was added to the filtrate, and the crystals thus precipitated were collected by filtration.

These crystals were dissolved in chloroform, and n-hexane was added thereto until a small quantity of crystals began to appear. The process materials were treated with activated carbon, and then n-hexane was added thereto in excess. The crystals thus precipitating were collected by filtration.

As a result, in one example of actual practice, 85 mg. (31 percent yield) of yellow crystals were obtained. The melting point, IR, and M.S. of these crystals were respectively the same as those of the crystals obtained by process A.

(2) Synthesis of butyl - 7,8 - dimethoxy - pyrimido[5,6 - blquinoxaline - 4(3H) one - 2- carboxylate, the compound (I), wherein R'=R4=H, R2,=R3=methoxy, R=butyl Process A: (a) 496 mg. of 2 - amino - 6,7 - dimethoxy - quinoxaline - 3 - carboxamide, the compound (II), wherein R'=R4=H, R2=R3=methoxy, were dissolved in 4 ml. of dimethylformamide. To the resulting solution, as it was agitated at OOC, 410 mg. of butyl oxalylchloride, the compound (III), wherein X=CI and R=bulyl, and 330 mg. of triethylamine were gradually added. After agitation for 1 hour at OOC, the resulting materials were left standing overnight at room temperature.

The materials were then added to 30 ml. of water, and the crystals thus precipitating out were collected by filtration and recrystallized from chloroform-nhexane.

As a result, 334 mg. (44 percent yield) of crystals were obtained.

(b) The crystals thus obtained were dissolved in 20 ml. of a-chloronaphthalene, and the resulting solution was heated at 2300C to 240"C for 3 hours. After cooling, n-hexane in excess was added to the solution, and the crystals thus precipitating out were collected by filtration. These crystals were recrystallized from chloroform-nhexane.

As a result, 280 mg. (88 percent yield) of yellow crystals having the following properties were obtained: m.p. above 230"C IR 3,100 to 2,800 cm-' 1,705 cm-;, 1,495 cm-', 1,300 cm-', 1,230 cm-' M.S. m/e ( ,YO) 358 (46) M+, 275 (42), 258 (100), 230 (46) (3) Synthesis of isopropyl - 7,8 - dimethoxypyrimido[5,6-blquinoxaline - 4(3) one - 2- carboxylate, the compound (I) wherein Rl=RA=H, R2=R3=methoxy, R=isopropyl Process A: (a) 1.24 g. of 2 - amino - 6,7 - dimethoxy - quinoxaline - 3 - carboxamide, the compound (II) wherein R'=R4=H, R2=R3=methoxy, and 606 mg. of triethylamine were dissolved in 20 ml. of dimethylformamide. As the reaction liquor was maintained at OOC and agitated, 903 mg. of isopropyl oxalylchloride, the compound (III) wherein X=CI, R=isopropyl were added dropwise thereto. The resulting reaction liquor was agitated at OOC for 2 hours and then left standing overnight at room temperature. The entire liquor was added to 100 ml. of ice water, and the crystals thus precipitating out were collected by filtration and dried.

As a result, 1.52 g. (84 percent yield) of light yellow crystals were obtained.

(b) The crystals thus obtained were dissolved in 30 ml. of a-chloronaphthalene, and the resulting solution was heated at 2250C to 235"C for 3 hours. After cooling, the crystals precipitating out were collected by filtration. These crystals were recrystallized from chloroform-n-hexane.

As a result, 880 mg. (61 percent yield) of yellow crystals having the following properties were obtained: m.p. higher than 250"C (decomposes) IR 3,600 to 3,300 cm-' 1,710 cm-', 1,600 cm-' 1,490 cm-', 1,230 cm-' M.S. m/e (%) 344 (1) M+, 258 (100), 215 (21) (4) Synthesis of benzyl - 7,8 - dimethoxypyrimido[5,6 - b]quinoxaline - 4(3H) one - 2- carboxylate, the compound (I) wherein R'=R4=H, R2=R3=methoxy, R=benzyl Process A: (a) 2.48 g. of 2 - amino - 6,7 - dimethoxy - quinoxaline - 3 - carboxamide, the compound (II) wherein R'=R4=H, R2=R3=methoxy, and 1.31 g. of triethylamine were dissolved in 40 ml. of dimethylformamide. As the reaction liquor was maintained at OOC with agitation, 2.58 g. of benzyl oxalylchloride were added dropwise thereto. The reaction liquor was then agitated at OOC for 2 hours, after which it was left standing overnight at room temperature. The entire quantity of this reaction liquor was added to 200 ml. of ice water, and the crystals precipitating out were collected by filtration and dried.

As a result, 2.75 g. (68 percent yield) of yellow crystals were obtained.

(b) The crystals thus obtained were dissolved in 80 ml. of chloronaphthalene, and the resulting solution was heated at 2200C to 2300C for 4 hours. After cooling, the crystals precipitating out were collected by filtration and then recrystallized from chloroform-n-hexane.

As a result, 1.33 g. (51 percent yield) of yellow crystals having the following properties were obtained: m.p. 225 to 235"C (decomposed) I.R. 3,640 to 3,200 cm-' 1,705 cm-', 1,500 cm-', 1,235 cm-'.

M.S. m/e (%) 392 (6) M+, 348 (30) 258 (100), 91(62) (5) Synthesis of pyrimido[5,6-b] quinoxaline-4(3H)-one-2-carboxylic acid, the compound (I) wherein R1=R2=R3=R4=H

To 405 mg. of ethyl-pyrimido[5,6 - b]quinoxaline - 4(3H) - one 2 carboxylate, the compound (I) wherein R=R=R =R4=H, R=ethyl, 18 ml. of a 15- percent aqueous solution of NaOH were added, and the reaction liquor was agitated overnight at room temperature. The crystals which precipitated out were collected by filtration and dissolved in 20 ml. of water. After removal of insoluble matter by filtration, the filtrate was adjusted to pH2 with 10-percent HCl, and the solution, was concentrated to approximately 10 ml. The crystals precipitating out were collected by filtration.

As a result, 320 mg. (88 percent yield) of yellow crystals having the following properties were obtained. m.p. higher than 250 C IR 3,380 cm-1, 1700 cm-1 M.S. m/e (%) 198 (100) M±44, 70 (42), 145 (37), 143 (70), 118 (36).

Claims (26)

WHAT WE CLAIM IS:

1. A substituted pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 - carboxylic acid compound represented by the formula:

wherein: R designates hydrogen, an alkyl group having I to 4 carbon atoms, a benzyl group, or a phenyl group; and each of R', R2, R3, and R4 independently designates hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen, a benzyloxy group, a hydroxy group, an alkylthio group having I to 4 carbon atoms, or an alkylenedioxy group having 1 to 4 carbon atoms and formed by the bonding of two of R', R2, R3 and R4, or a pharmacologically acceptable salt of said compound.

2. Ethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 - carboxylate.

3. Ethyl - 7,8 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate.

4. Ethyl - 7,8 - dimethylpyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate.

5. Ethyl - 7,8 - dichloro - pyrimido{5,6 - b]quinoxaline - 4(311) - one - 2 carboxylate.

6. Ethyl - 7 - methyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate.

7. Ethyl- 8 - methyl - pyrimido[5,6 - b]quinoxaline -3(4H)- one - 2 - carboxylate.

8. Ethyl- 6 - methyl - pyrimido[5,6 - b]quinoxaline -3(4H)- one - 2 - carboxylate.

9. Ethyl - 9 - methyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate.

10. Ethyl - 7,8 - di - n - butoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) one - 2 - carboxylate.

11. Ethyl - 7,8 - diethyl - pyrimido[5,6 - b]quinoxaline - 4(311) - one - 2 carboxylate.

12. Ethyl - 6,9 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(311) - one 2 - carboxylate.

13. Ethyl - 7,8 - methylenedioxy - pyrimido[5,6 - b]quinoxaline - 4(311) - one - 2 - carboxylate.

14. Butyl - 7,8 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one 2 - carboxylate.

15. Isopropyl - 7,8 - dimethoxy - pyrimido[5,6 -b]quinoxaline - 4(3H) one - 2 - carboxylate.

16. Benzyl - 7,8 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one 2 - carboxylate.

17. Pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 - carboxylic acid.

18. Ethyl - 6,7,8,9 - tetramethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) one - 2 - carboxylate.

19. A process for producing substituted pyrimido - [5,6 - b]quinoxaline - 4 (3H)- one - 2- carboxylic acid compound as claimed in Claim 1, or pharmacologically acceptable salts of said compounds, said process comprising: reacting a 2 - amino - quinoxaline - 3 - carboxamide compound represented by the formula:

with an oxalic compound represented by the general formula:

thereby to form an N - (3 - carbamoylquinoxaline - 2 - yl) - oxamic compound represented by the formula:

where: X designates a halogen in the general formula (III), R', R2, R3, and R4 in the general formulae (II), (III), and (IV) being respectively the same as in the general formula (I): causing the compound thus formed to undergo intramolecular ring closure by heating; and where needed, transforming the product thus formed into a pharmacologically acceptable salt thereof.

20. A process for producing substituted pyrimido - [5,6 - b]quinoxaline 4(3H)- one - 2- carboxylic acid compounds as claimed in Claim 1, or pharmacologically acceptable salts of said compounds, said process comprising: reacting a 2 - amino - quinoxaline - 3 - carboxamide compound represented by the formula

under heating with an oxalic compound represented by the general formula:

where: R designates an alkyl group having 1 to 4 carbon atoms, a benzyl group, or a phenyl group in the general formula (III); R, R, R, R and R4 in the general formulae (Il) and (III) being respectively the same as in the general formula (I): and where needed, transforming the product thus formed into a pharmacologically acceptable salt thereof.

21. A medicine for allergic asthma comprising a substituted pyrimido[5,6 b]quinoxaline - 4(3H) - one - 2 - carboxylic acid compound of the formula:

wherein: R designates hydrogen, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a phenyl group; and each of R, R, R , and R4 independently designates hydrogen, and alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen, a benzyloxy group, a hydroxyl group, an alkylthio group having 1 to 4 carbon atoms, or an alkylenedioxy group having 1 to 4 carbon atoms and formed by the bonding of two of R, R, R , and R4, or a pharmacologically acceptable salt of said compound, together with a non-toxic pharmaceutically acceptable carrier or diluent therefor.

22. A medicine as claimed in Claim 21, in which said substituted pyrimido[5,6 - b]quinoxaline - 4(3H)- one - 2- carboxylic acid compound consists of: ethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 - carboxylate, ethyl - 7,8 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 7,8 - dimethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 7,8 - dichloro - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 7 - methyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 8 - methyl - pyrimido[5,6 - b]quinoxaline - 4 - (3H) - one - 2 carboxylate, ethyl - 6 - methyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 9 - methyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 7,8 - di - n - butoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one 2 - carboxylate, ethyl - 7,8 - diethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, ethyl - 6,9 - dimethoxy - pyrimido[5,6-b]quinoxaline - 4(3 H) - one - 2 - carboxylate, ethyl - 7,8 - methylenedioxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, butyl - 7,8 - dimethoxy - pyrimido[5,6 - blquinoxaline - 4(311) - one - 2 carboxylate, isopropyl - 7,8 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one 2 - carboxylate, benzyl - 7,8 - dimethoxy - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate, pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 - carboxylic acid, or ethyl 6,7,8,9 - tetramethyl - pyrimido[5,6 - b]quinoxaline - 4(3H) - one - 2 carboxylate.

23. A compound or salt as claimed in Claim 1 substantially as herein described with reference to any of the specific examples.

24. A process according to Claim 19 or 20, substantially as herein described with reference to any of the specific examples.

25. A compound (I) or salt thereof as defined in Claim 1 when made by a process as claimed in any of Claims 19, 20 and 24.

26. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 18, 23 and 25 together with a non-toxic, pharmaceutically acceptable carrier or diluent therefor.