KR810001132B1 - Process for preparing pyrimid quinoxaline derivatives - Google Patents

Abstract

Title compds. (I; R = H, C1-4 alkyl, benzyl, phenyl; R1-4 = C1-4 alkyl, alkoxy, halo, benzyloxy, OH, alkylthio, alkylenedioxy), useful as treating medicines of appergic asthma, were prepd. by reacting 2-amino-quinoxaline-3-carboxyamides (II) with acids (III; X = halo, OR) to give N-(3-carbamoyl-quinoxalin-2-yl)oxamic acids(IV), which were intra-cyclized to give substituted pyrimid[5,6-b quinoxalin-4(3H)-one-2-carboxylic acid.

Description

Preparation of pyrimid quinoxaline derivatives

The present invention relates to pyrimid quinoxaline, a method for producing the same, and an allergic asthma medicine comprising the compound.

Recently developed sodium chromoglycol has been reported by Cox to be effective for allergic bronchial asthma (Adv. In Drug Res. 5 115 (1970)).

This compound is thought to have its effect by inhibiting release to chemicals and mediators from mast cells resulting from antigen antibodies caused by leagin antibodies. However, this compound is currently used as a powder inhalant if there is a drawback that it is not absorbed by oral administration.

It goes without saying that allergic asthma medications that can be administered orally are useful.

According to the study of the present inventors, some kinds of novel pyrimid quinoxaline derivatives have anti-allergic effects such as sodium chromoglycol in animal experiments, and also show strong effect by oral administration with intravenous injection. This suggests that this compound is useful as an allergic asthma prophylactic agent.

Accordingly, it is an object of the present invention to provide an allergic asthma drug that can be administered orally.

Another object of the present invention is to provide a novel pyridid quinoxaline derivative.

Another object of the present invention is to provide a method for preparing the pyrimid quinoxaline derivative.

The present invention provides and uses a substituted pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylic acid compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof. To achieve their purpose.

1. Pyrimid Quinoxaline Derivatives

The pyrimidquinoxaline compound provided by the present invention is a substituted pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylic acid represented by the following general formula (1), an ester thereof or a pharmaceutical thereof Phase is an acceptable salt.

(Wherein R represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a phenyl group. R ¹ , R ² , R ³ and R ⁴ each represent hydrogen, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms). , A halogen, benzyloxy group, hydroxy, an alkylthio group having 1 to 4 carbon atoms, or an alkylene dioxy group having 1 to 4 carbon atoms by a combination thereof.

In the present invention, the above-mentioned specific ones are considered as the substitution R ¹ , R ² , R ³ and R ⁴ . Anything other than the above may be synthesized and will have a significant effect.

As R <^1> -R <^4> , what was shown next besides H is considered, respectively.

Methyl, ethyl, butyl, methoxy, isopropoxy, butoxy, chlor, brorom, benzyloxy, hydroxy, methylthio, butylthio, and the like.

The specific example of compound (1) is as follows.

Here, [A] represents the said substituent and some [A] may be same or different.

(1) Non-substituted (d) 9-positioned

R ¹ = R ² = R ³ = R ⁴ = HR ¹ = R ² = R ³ = H

(2) monosubstituted R ⁴ = [A]

(A) 6-position ring (3) Disubstitute

R ² = R ³ = R ⁴ = H (A) 6,9-position ring

R ¹ = [A] R ² = R ³ = H

(B) 7-position ring R ¹ = [A]

R ¹ = R ³ = R ⁴ = HR ⁴ = [A]

R ² = [A] (b) 7,8- position ring

(C) 8-position ring R ¹ = R ⁴ = H

R ¹ = R ² = R ₄ = HR ² = [A]

R ³ = [A] R ³ = [A]

When the substituents are adjacent, such as the 7,8-position ring, R ² and R ³ are bonded to each other to form (R ² -R ³ ) methylenedioxy, ethylenedioxy, and the like as shown next.

(C) 6,7-position

R ³ = R ⁴ = H

R ¹ = [A]

R ² = [A] or as shown below

R ¹ -R ² = methylenedioxy or ethylene dioxy

(D) 6,8-substituted ring R ⁴ = [A]

R ² = R ⁴ = H (bar) 8,9-position ring

R ¹ = [A] R ¹ = R ² = H

R ³ = [A] R ³ = [A]

(E) 7,9-substituted R ⁴ = [A] or

R ¹ = R ³ = HR ³ -R ⁴ = methylenedioxy or ethylene dioxy

R ² = [A]

(4) trisubstitute

(5) tetra substituent

Among these derivatives, 7-, 8- and 7, 8-position substitutions are often easy to obtain raw materials and synthesis.

Specific examples of such a compound include the following ones.

R ¹ to R ⁴ = H (unsubstituted)

6,9-dimethyl, 6,9-dimethoxy, 6,9-dichlor, 6-methyl, 9-methyl, 6,9-dibutyl, 6-butyl, 9-butyl, 6,9-diisobutyl , 6, -methoxy, 9-methoxy, 6,9-dibutoxy, 6-butoxy, 9-butoxy, 6,9-diisopropoxy, 6-chlor, 9-chlor, 6,9- Diburom, 6-benzyloxy-9-methoxy, 6,9-dibenzyloxy, 6-hydroxy-9-methoxy, 6,9-hydroxy, 6,9-dimethylthio, 6-methylthio, 6,9-dibutylthio, 6-isopropylthio, 6, -butylthio, 7,8-dimethyl, 7,8-dimethoxy, 7,8-dichlor, 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-chlor, 8-chlor, 7,8-dibrom, 7-benzyloxy-8-methoxy, 7,8-dibenzyloxy, 7-hydroxy-8-methoxy, 7,8-hydroxy, 7,8-dimethylthio, 7-methylthio, 7,8-dibutylthio, 7-isopropylthio, 7-butylthio, 7,8-methylenedioxy, 7,8- Diethylenedioxy, 6,7-dimethyl, 6,7-dimethoxy, 6,7-dichlor, 6,7 -Dibutyl, 6,7-diisopropyl, 6,7-dibutoxy, 6,7-diisopropoxy, 6,7-dibrom, 6-benzyloxy-7-methoxy, 6,7-di Benzyloxy, 6-hydroxy-7-methoxy, 6,7-hydroxy, 6,7-dimethylthio, 6,7-dibutylthio, 6,7-methylenedioxy, 6,7-ethylenedioxy , 6,8-dimethyl, 6,8-dimethoxy, 6,8-dichlor, 6,8-dibutyl, 6,8-diisopropyl, 6,8-dibutoxy, 6,8-diisopro Foxy, 6,8-Dibrom, 6-zenyloxy-8-methoxy, 6,8-dibenzyloxy, 6-hydroxy-8-methoxy, 6,8-hydroxy, 6,8-dimethylthio , 6,8-dibutylthio, 7,9-dimethyl, 7,9-dimethoxy, 7,9-dichlor, 7,9-dibutyl, 7,9-diisopropyl, 7,9-dibutoxy , 7,9-diisopropoxy, 7,9-dibrom, 7-benzyloxy-9-methoxy, 7,9-dibenzyloxy, 7-hydroxy-9-methoxy, 7,9-hydrate Roxy, 7,9-dimethylthio, 7,9-dibutylthio, 8,9-dimethyl, 8,9-dimethoxy, 8,9-dichlor, 8,9-dibutyl, 8,9-diiso Propyl, 8,9-dibutoxy, 8,9-diisopropoxy, 8,9-dibrom, 8-benzyloxy-9-methoxy, 8,9-dibenzyl C, 8-hydroxy-9-methoxy, 8,9-hydroxy, 8,9-dimethylthio, 8-methylthio, 8,9-dibutylthio, 9-isopropylthio, 9-butylthio, 8,9-methylenedioxy, 8,9-ethylenedioxy, 6,7,8-trimethyl, 6,7,8-trimethoxy, 6,7,8-trichlor, 6,7,8-tree Butyl, 6,7,8-tributoxy, 7,8,9-trimethyl, 7,8,9-trimethoxy, 7,8,9-trichlor, 7,8,9-tributyl, 7, 8,9-tributoxy, 6,7,9-trimethyl, 6,7,9-trimethoxy, 6,7,9-trichlor, 6,7,9-tributyl, 6,7,9- -Tributoxy, 6,8,9-trimethyl, 6,8,9-trimethoxy, 6,8,9-trichlor, 6,8,9-tributyl, 6,8,9-tributoxy , 6,6,8,9-tetrimethyl, 6,7,8,9-tetrimethoxy, 6,7,8,9-tetrichlor, 6,7,8,9-tetributyl, 6 , 7,8,9-tetributoxy.

In these cases, R may be any of the above, but specifically for example H (ie free acid).

Specific examples of R when this substituted pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylic acid compound is ester are methyl, ethyl, n-propyl, iso-propyl, n -Butyl, t-butyl, benzyl, phenyl others.

Also included in the present invention is the case where the carboxylic acid compound of R = H is a pharmaceutically acceptable salt. The cation component constituting the salt may be a metal and an amine cation (containing ammonium). Specifically, for example, Na, K, Mg, Ca, Al, Cu, other ammonia, tris (hydroxy methyl) amino methane, N, N-bis (hydroxyethyl) piperdine, 2-amino- 2-methyl-1- furopanool, ethanolamines, etc. are mentioned.

This substituted pyrimid [5,6-b] quinoxalin-4 (3H) -one-2-carboxylic acid compound has basic nitrogen in the 5- and 10-positions, so that a salt can be formed together with the acid. Salts in this case are included in the present invention so long as they are pharmaceutically acceptable. Examples of the acid in this case include hydrogen chloride, sulfuric acid, hydrogen sulfide, methanesulfonic acid, and the like.

2. Synthesis of Compound

The compound of the formula (1) can be synthesized by any method for combination purposes, but one preferred method is to go through the following steps.

(1) synthesis method

(R and R ¹ to R ⁴ have the same meanings as above. X represents halogen or OR.)

In this synthesis method, compound (IV) is obtained as a semi-intermediate, and it is heated and closed. However, if desired, the compound (1) can be obtained by reacting as a closed ring condition from the beginning. However, it is advantageous to first synthesize intermediate compound (IV) under relatively mild conditions, to isolate it if necessary, and then to carry out the ring closure step. It is because isolation | purification of the following compound 1 becomes very easy.

(A) Process A-1

In this synthesis method A, the 2-amino-quinoxaline-3-carboxyamide compound of the general formula (II) which is a starting material is used in the presence of a solvent, preferably in the presence of a base, the monohydric acid hydroxide compound of the general formula (III), Preferably, N- (3-carbamoyl-quinoxalin-2-yl) oxamic acid compound of the general formula (IV) is synthesized by reacting with a mono ester monofluoride.

The preferable reaction conditions of step A-1 are as follows.

Appropriate Reaction Condition of Step A-1

Temperature: -40 to 100 ° C, preferably -20 to 50 ° C

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

Base: ammonia, triethylamine, piperidine, morpholine, pyridine, and the like _{amines, NaHCO 3, Na 2 CO 3} , K 2 CO 3, an alkyl group, such as NaOH, KOH, NaH.

Solvent: tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, chloroform, methylene chloride, dimethylformamide, dimethylacetamide, dimethylsulfoxide, benzene, toluene, high boiling point solvent that can be used in later process A-2, etc. That is, α-chlornaphthalene, diphenyl ether, "Dau'ssam" (catalyst made by Dow Chemical), mineral oil, diethyl oxalate and di-n-butyl oxalate.

The amount used is 1 to 100 times of compound (II), preferably 10 to 50 times (weight).

Compound (II) is used in a molar ratio of 0.5 to 5, preferably 1 to 2 equivalents relative to compound (II).

The base is used in a molar ratio of 0.5 to 5, preferably 1 to 2 equivalents relative to compound (II).

After completion of the reaction, Compound (IV) is added with excess water and filtered when the crystal precipitates. If the crystal does not precipitate, the compound (IV) is a common solvent which is not mixed with water such as chloroform and ethyl acetate. The material can be isolated by extraction and concentration.

(B) Process A-2

Thus obtained compound (IV) is heated in a high boiling point solvent to dehydrate and close the ring, whereby pyrimid [5,6-b] quinoxaline-4 (3H) -one-2 carboxylic acid compound of the general formula (1) is preferred. Haero esters are obtained.

The preferable reaction conditions of step A-2 are as follows.

Appropriate Reaction Conditions for Process A-2

Temperature: 50 to 400 ° C, preferably 150 to 300 ° C

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

Solvent: α-chlornaphthalene, dimenyl ether, "Dauxam" (catalyst made by Dow Chemical), mineral oil, diethyl oxalate, di-n-butyl oxalate and the like. 1 to 100 times of compound (IV), preferably 10 to 50 (weight)

The desired compound (1) can be obtained by converting the R group of the produced compound (1) or by converting it into a pharmaceutically acceptable salt.

(C) Process A-0

Compound (II) can be made by any suitable method. Specifically J. che m SOC 1945 622, or J.am. chem SOC. 66 1957 (1941).

And, except for a small number of di- and tetra-substituted compounds, when compound (II) is synthesized by the method described in the literature, two kinds of compounds of isomers are obtained. In that case, if separation of the isomeric mixture is difficult, the mixture may be used as a raw material. (In this case, a mixture of two kinds of isomers of compound (1) is produced.)

Substituents which can obtain compound (II) as a single substance are as follows.

(1) 6,7-disubstituted

R ¹ = R ⁴ = H, R ² = R ³ = [A]

(2) 5,8-disubstituted bodies

R ² = R ³ = H, R ¹ = R ⁴ = [A]

(3) 5,6,7,8-tetrasubstituted

R ¹ = R ² = R ³ = R ⁴ = [A]

Specific examples of compound (II) correspond to those exemplified for compound (1). However, the positions of the groups R ¹ to R ⁴ are not in the 6--9-position (compound (1)) but in the 5--8-position (compound (II)).

(2) Synthesis Method B

One other preferred method of synthesizing Compound (1) is through the following process.

In the synthesis method B, when the 2-aminoquinoxaline-3-carboxyamide compound represented by the general formula (II) is heated and reacted with the hydroxyl compound of the general formula (IV), preferably the diester hydroxide, the compound (1) ) Is obtained in the form of an ester.

As in the case of the synthesis method A, the intermediate for converting waste may be synthesized once, and then it may be heated and closed. This reaction is carried out in a solvent-free (raw compound (VI) can be said to act as a solvent) or a high boiling point solvent.

Appropriate reaction conditions of step B-1 are as follows.

Appropriate Reaction Conditions for Process B-

Temperature: 50 to 400 ° C, preferably 150 to 300 ° C

Time: 30 minutes to 3 days, preferably 5 hours to 1 day

-클로르나프탈렌, 디페닐에에테르「다우삼」,광유, 디에틸옥살레이트, 디-n-부틸옥살레이트, 기타 화합물(Ⅱ)의 1∼100배, 바람직하게는 5∼20배(중량)Solvent:

-Chlornaphthalene, diphenyl ether "Dauxam", mineral oil, diethyl oxalate, di-n-butyl oxalate, 1 to 100 times, preferably 5 to 20 times (weight) of other compound (II).

Compound (IV) is used in an amount of 1 to 100, preferably 2 to 50 equivalents, relative to compound (II).

After completion of the reaction, Compound (1) is isolated by adding a solvent having a small solvent, such as n-hexane and petroleum benzene, to the reaction solution to precipitate.

(3) Conversion of Compound (1)

In the synthesis methods A and B described above, the hydroxyl compounds (III) and (VI) are preferably esters (R ≒ H), and in that case, the resulting compound (1) is also obtained as an ester.

In view of other effects, when compound (1) of a type other than ester is required, the ester compound (1) may be converted into another type according to the conventional method.

Preferable reaction conditions in the case of conversion to free carboxylic acid by hydrolysis are as follows. Alkali metal salts are produced when alkali is used as the hydrolyzing agent, and thus, neutralized with acid to obtain free carboxylic acid, but needless to say that the alkali metal salt can be recovered as a target.

Proper Hydrolysis Conditions

Alkali: NaOH, KOH, K ₂ CO ₃ , Na ₂ CO ₃ , NaH, etc.

Acid: hydrochloric acid, sulfuric acid, hydrochloric acid, P-toluenesulfonic acid, acetic acid, etc.

Temperature: 0 to 200 ° C, preferably 20 to 100 ° C

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

Solvent: water, water-dioxane, water-alcohol, benzene, toluene

1 to 100 times with respect to compound (1), preferably 2 to 50 times (weight)

3. Allergic Asthma Drugs

Compound (1) and its salts may be used for various uses, but one use is for allergic asthma drugs.

As an allergic asthma medicine, inhalation is administered 1 to 20 mg once a day in the bronchus three to four times a day, intravenous injection 1 to 10 mg once a day 4 to 5 injections per day, oral administration In the case of rectal administration, 1 to 50 mg three times a day, 1 to 50 mg may be administered two to three times a day.

The pharmaceutical form is arbitrary, and it is common to use 1 type, or 2 or more types of the compound (1) and its salt in the form of a composition containing a usual pharmaceutical carrier, excipient, or other additives or suppositories.

4. Experimental Example

Evaluation of the antiallergic effect of the compound of the present invention was performed by passive skin hypersensitivity test (PCA) in rats.

Five times recrystallized egg white albumin and Bodet alla pertussis vaccine were intracutaneously administered to rats (SLC-based wister rats), and serum was collected 13 days later. The obtained serum contains an antibody having similar properties to human leagin and exhibits an antibody value of 256 or more. After diluting this type of serum by 128-fold and intradermal administration to rat's back, 48 hours later, the compound of the present invention was suspended in 1% traganto solution in the amount shown in Table-1, and orally administered, followed by egg whitening after 20 minutes. Intravenously administer a physiological saline solution containing albumin and pigment (Evans Blue) 30 minutes later, exfoliate the abdominal skin, and extract the amount of pigment leaked as a result of the antigen antibody reaction with Na ₂ SO ₄ and acetone. Thus, colorimetric determination was made with light having a wavelength of 620 µm. The results are shown in Table-1.

TABLE 1

Compounds 9 and 10 are mixtures of 7-methyl and 8-methyl derivatives and 6-methyl and 9-methyl derivatives, respectively.

(2) Safety of the compound of the present invention

Of these compounds, in particular the compounds of 1,2,3,9,12 and 14 are potent, for example ethyl-7,8-dimethoxy-pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylate was orally administered to 3000 mg / kg rats, but there was no death and no change in general symptoms.

It is considered that the safety of the compound of the present invention is high.

LD 50 (50% lethal dose) was 3000 mg / kg or more.

(3) Synthesis Example

(1) ethyl-pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylate (compound I, R ¹ = R ² = R ³ = R ⁴ = H, R = ethyl) Synthesis of

[A law]

(a) N- (3-carbamoyl-quinoxalin-2-yl) ethyl oxamate (Compound IV)) (R ¹ = R ² = R ³ = R ⁴ = H, R = ethyl, X = (l ) Synthesis (Step A-1)

758 mg of triethylamine and 940 mg of 2-aminoquinoxaline-3-carboxyamide were added to 10 ml of dimethylformamide, cooled to 0 ° C., 1.02 g of ethyl oxylyl chloride was added, stirred at 0 ° C. for 2 hours, and then at room temperature overnight. Stir.

It is poured into 75 ml of water, and the precipitated crystals are filtered off and dried. Recrystallization from chloroform-nucleic acid gave 800 mg of yellow crystals (yield 56%).

m.p (melting point) 207 ~ 208 ℃

IR (Infrared Spectra)

3430 cm- ¹ (NH of amide), 1735 cm- ¹ (C = O of ester), 1690 cm- ¹ (C = O of amide)

(b) Synthesis of ethylpyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylate (Step A-2)

-클로로 나프탈렌 20ml에 녹여, 생성한 물을 제거하면서 220

∼230℃로 4시간 가열한다. 냉각 후, 대과잉의 n-헥산을 가하고, 석출한 결정을 여취한다. 클로로포름에 녹여서 활성탄 처리한 후, 클로로포름-n-헥산으로 재결정시킨다.720 mg of N (3-carbamoyl-quinoxalin-2-yl) oxamate

Dissolve in 20 ml of chloronaphthalene and remove the water produced.

It heats at -230 degreeC for 4 hours. After cooling, a large excess of n-hexane is added to precipitate the precipitated crystals. It is dissolved in chloroform and treated with activated carbon, and then recrystallized with chloroform-n-hexane.

510 mg of yellow crystals (yield 76%) were obtained.

m.p. 237.5 to 240 ° C

IR 3,200-2,900 cm ^-1 , 1,705 cm ^-1 (C = O of ester), 1,695 cm ^-1 (C = O of 4th position), 1,295-1,260 cm ^-1 (C = O of ester)

MS (mass spectra) m / e (%) 270 (24) ⁺ , 198 (64), 170 (100), 143 (31)

As described above, the following compounds were synthesized.

TABLE 2a

TABLE 2b

B law

188 mg of 2-amino-quinoxaline-3-galoxyamide (Compound (II), R ¹ = R ² = R ³ = R ⁴ = H) was added to 5 ml of diethyl oxalate (Compound (VI), R = R). ⁰ = ethyl) and refluxed for 24 hours while removing water and byproduct ethanol. 10 ml of n-hexane is added, an insoluble matter is allowed to rest, and a large amount of n-hexane is added to the filtrate to precipitate the precipitated crystals.

The crystals are dissolved in chloroform, n-hexane is added until a small amount of crystals begin to appear, activated carbon treatment is carried out, and excess n-hexane is added to the filtrate to precipitate precipitated crystals.

85 mg of yellow crystals (yield 31%) were obtained.

The melting point, 1R, M.S, is consistent with the decision obtained by method A

(2) Butyl-7,8-dimethoxy-pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxylate (Compound (I), R ¹ = R ⁴ = H, R ² = R ³ = methoxy, R = butyl)

[A law]

(a) 496 mg of 2-amino-6,7-dimethoxy-quinoxaline-3-carboxamide (compound (II), R ¹ = R ⁴ = H, R ₂ = R ³ = methoxy) It is dissolved in 4 ml, 410 mg of butyloxaric chloride (compound (III), X = Cl, R = butyl) and 330 mg of triethylamine are added at 0 ° C with gentle stirring, and stirred at 0 ° C for 1 hour, and then left at room temperature overnight. .

The mixture is poured into 30 ml of water, and the precipitated crystals are filtered off and recrystallized with chloroform-n-hexane.

334 ml (44% yield) of crystals are obtained.

-클로로나프탈렌 20ml에 녹여, 230°∼240℃에서 3시간 가열한다. 냉각 후, 대과잉의 n-헥산을 가하여 석출한 결정을 여취한다.(b) of the obtained crystal

It is dissolved in 20 ml of chloronaphthalene and heated at 230 ° to 240 ° C. for 3 hours. After cooling, a large amount of n-hexane is added to precipitate the precipitated crystals.

Recrystallize with chloroform-n-hexane.

280 mg (88% yield) of yellow crystals are obtained.

m, p. 230 ℃ or higher

^{3100~2800cm -1, 1705cm -1, 1495cm -1} , 1300cm -1, 1230cm -1

MS m / e (%) 358 (46) M ⁺ , 275 (42), 258 (100), 230 (46)

(3) Isopropyl-7,8-dimethoxy-pyridine [5,6-b] quinoxaline-4 (3H) -one-2-carboxylate (compound) (1), R ¹ = R ⁴ = H , R ² = R ³ = methoxy, R = isopropyl)

[A law]

(a) 2-amino-6,7-dimethoxy-quinoxaline-3-carboxyamide (Compound (II), R ¹ = R ⁴ = H, R ² = R ³ = methoxy) 1.24 g and triethylamine 606 mg was dissolved in 20 ml of dimethyl formamide, the reaction solution was kept at 0 ° C, and 903 mg of isopropyl oxarylyl chloride (Compound (III), X = Cl, R = isopropyl) was added dropwise with stirring, and the mixture was stirred at 0 ° C for 2 hours. After stirring, it is left at room temperature overnight. The whole is poured into 100 ml of ice-water, and the precipitated crystal | crystallization is filtered and dried.

1.52 g (84% yield) of pale yellow crystals were obtained.

클로트나프탈렌 30ml에 녹여, 225∼235℃에서 3시간 가열한다.(b) the decision obtained;

It is dissolved in 30 ml of chlornaphthalene and heated at 225 to 235 ° C for 3 hours.

After cooling, the precipitated crystals are filtered out. Recrystallization with chloroform-n-hexane gave 880 mg (yield 61%) of yellow crystals.

m.p. 250 ℃ or higher (decomposition)

^{IR 3600~3300cm -1, 1710cm -1, 1600cm} -1, 1490cm -1, 1230cm -1

MS m / e (%) 344 (1) M ⁺ , 258 (100) 215 (21)

(4) benzyl-7,8-dimethoxy-pyrimid [5,6-b] quinoxaline-4 (3H) -one-2-carboxytate (compound (1), R ¹ = R ⁴ = H, R ² = R ³ = methoxy, R = benzyl)

[A law]

(a) 2-amino-6,7-dimethoxy-quinoxaline-3-carboxyamide (Compound (II), R ¹ = R ⁴ = H, R ² = R ³ = methoxy) 2.48 g and triethylamine 1.31 g is dissolved in 40 ml of dimethylformamide, the reaction solution is maintained at 0 ° C., 2.58 g of benzyl oxarylyl chloride is added dropwise while stirring, stirred at 0 ° C. for 2 hours, and left at room temperature overnight.

The whole is poured into 200 ml of ice water, and the precipitated crystal | crystallization is filtered and dried.

2.75 g (yield 68%) of yellow crystals are obtained.

(b) The obtained crystals are dissolved in 80 ml of α-chloronaphthalene and heated at 220 ° to 230 ° C. for 4 hours. After cooling, the precipitated crystals are filtered out. Recrystallization with chloroform-n hexane gave 1.33 g (51% yield) of yellow crystals.

m.p 225 to 235 ° C (decomposition)

^{IR 3640~3200cm -1, 1705cm -1, 1500cm} -1, 1235cm -1

MS m / e (%) 392 (6) M ⁺ , 348 (30), 258 (100), 91 (62)

(5) of pyrimid [5,6-b] quinoxaline-4- (3H) -one-2-carboxylic acid (compound (1), R ¹ = R ² = R ³ = R ⁴ = R = H) synthesis

405 mg of ethyl-pyrimid [(5,6-b] quinoxaline-4 (3H) -one-2carboxylate (Compound (1), R ¹ = R ² = R ³ = R ⁴ = H, R = ethyl) To this was added 18 ml of 15% NaOH water and stirred at room temperature overnight.

Precipitate the crystals and dissolve in 20 ml of water. After insoluble filtration, the filtrate is brought to pH 2 as 10% HCl and the solution is concentrated to about 10 ml.

Ingest the precipitated decision.

320 mg of yellow crystals (yield 88%) are obtained.

m.p. 250 ℃ or higher

IR 3380cm ^-1 , 1700cm ^-1

MS m / e (%) 198 (100) M ⁺ -44,170 (42), 145 (37), 143 (70), 118 (36)

Claims (1)

N- (3- represented by the following general formula (IV) by reacting a 2-amino-quinoxaline-3-carboxyamide compound represented by the following general formula (II) with a hydroxyl compound represented by the following general formula (III) Carbamoyl-quinoxalin-2-yl) oxamic acid compound, which is produced by intramolecular cyclization, is substituted pyrimid [5,6-b] quinox represented by the following general formula (1): Preparation of a saline-4 (3H) -one-2-carboxylic acid compound or a pharmacologically acceptable salt thereof

Where R represents hydrogen, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a phenyl group. R ¹ , R ² , R ³ and R ⁴ each represent hydrogen, an alkyl group having 1 to 4 carbon atoms, or an alkoxy having 1 to 4 carbon atoms. A group, a halogen, a benzyloxy group, a hydroxyl group, a C1-C1-4 alkylthio group, or a C1-C4 alkylene thioxy group by a combination of both is shown. X represents halogen or OR.)